Acute and Chronic inflammationAcute and Chronic inflammation

Fatima Obeidat, MDFatima Obeidat, MD

InflammationInflammation- Is a protective response involving host cells, blood vessels, and - Is a protective response involving host cells, blood vessels, and

proteins that is intended to eliminate the initial cause of cell injury, proteins that is intended to eliminate the initial cause of cell injury, as well as the necrotic cells resulting from the original insult, and to as well as the necrotic cells resulting from the original insult, and to initiate the process of repairinitiate the process of repair..

- It accomplishes its protective mission by first diluting, destroying, - It accomplishes its protective mission by first diluting, destroying, or otherwise neutralizing harmful agents (e.g., microbes, toxins).or otherwise neutralizing harmful agents (e.g., microbes, toxins).

- It then sets into motion the events that eventually heal and repair - It then sets into motion the events that eventually heal and repair the sites of injurythe sites of injury

- Although it helps clear noxious stimuli and initiates repair the - Although it helps clear noxious stimuli and initiates repair the inflammatory reaction and the subsequent repair process can inflammatory reaction and the subsequent repair process can themselves cause considerable harm themselves cause considerable harm

- Therefore, injury may accompany entirely normal, beneficial- Therefore, injury may accompany entirely normal, beneficial

IInflammatory reactions, and the damage may even become thenflammatory reactions, and the damage may even become the dominant feature :dominant feature :a. If the reaction is very strong (e.g., when the infection is severe) a. If the reaction is very strong (e.g., when the infection is severe) b. If it is prolonged ( when the eliciting agent resists eradication),b. If it is prolonged ( when the eliciting agent resists eradication),c. Or if the reaction is inappropriate (e.g., when it is directed against c. Or if the reaction is inappropriate (e.g., when it is directed against

self-antigens in autoimmune diseases, or against usually harmless self-antigens in autoimmune diseases, or against usually harmless environmental antigens (e.g., in allergic disordersenvironmental antigens (e.g., in allergic disorders

- Some of the diseases of humans are disorders that result from - Some of the diseases of humans are disorders that result from inappropriate, often chronic, inflammation. Thus, the process of inappropriate, often chronic, inflammation. Thus, the process of inflammation is fundamental to virtually all of clinical medicine. inflammation is fundamental to virtually all of clinical medicine.

- The cells and molecules of host defense, including leukocytes and - The cells and molecules of host defense, including leukocytes and proteins, normally circulate in the blood, and the goal of the proteins, normally circulate in the blood, and the goal of the inflammatory reaction is to bring them to the site of infection or inflammatory reaction is to bring them to the site of infection or tissue damagetissue damage

- Inflammation can be acute or chronic- Inflammation can be acute or chronic

Acute inflammation Acute inflammation - Is rapid in onset and of short duration, lasting from a few minutes - Is rapid in onset and of short duration, lasting from a few minutes

to as long as a few days, to as long as a few days, - Characterized by fluid and plasma protein exudation and a - Characterized by fluid and plasma protein exudation and a predominantly neutrophilic leukocyte accumulationpredominantly neutrophilic leukocyte accumulationChronic inflammation Chronic inflammation

a. Isa. Is more insidious and of longer duration (days to years), more insidious and of longer duration (days to years),b. Typified by influx of lymphocytes and macrophages with b. Typified by influx of lymphocytes and macrophages with

associated vascular proliferation and fibrosis (scarring)associated vascular proliferation and fibrosis (scarring) Note:Note:

- These two basic forms of inflammation may coexist, and many- These two basic forms of inflammation may coexist, and many variables modify their course and histologic appearancevariables modify their course and histologic appearance

The external manifestations of inflammation, often called its The external manifestations of inflammation, often called its cardinal signs, occuring as a consequence of the vascular changes cardinal signs, occuring as a consequence of the vascular changes and leucocyte activation and are :and leucocyte activation and are :1.Heat (calor) ,2. Redness (rubor)3. Swelling (tumor1.Heat (calor) ,2. Redness (rubor)3. Swelling (tumor 4. Pain (dolor), 5. Loss of function4. Pain (dolor), 5. Loss of function

Inflammation is normally controlled and self-limited Inflammation is normally controlled and self-limited a. The mediators of inflammation and cells are activated only in a. The mediators of inflammation and cells are activated only in

response to the injurious stimulus and are short livedresponse to the injurious stimulus and are short lived injurious injuriousb. The mediators are degraded or become inactive as the injurious b. The mediators are degraded or become inactive as the injurious

agent is eliminated. agent is eliminated. c. In addition, various anti-inflammatory mechanisms become activec. In addition, various anti-inflammatory mechanisms become active

I. Acute InflammationI. Acute Inflammation. . - The response delivers leukocytes and plasma proteins to sites of- The response delivers leukocytes and plasma proteins to sites of

Erythema and swellingErythema and swelling

injury and once there, leukocytes clear the invaders and begin the injury and once there, leukocytes clear the invaders and begin the process of digesting and getting rid of necrotic tissues. process of digesting and getting rid of necrotic tissues.

- Acute inflammation has two major components- Acute inflammation has two major components1. Vascular changes1. Vascular changes:: a. Vasodilation: Alterations in vessel caliber resulting in increased blood a. Vasodilation: Alterations in vessel caliber resulting in increased blood

flow to the site of inflammation. flow to the site of inflammation. b. Increased vascular permeability : Changes in the vessel wall that permit b. Increased vascular permeability : Changes in the vessel wall that permit

plasma proteins to leave the circulationplasma proteins to leave the circulation c. Endothelial cells are activated, resulting in increased adhesion of c. Endothelial cells are activated, resulting in increased adhesion of

leukocytes to endothelium and transmigration of the leukocytesleukocytes to endothelium and transmigration of the leukocytes2. Cellular events2. Cellular events

a. Emigration of the leukocytes from the circulation and accumulation in a. Emigration of the leukocytes from the circulation and accumulation in the focus of injury (cellular recruitment )the focus of injury (cellular recruitment )

b. Followed by activation of the leukocytesb. Followed by activation of the leukocytes

Stimuli for Acute Inflammation Stimuli for Acute Inflammation 1. Infections are among the most common and medically important causes of inflammation. 1. Infections are among the most common and medically important causes of inflammation. 2. Trauma (blunt and penetrating)2. Trauma (blunt and penetrating)3. Physical and chemical agents 3. Physical and chemical agents 4. Tissue necrosis (from any cause) like ischemia 4. Tissue necrosis (from any cause) like ischemia 5. Foreign bodies (splinters, dirt, sutures). 5. Foreign bodies (splinters, dirt, sutures). 6. Immune reactions6. Immune reactionsRecognition of Microbes, Necrotic Cells, and Foreign Substances Recognition of Microbes, Necrotic Cells, and Foreign Substances

- The phagocytes, dendritic cells (cells in connective tissue capture microbes and initiate - The phagocytes, dendritic cells (cells in connective tissue capture microbes and initiate responses to them), and epithelial cells, express receptors that are designed to sense responses to them), and epithelial cells, express receptors that are designed to sense the presence of infectious pathogen and substances released from dead cells the presence of infectious pathogen and substances released from dead cells

- These receptors called "pattern recognition receptors- These receptors called "pattern recognition receptors " because " because they recognize structures (i.e., molecular patterns) that are they recognize structures (i.e., molecular patterns) that are common to many microbes or to dead cells.common to many microbes or to dead cells.

A. Toll-like receptors (TLRsA. Toll-like receptors (TLRs)) : :- Are microbial sensors that are named for the founding member - Are microbial sensors that are named for the founding member

called Toll.called Toll.- There are ten LRs, which recognize products of bacteria (such as - There are ten LRs, which recognize products of bacteria (such as

endotoxin) and virusesendotoxin) and viruses- TLRs and the other receptors recognize products of different - TLRs and the other receptors recognize products of different types of microbes and thus provide defense against essentially all- types of microbes and thus provide defense against essentially all-

essentially all classes of infectious pathogensessentially all classes of infectious pathogens- Recognition of microbes by these receptors activates transcription - Recognition of microbes by these receptors activates transcription

factors that stimulate the production of a number of secreted and factors that stimulate the production of a number of secreted and membrane proteinsmembrane proteins

These proteins include mediators of inflammation ,antiviral cytokines These proteins include mediators of inflammation ,antiviral cytokines (interferons), and proteins that promote lymphocyte activation(interferons), and proteins that promote lymphocyte activation The The inflammasomeinflammasome::

- Is a multi-protein cytoplasmic complex that recognizes products of - Is a multi-protein cytoplasmic complex that recognizes products of dead cells, such as uric acid crystals and some microbial products. dead cells, such as uric acid crystals and some microbial products. - Triggering of the inflammasome results in activation of caspase-1- Triggering of the inflammasome results in activation of caspase-1, that cleaves precursors of interleukin-1βinto its active form, that cleaves precursors of interleukin-1βinto its active form- IL-1 is a mediator of leukocyte recruitment and phagocytosiss. - IL-1 is a mediator of leukocyte recruitment and phagocytosiss. - Gout, is caused by deposition of urate crystals, which are ingested - Gout, is caused by deposition of urate crystals, which are ingested by phagocytes activating inflammasome, resulting in IL-1 productionby phagocytes activating inflammasome, resulting in IL-1 production and acute inflammation.and acute inflammation.- IL-1 antagonists are effective treatments in cases of gout that are - IL-1 antagonists are effective treatments in cases of gout that are resistant to anti-inflammatory therapyresistant to anti-inflammatory therapy

I. Vascular ChangesI. Vascular ChangesA. Changes in Vascular Caliber and Flow A. Changes in Vascular Caliber and Flow - - Are initiated rapidly after infection or injury Are initiated rapidly after infection or injury 1. Transient vasoconstriction (lasting only for seconds)1. Transient vasoconstriction (lasting only for seconds)2. Arteriolar vasodilation : which results in locally increased blood 2. Arteriolar vasodilation : which results in locally increased blood

flow and engorgement of the down-stream capillary beds and this flow and engorgement of the down-stream capillary beds and this vascular expansion is the cause of the vascular expansion is the cause of the rednessredness ( ( erythema) erythema) and and ((warmth)warmth) characteristic of acute inflammation. characteristic of acute inflammation.

3. The microvasculature becomes more permeable, and protein-rich 3. The microvasculature becomes more permeable, and protein-rich fluid moves into the extravascular tissues fluid moves into the extravascular tissues 4. Stasis : Increased permeability causes the red cells in the flowing 4. Stasis : Increased permeability causes the red cells in the flowing

blood to become more concentrated, thereby increasing blood blood to become more concentrated, thereby increasing blood viscosity and slowing the circulation and these changes are viscosity and slowing the circulation and these changes are reflected microscopically by numerous dilated small vesselsreflected microscopically by numerous dilated small vessels

packed the red blood cells, called spacked the red blood cells, called stasis.tasis. - As stasis develops, leukocytes (principally neutrophils) begin to- As stasis develops, leukocytes (principally neutrophils) begin to accumulate along the vascular endothelial surface-a process accumulate along the vascular endothelial surface-a process called called marginationmargination

B.B. Increased Vascular Permeability Increased Vascular Permeability- Increasing vascular permeability leads to the movement of protein-- Increasing vascular permeability leads to the movement of protein-

rich fluid and even blood cells into the extravascular tissuesrich fluid and even blood cells into the extravascular tissues- This in turn increases the osmotic pressure of the interstitial fluid , - This in turn increases the osmotic pressure of the interstitial fluid ,

leading to more outflow of water from the blood into the tissues leading to more outflow of water from the blood into the tissues and the resulting protein- rich fluid accumulationand the resulting protein- rich fluid accumulation is called an is called an exudate exudate and must be distinguished fromand must be distinguished from transudates transudates

- Transudates: - Transudates: Are caused by increased hydrostatic pressure, Are caused by increased hydrostatic pressure, usually a onsequence of reduced venous return and have low usually a onsequence of reduced venous return and have low concentrations of protein with no or few red blood cells. concentrations of protein with no or few red blood cells.

and accumulate in various non-inflammatory conditions and accumulate in various non-inflammatory conditions Note: Fluid accumulation in extravascular spaces, whether exudate Note: Fluid accumulation in extravascular spaces, whether exudate

or a transudate, produces tissue or a transudate, produces tissue edema.edema.

Mechansims of increased vascular permeability in acute Mechansims of increased vascular permeability in acute inflammatory reactionsinflammatory reactions

a-Endothelial cell contraction a-Endothelial cell contraction : Immediate transient response : Immediate transient response

- - LeadingLeading to intercellular gaps in postcapillary venules to intercellular gaps in postcapillary venules

- Is the most common cause of increased vascular permeability and - Is the most common cause of increased vascular permeability and is a reversible processis a reversible process

- It occurs rapidly after binding of histamine, bradykinin, - It occurs rapidly after binding of histamine, bradykinin, leukotrienes, and many other mediators to specific receptors leukotrienes, and many other mediators to specific receptors

- Is usually short-lived (15 to 30 minutes)- Is usually short-lived (15 to 30 minutes) b. Endothelial cell retractionb. Endothelial cell retraction..- It is slower and prolonged process- It is slower and prolonged process

Margination of neutrophilsMargination of neutrophils

- Resulting from changes in the cytoskeleton- Resulting from changes in the cytoskeleton- May be induced by cytokines such as tumor necrosis factor (TNF) - May be induced by cytokines such as tumor necrosis factor (TNF)

and interleukin-1 (IL-1).and interleukin-1 (IL-1). - This reaction may take 4 to 6 hours to develop after the initial - This reaction may take 4 to 6 hours to develop after the initial

trigger and persist for 24 hours or more trigger and persist for 24 hours or more c. Endothelial cell injury : immediate sustained responsec. Endothelial cell injury : immediate sustained response

- Results in vascular leakage by causing endothelial cell necrosis - Results in vascular leakage by causing endothelial cell necrosis and detachment. and detachment.

- Endothelial cells are damaged after severe injury such as with - Endothelial cells are damaged after severe injury such as with burns and Some infections burns and Some infections

- In most cases, leakage begins immediately after the injury- In most cases, leakage begins immediately after the injury- The leakage persists for several hours (or days) until the damaged - The leakage persists for several hours (or days) until the damaged

vessels are thrombosed or repaired Venules, capillaries, and vessels are thrombosed or repaired Venules, capillaries, and arterioles can all be affected, depending on the site of the injury.arterioles can all be affected, depending on the site of the injury.

ExudateExudate

Note:Note:- Direct injury to endothelial cells may induce a delayed prolonged - Direct injury to endothelial cells may induce a delayed prolonged leakage that begins after a delay of 2 to 12 hours, lasts for severalleakage that begins after a delay of 2 to 12 hours, lasts for several hours or even days and involves venules and capillaries.hours or even days and involves venules and capillaries.- The response is called - The response is called delayed prolonged leakagedelayed prolonged leakaged. Leukocyte-mediated endothelial injury d. Leukocyte-mediated endothelial injury - May occur as a consequence of leukocyte accumulation along the- May occur as a consequence of leukocyte accumulation along the vessel wallvessel wall- This process is largely restricted to venules and pulmonary and - This process is largely restricted to venules and pulmonary and glomerular capillaries where leukocytes adhere for prolongedglomerular capillaries where leukocytes adhere for prolonged periods to the endothelium periods to the endothelium e. Increased transcytosis e. Increased transcytosis - It occurs via an intracellular vesicular pathway augments venular- It occurs via an intracellular vesicular pathway augments venular permeability ,especially after exposure to certain mediators like permeability ,especially after exposure to certain mediators like vascular endothelial growth factors (VEGF)vascular endothelial growth factors (VEGF)

- it occurs via channels formed by fusion of intracellular- it occurs via channels formed by fusion of intracellular vesiclesvesiclesf.f. Leakage from new blood vesselsLeakage from new blood vessels- The process is called angiogenesis- The process is called angiogenesis- These vessel sprouts remain leaky until the proliferating - These vessel sprouts remain leaky until the proliferating endothelial cells mature sufficiently to form intercellular junctionsendothelial cells mature sufficiently to form intercellular junctions- New endothelial cells have increased expression of receptors for - New endothelial cells have increased expression of receptors for

vasoactive mediators and some of the factors that induce vasoactive mediators and some of the factors that induce angiogenesis like VEGF (vascular endothelial growth factor) angiogenesis like VEGF (vascular endothelial growth factor) directly induce vascular permeability permeabilitydirectly induce vascular permeability permeability

NOTE:NOTE:- - - Although these mechanisms of vascular permeability are - Although these mechanisms of vascular permeability are

separable, all of them may participate in the response to a separable, all of them may participate in the response to a particular stimulus, for example in a thermal burn, leakage particular stimulus, for example in a thermal burn, leakage results from chemically mediated endothelial contraction, and results from chemically mediated endothelial contraction, and fromfrom

direct injury and leukocyte-mediated endothelial damagedirect injury and leukocyte-mediated endothelial damageResponses of Lymphatic VesselsResponses of Lymphatic Vessels

- In inflammation, lymph flow is increased and helps drain edema - In inflammation, lymph flow is increased and helps drain edema fluid, leukocytes, and cell debris from the extravascular space.fluid, leukocytes, and cell debris from the extravascular space.

- In severe inflammation by microbes, the lymphatics may transport - In severe inflammation by microbes, the lymphatics may transport the offending agent, contributing to its disseminationthe offending agent, contributing to its dissemination

- The lymphatics may become secondarily inflamed (- The lymphatics may become secondarily inflamed (lymphangitislymphangitis), ), as may the draining lymph nodes (as may the draining lymph nodes (lymphadenitislymphadenitis).-).-

- For clinicians, the presence of red streaks near a skin wound is a - For clinicians, the presence of red streaks near a skin wound is a sign of an infection in the wound. sign of an infection in the wound.

- This streaking follows the course of the lymphatic channels and is - This streaking follows the course of the lymphatic channels and is diagnostic of lymphangitis; ay be accompanied by painful diagnostic of lymphangitis; ay be accompanied by painful enlargement of the draining lymph noit mdes, indicating enlargement of the draining lymph noit mdes, indicating lymphadenitis.lymphadenitis.

II. Cellular Events: Leukocyte Recruitment and ActivationII. Cellular Events: Leukocyte Recruitment and Activation

- Leukocytes ingest offending agents, kill microbes, and eliminate - Leukocytes ingest offending agents, kill microbes, and eliminate necrotic tissue and foreign substancesnecrotic tissue and foreign substances

- Once, the leucocytes are activated, they may induce tissue - Once, the leucocytes are activated, they may induce tissue damage and prolong inflammation, since the leukocyte products damage and prolong inflammation, since the leukocyte products that destroy microbes can also injure normal host tissues. that destroy microbes can also injure normal host tissues.

- Therefore, host defense mechanisms include checks and balances - Therefore, host defense mechanisms include checks and balances that ensure that leukocytes are recruited and activated only when that ensure that leukocytes are recruited and activated only when and where they are needed and where they are needed

- Leukocytes normally flow rapidly in the blood, and in inflammation, - Leukocytes normally flow rapidly in the blood, and in inflammation, they have to be stopped and brought to the offending agent or the they have to be stopped and brought to the offending agent or the site of tissue damage, which are typically outside the vessels. site of tissue damage, which are typically outside the vessels.

- The sequence of events in the recruitment of leukocytes from the - The sequence of events in the recruitment of leukocytes from the vascular lumen to thevascular lumen to the extravascular space consists of:extravascular space consists of:

1. Margination and Rolling 1. Margination and Rolling

- As blood flows from capillaries into postcapillary venules, - As blood flows from capillaries into postcapillary venules, circulating cells are swept by laminar flow against the vessel wall. circulating cells are swept by laminar flow against the vessel wall.

- Because the smaller red cells tend to move faster than the larger - Because the smaller red cells tend to move faster than the larger white cells, leukocytes are pushed out of the central axial columnwhite cells, leukocytes are pushed out of the central axial column and thus have a better opportunity to interact with endothelium.and thus have a better opportunity to interact with endothelium.a. Margination a. Margination : Means the process of leukocyte accumulation at : Means the process of leukocyte accumulation at

the periphery of vesselsthe periphery of vessels- If the endothelial cells are activated by cytokines and other - If the endothelial cells are activated by cytokines and other

mediators produced locally, they express adhesion molecules to mediators produced locally, they express adhesion molecules to which the leukocytes attach looselywhich the leukocytes attach loosely

b. Rolling b. Rolling : The leukocytes bind and detach and thus begin to tumble : The leukocytes bind and detach and thus begin to tumble on the endothelial surface on the endothelial surface

- It is weak and transient binding between leukocytes and endothelial- It is weak and transient binding between leukocytes and endothelial

cells and mediated by the cells and mediated by the selectinselectin family of adhesion molecules family of adhesion molecules- Selectins are receptors expressed on leukocytes and endothelium- Selectins are receptors expressed on leukocytes and endothelium that contain an extracellular domain that binds sugars.that contain an extracellular domain that binds sugars.Types of selectins Types of selectins a. E-selectin (also called CD62E), expressed on endothelial ells; a. E-selectin (also called CD62E), expressed on endothelial ells; b. P-selectin (CD62P), present on platelets and endothelium b. P-selectin (CD62P), present on platelets and endothelium c. L-selectin (CD62L), present on the surface of most leukocytes.c. L-selectin (CD62L), present on the surface of most leukocytes.- Selectins bind sialylated oligosaccharides (e.g., sialyl-Lewis X on- Selectins bind sialylated oligosaccharides (e.g., sialyl-Lewis X on leukocytes) that are attached to mucin-like glycoproteins on cellsleukocytes) that are attached to mucin-like glycoproteins on cells- The endothelial selectins are typically expressed at low levels or - The endothelial selectins are typically expressed at low levels or are not present at all on un-activated endothelium, and are up– are not present at all on un-activated endothelium, and are up– regulated after stimulation by cytokines and other mediators.regulated after stimulation by cytokines and other mediators. - Therefore, binding of leukocytes is largely restricted to endothelium- Therefore, binding of leukocytes is largely restricted to endothelium

at sites of infection or tissue injury (where the mediators areat sites of infection or tissue injury (where the mediators are produced) and for examplesproduced) and for examplesa. In unactivated endothelial cells, P-selectin is found primarily in a. In unactivated endothelial cells, P-selectin is found primarily in

intracellular Weibel-Palade bodies; however, within minutes of intracellular Weibel-Palade bodies; however, within minutes of exposure to mediators such as histamine or thrombin, P-selectin is exposure to mediators such as histamine or thrombin, P-selectin is distributed to the cell surface, where it can facilitate leukocyte bindingdistributed to the cell surface, where it can facilitate leukocyte binding

b. E-selectin and the ligand for L-selectin, which are not expressed on b. E-selectin and the ligand for L-selectin, which are not expressed on normal endothelium, are induced after stimulation by the cytokines IL-1 normal endothelium, are induced after stimulation by the cytokines IL-1 and TNF and TNF

3. Firm adhesion3. Firm adhesion- Mediated by - Mediated by integrinsintegrins expressed on leukocyte cell surfaces interacting expressed on leukocyte cell surfaces interacting

with their ligands on endothelialwith their ligands on endothelial cellscells - Integrins are transmembrane glycoproteins that mediate the - Integrins are transmembrane glycoproteins that mediate the

adhesion of leukocytes to endothelium and of various cells to the adhesion of leukocytes to endothelium and of various cells to the extracellular matrixextracellular matrix

- Are normally expressed on leukocyte plasma membranes in - Are normally expressed on leukocyte plasma membranes in a low-affinity form and do not adhere to their specific ligands untila low-affinity form and do not adhere to their specific ligands until the leukocytes are activated by chemokinesthe leukocytes are activated by chemokinesNote:Note:- Chemokines are mediators that are secreted by many cells at - Chemokines are mediators that are secreted by many cells at

sites of inflammation and are displayed on the endothelial surface. sites of inflammation and are displayed on the endothelial surface. - When the adherent leukocytes encounter the and displayed - When the adherent leukocytes encounter the and displayed

chemokines, the cells are activated, and their integrins undergo chemokines, the cells are activated, and their integrins undergo conformational changes and cluster together, thus converting to a conformational changes and cluster together, thus converting to a high-affinity formhigh-affinity form..

- At the same time, other cytokines, notably TNF and IL-1- At the same time, other cytokines, notably TNF and IL-1

activate endothelial cells to increase their expression of ligands for activate endothelial cells to increase their expression of ligands for integrins and these ligands include the following: integrins and these ligands include the following: a. Intercellular adhesion molecule-1 (ICAM-1), which binds to the a. Intercellular adhesion molecule-1 (ICAM-1), which binds to the

integrins leukocyte function-associated antigen-1 (LFA-1) and integrins leukocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1).macrophage-1 antigen (Mac-1).

b. Vascular cell adhesion molecule-1 (VCAM-1), which binds to the b. Vascular cell adhesion molecule-1 (VCAM-1), which binds to the integrin very late antigen-4 (VLA-4) –integrin very late antigen-4 (VLA-4) –

- Engagement of integrins by their ligands delivers signals to the - Engagement of integrins by their ligands delivers signals to the leukocytes that lead to cytoskeletal changes that mediate firm leukocytes that lead to cytoskeletal changes that mediate firm attachment to the substrateattachment to the substrate

- The net result of cytokine-stimulate increased integrin affinity and - The net result of cytokine-stimulate increased integrin affinity and

increased expression of integrin increased expression of integrin - ligands is stable attachment of leukocytes to endothelial cells at - ligands is stable attachment of leukocytes to endothelial cells at

sites of inflammationsites of inflammation

4. Transmigration 4. Transmigration - After being arrested on the endothelial surface, leukocytes migrate - After being arrested on the endothelial surface, leukocytes migrate

through the vessel wall primarily by squeezing between cells at through the vessel wall primarily by squeezing between cells at intercellular junctions(called diapedesis) and this process occurs intercellular junctions(called diapedesis) and this process occurs mainly in the venules of the systemic vasculature and in capillaries in mainly in the venules of the systemic vasculature and in capillaries in the pulmonary circulation. the pulmonary circulation.

- Migration of leukocytes is driven by chemokines which stimulate - Migration of leukocytes is driven by chemokines which stimulate movement of the leukocytes toward their chemical gradient.movement of the leukocytes toward their chemical gradient.

- In addition, platelet endothelial cell adhesion molecule-1 (PECAM-1) - In addition, platelet endothelial cell adhesion molecule-1 (PECAM-1) which is expressed on leukocytes and endothelial cells, mediates the which is expressed on leukocytes and endothelial cells, mediates the binding events needed for leukocytes to traverse the endothelium.binding events needed for leukocytes to traverse the endothelium.

- After passing through the endothelium, leukocytes secrete - After passing through the endothelium, leukocytes secrete collagenases that enable them to pass through the vascular collagenases that enable them to pass through the vascular basement membranebasement membrane

5. Chemotaxis 5. Chemotaxis - Means movement of leukocytes toward sites of infection or injury along a chemical - Means movement of leukocytes toward sites of infection or injury along a chemical

gradient gradient - Both exogenous and endogenous substances can be chemotactic for leukocytes, - Both exogenous and endogenous substances can be chemotactic for leukocytes,

including the following: including the following: a. Bacterial productsa. Bacterial productsb. Cytokines, especially those of the b. Cytokines, especially those of the chemokinechemokine family familyc. Components of the complement system, particularly C5c. Components of the complement system, particularly C5d. Products of the lipoxygenase pathway of arachidonic acid) (AA) d. Products of the lipoxygenase pathway of arachidonic acid) (AA) metabolism, particularly leukotriene B4 (LTB4metabolism, particularly leukotriene B4 (LTB4- These mediators are produced in response to infections and tissue damage and - These mediators are produced in response to infections and tissue damage and

during immunologic reactionsduring immunologic reactions - Chemotactic molecules bind to specific cell surface receptors which triggers the - Chemotactic molecules bind to specific cell surface receptors which triggers the

assembly of cytoskeletal contractile elements assembly of cytoskeletal contractile elements

necessary for movement and leukocytes move by extending necessary for movement and leukocytes move by extending pseudopods that anchor to the ECM and pull the cell in the pseudopods that anchor to the ECM and pull the cell in the direction off the extensiondirection off the extension

- The direction of such movement is specified by a higher density of - The direction of such movement is specified by a higher density of chemokine receptors at the leading edge of the cell. chemokine receptors at the leading edge of the cell.

- Thus, leukocytes move to and are retained at the site where they - Thus, leukocytes move to and are retained at the site where they are neededare needed

The type of emigrating leukocyte varies with the age of the The type of emigrating leukocyte varies with the age of the inflammatory response and with the type of inflammatory response and with the type of stimulusstimulus

- In most forms of acute inflammation, - In most forms of acute inflammation, neutrophils predominate in neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours and are the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hoursreplaced by monocytes in 24 to 48 hours

- Several factors account for this early abundance of neutrophils: - Several factors account for this early abundance of neutrophils: a. These cells are the most numerous leukocytes in the blooda. These cells are the most numerous leukocytes in the blood

b. They respond more rapidly to chemokinesb. They respond more rapidly to chemokines c. They may attach more firmly to the adhesion molecules that are c. They may attach more firmly to the adhesion molecules that are

rapidly induced on endothelial cells, such as P- and E-selectinsrapidly induced on endothelial cells, such as P- and E-selectinsd. Neutrophils are short-lived-they die by apoptosis and disappear d. Neutrophils are short-lived-they die by apoptosis and disappear

within 24 to 48 hours-while monocytes survive longer. within 24 to 48 hours-while monocytes survive longer. - There are exceptions to this pattern of cellular infiltration- There are exceptions to this pattern of cellular infiltration6. Leukocyte Activation 6. Leukocyte Activation - Once leukocytes have been recruited to the site of infection or - Once leukocytes have been recruited to the site of infection or

tissue necrosis, they must be activated to perform their functionstissue necrosis, they must be activated to perform their functions- Stimuli for activation include microbes, products of necrotic cells, - Stimuli for activation include microbes, products of necrotic cells,

and several mediators and several mediators - Leukocytes use various receptors to sense the presence of - Leukocytes use various receptors to sense the presence of microbes, dead cells, and foreign substancesmicrobes, dead cells, and foreign substances

- Engagement of these cellular receptors induces a number of - Engagement of these cellular receptors induces a number of responses in leukocytes that are part of their normal defensive responses in leukocytes that are part of their normal defensive functions and are grouped under the term functions and are grouped under the term leukocyte activationleukocyte activation

- - Leukocyte activation results in the enhancement of the following Leukocyte activation results in the enhancement of the following functions:functions:

A. A. Phagocytosis of particlesPhagocytosis of particlesB. Intracellular destruction of phagocytosed microbes and dead cells B. Intracellular destruction of phagocytosed microbes and dead cells

by substances produced in phagosomes, including reactive by substances produced in phagosomes, including reactive oxygen and nitrogen species and lysosomal enzymesoxygen and nitrogen species and lysosomal enzymes

C. Liberation of substances that destroy extracellular microbes and C. Liberation of substances that destroy extracellular microbes and dead tissues, which are largely the same as the substances dead tissues, which are largely the same as the substances produced within phagocytic vesiclesproduced within phagocytic vesicles

- A recently discovered mechanism by which neutrophils destroy - A recently discovered mechanism by which neutrophils destroy extracellular microbes is the formation of extracellular trapsextracellular microbes is the formation of extracellular traps

D. Production of mediators, including arachidonic acid metabolites D. Production of mediators, including arachidonic acid metabolites and cytokines, that amplify the inflammatory reaction, by and cytokines, that amplify the inflammatory reaction, by recruiting and activating more leukocytesrecruiting and activating more leukocytes

A. Phagocytosis consists of three stepsA. Phagocytosis consists of three steps 1. Recognition and attachment of the particle to the ingesting 1. Recognition and attachment of the particle to the ingesting

leukocyte;leukocyte;

2. Engulfment, with subsequent formation of a phagocyticvacuole; 2. Engulfment, with subsequent formation of a phagocyticvacuole;

3. killing and degradation of the ingested material3. killing and degradation of the ingested material

11. Recognition and attachment of the particle to the ingesting . Recognition and attachment of the particle to the ingesting leukocyteleukocyte

- Leukocytes bind and ingest most microorganism- Leukocytes bind and ingest most microorganisms s and dead cells and dead cells by means of specific surface receptors by means of specific surface receptors

- Some of these receptors recognize components of the microbes - Some of these receptors recognize components of the microbes and dead cells and other receptors recognize host proteins, and dead cells and other receptors recognize host proteins, called called

opsoninsopsonins, , that coat microbes and target them for phagocytosis that coat microbes and target them for phagocytosis (process called (process called opsonization), anopsonization), and the he most important d the he most important opsoninsopsonins areare

A. (IgG) class that bind to microbial surface antigens, A. (IgG) class that bind to microbial surface antigens, B. Breakdown products of the complement protein C3 B. Breakdown products of the complement protein C3 C. Plasma carbohydrate-binding lectins called collectinsC. Plasma carbohydrate-binding lectins called collectins- These opsonins either are present in the blood ready to coat - These opsonins either are present in the blood ready to coat microbes or are produced in response to the microbes. microbes or are produced in response to the microbes. - Leukocytes express receptors for opsonins that facilitate rapid - Leukocytes express receptors for opsonins that facilitate rapid

phagocytosis and these receptors include : phagocytosis and these receptors include : 1. The Fc receptor for IgG (called FcγRI )1. The Fc receptor for IgG (called FcγRI )2. Complement receptors 1 and 3 (CR1 and CR3) 2. Complement receptors 1 and 3 (CR1 and CR3) 3. C1q for the collectins3. C1q for the collectins

- Binding of opsonized particles to these receptors triggers - Binding of opsonized particles to these receptors triggers engulfment and induces cellular activation that enhances engulfment and induces cellular activation that enhances degradation of ingested microbes degradation of ingested microbes

2. Engulfment2. Engulfment- In this process, pseudopods are extended around the object, - In this process, pseudopods are extended around the object, eventually forming a phagocytic vacuole. eventually forming a phagocytic vacuole. - The membrane of the vacuole then fuses with the membrane - The membrane of the vacuole then fuses with the membrane of a lysosomal granule, resulting in discharge of the granule's of a lysosomal granule, resulting in discharge of the granule's

contents into the contents into the phagolysosomephagolysosome

3. Killing and Degradation of Phagocytosed Microbes3. Killing and Degradation of Phagocytosed Microbes- The culmination of the phagocytosis of microbes is killing and - The culmination of the phagocytosis of microbes is killing and

degradation of the ingested particlesdegradation of the ingested particles- The key steps in this reaction are the production of microbicidal - The key steps in this reaction are the production of microbicidal

substances within lysosomes and fusion of the lysosomes with substances within lysosomes and fusion of the lysosomes with phagosomes, thus exposing the ingested particles to the phagosomes, thus exposing the ingested particles to the

destructive mechanisms of the leukocytesdestructive mechanisms of the leukocytes- The most important microbicidal substances are reactive oxygen- The most important microbicidal substances are reactive oxygen species (ROS) and lysosomal enzymes. species (ROS) and lysosomal enzymes. - The production of ROS involves the following steps:- The production of ROS involves the following steps:a. Phagocytosis and the engagement of various cellular a. Phagocytosis and the engagement of various cellular receptors stimulate an receptors stimulate an oxidative burst,oxidative burst, also called the also called the respiratory respiratory

burst,burst, which is characterized by a rapid increase in oxygen which is characterized by a rapid increase in oxygen glucose oxidation, and production of ROS.glucose oxidation, and production of ROS.

1. The generation of the oxygen metabolites is due to rapid 1. The generation of the oxygen metabolites is due to rapid activation of a leukocyte NADPH oxidase, called the pactivation of a leukocyte NADPH oxidase, called the phagocyte hagocyte oxidase,oxidase, which oxidizes NADPH-(reduced nicotinamide adenine which oxidizes NADPH-(reduced nicotinamide adenine dinucleotide phosphate) and, in the process, dinucleotide phosphate) and, in the process,

converts oxygen to superoxide ion (converts oxygen to superoxide ion (consumption, glycogen catabolism glycogenolysis), increased consumption, glycogen catabolism glycogenolysis), increased 2. Superoxide is then converted by spontaneous dismutation into 2. Superoxide is then converted by spontaneous dismutation into

hydrogen peroxide (+ 2H → Hhydrogen peroxide (+ 2H → H22OO22). ).

Note:Note:- The quantities of H- The quantities of H22OO22 produced generally are insufficient to produced generally are insufficient to kill kill

most bacteria (although superoxide and hydroxyl radical most bacteria (although superoxide and hydroxyl radical formation may be sufficient to do so). formation may be sufficient to do so).

3. The enzyme myeloperoxidase (MPO): is contained within 3. The enzyme myeloperoxidase (MPO): is contained within lysosomes of neutrophils (calledlysosomes of neutrophils (called azurophilic granules azurophilic granules) )

- In the presence of a halide such as Cl- In the presence of a halide such as Cl--, MPO converts H, MPO converts H22OO22 to to HOClHOCl•• (hypochlorous radical). (hypochlorous radical).

- HOCl- HOCl•• is a powerful oxidant and antimicrobial agent(NaOCl ) that is a powerful oxidant and antimicrobial agent(NaOCl ) that kills bacteriaby halogenation, or by protein and lipid peroxidationkills bacteriaby halogenation, or by protein and lipid peroxidation

..Note:Note:- Fortunately, the phagocyte oxidase is active only after its cytosolic - Fortunately, the phagocyte oxidase is active only after its cytosolic

subunit translocates to the membrane of the phagolysosome; subunit translocates to the membrane of the phagolysosome; thus, the reactive endproducts are generated mainly within the thus, the reactive endproducts are generated mainly within the vesicles, and the phagocyte itself is not damagedvesicles, and the phagocyte itself is not damaged

- H- H22OO22 is eventually broken down to water and O is eventually broken down to water and O22 by the actions of by the actions of

catalase, and the other ROS also are degraded catalase, and the other ROS also are degraded - The dead microorganisms are then degraded by the action of- The dead microorganisms are then degraded by the action of lysosomal acid hydrolases and perhaps the most important lysosomal acid hydrolases and perhaps the most important

lysosomal enzyme involved in bacterial killing is elastaselysosomal enzyme involved in bacterial killing is elastase- Several other constituents of leukocyte granules are capable of - Several other constituents of leukocyte granules are capable of

killing infectious pathogens and these include:killing infectious pathogens and these include:

a. Bactericidal permeability-increasing protein (causing hospholipase a. Bactericidal permeability-increasing protein (causing hospholipase activation and membrane phospholipid degradation activation and membrane phospholipid degradation

b. Lysozyme (causing degradation of bacterial coat oligosaccharides), b. Lysozyme (causing degradation of bacterial coat oligosaccharides), c. Major basic protein (an important eosinophil granule constituent that is c. Major basic protein (an important eosinophil granule constituent that is

cytotoxic for parasites) cytotoxic for parasites) d. Defensins (creating holes in their membranes of microbes)d. Defensins (creating holes in their membranes of microbes) Secretion of Microbicidal Substances Secretion of Microbicidal Substances - The microbicidal mechanisms of phagocytes are largely sequestered - The microbicidal mechanisms of phagocytes are largely sequestered

within phagolysosomes in order to protect the leukocytes from within phagolysosomes in order to protect the leukocytes from damaging themselves. damaging themselves.

- Leukocytes also actively secrete granule components including - Leukocytes also actively secrete granule components including enzymes such as elastase, which destroy and digest extracellular enzymes such as elastase, which destroy and digest extracellular

microbes and dead tissues, as well as antimicrobial peptidesmicrobes and dead tissues, as well as antimicrobial peptides - The contents of lysosomal granules are secreted into the extracellular - The contents of lysosomal granules are secreted into the extracellular

milieu by several mechanismsmilieu by several mechanisms

A. Regurgitation during feeding.A. Regurgitation during feeding.- The phagocytic vacuole may remain transiently open to the - The phagocytic vacuole may remain transiently open to the outside before complete closure of the phagolysosome outside before complete closure of the phagolysosome B. Frustrated phagocytosis B. Frustrated phagocytosis - If cells encounter materials that cannot be easily ingested, such - If cells encounter materials that cannot be easily ingested, such

as immune complexes deposited on immovable surfaces (e.g., as immune complexes deposited on immovable surfaces (e.g., glomerular basement membrane), the attempt to phagocytose glomerular basement membrane), the attempt to phagocytose them triggers strong leukocyte activation, and lysosomal them triggers strong leukocyte activation, and lysosomal enzymes are released into the surrounding tissue enzymes are released into the surrounding tissue

C. The membrane of the phagolysosome may be damaged if C. The membrane of the phagolysosome may be damaged if potentially injurious substances, such as silica particles, are potentially injurious substances, such as silica particles, are phagocytosed.phagocytosed.

Neutrophil Extracellular Traps (NETs) Neutrophil Extracellular Traps (NETs) --- Are extracellular fibrillar networks produced by neutrophils in - Are extracellular fibrillar networks produced by neutrophils in

response to infectious pathogens (mainly bacteria and fungi) and response to infectious pathogens (mainly bacteria and fungi) and inflammatory mediators inflammatory mediators

- NETs contain a framework of nuclear chromatin with embedded- NETs contain a framework of nuclear chromatin with embedded granule proteins, such as antimicrobial peptides and enzymes and granule proteins, such as antimicrobial peptides and enzymes and

provide a high concentration of antimicrobial substances at sites of provide a high concentration of antimicrobial substances at sites of infection, and prevent the spread of the microbes by trapping them infection, and prevent the spread of the microbes by trapping them in fibrils in fibrils

- In the process, the nuclei of the neutrophils are lost, leading to - In the process, the nuclei of the neutrophils are lost, leading to death of the cells. NETs also have been detected in blood death of the cells. NETs also have been detected in blood neutrophils during sepsis. microbes by trapping them in the fibrilsneutrophils during sepsis. microbes by trapping them in the fibrils

- The nuclear chromatin in the NETs, which includes histones and - The nuclear chromatin in the NETs, which includes histones and associated DNA, has been postulated to be a source of nuclear associated DNA, has been postulated to be a source of nuclear antigens in systemic autoimmune diseases like SLE (systemic antigens in systemic autoimmune diseases like SLE (systemic lupus erythematosus)lupus erythematosus)

Leukocyte activationLeukocyte activation

Leukocyte-Induced Tissue Leukocyte-Induced Tissue Injury Injury

- - Because leukocytes are capable of secreting potentially harmful Because leukocytes are capable of secreting potentially harmful substances such as enzymes and ROS, they are important causes substances such as enzymes and ROS, they are important causes of injury to normal cells and tissues under several circumstances:of injury to normal cells and tissues under several circumstances:

a. In certain infections that are difficult to eradicate, such as a. In certain infections that are difficult to eradicate, such as tuberculosis and some viral diseases, the host response tuberculosis and some viral diseases, the host response

contributes more to the pathologic process than does the microbe contributes more to the pathologic process than does the microbe itself.itself.

b. As a normal attempt to clear damaged and dead tissues ( after a b. As a normal attempt to clear damaged and dead tissues ( after a myocardial infarction), In an infarct, inflammation may exacerbate myocardial infarction), In an infarct, inflammation may exacerbate the injurious consequences of the ischemia, especially upon the injurious consequences of the ischemia, especially upon reperfusion reperfusion

c. When the inflammatory response is inappropriately directed c. When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases, or when against host tissues, as in certain autoimmune diseases, or when

the host reacts excessively against nontoxic environmental the host reacts excessively against nontoxic environmental substances, such as allergic diseases including asthma substances, such as allergic diseases including asthma

- In all of these situations, the mechanisms by which leukocytes damage - In all of these situations, the mechanisms by which leukocytes damage normal tissues are the same as the mechanisms involved in the normal tissues are the same as the mechanisms involved in the clearance of microbes and dead tissues, because once the leukocytes clearance of microbes and dead tissues, because once the leukocytes are activated, their effector mechanisms do not distinguish between are activated, their effector mechanisms do not distinguish between offender and hostoffender and host

Defects in Leukocyte Function Defects in Leukocyte Function

- There are acquired and inherited defects in leukocyte function. - There are acquired and inherited defects in leukocyte function. I. The most common causes of acquired defective inflammation areI. The most common causes of acquired defective inflammation area. Bone marrow suppression caused by tumors or treatment with a. Bone marrow suppression caused by tumors or treatment with

chemotherapy or radiation (resulting in decreased leukocyte numberschemotherapy or radiation (resulting in decreased leukocyte numbersb. In diabetes (causing abnormal leukocyte functions). b. In diabetes (causing abnormal leukocyte functions).

II. Examples of inherited diseases are the following:II. Examples of inherited diseases are the following: 1. defects in leukocyte adhesion1. defects in leukocyte adhesion.. A. In A. In leukocyte adhesion deficiency type 1 (LAD-1)leukocyte adhesion deficiency type 1 (LAD-1) defective defective

synthesis of the CD18 synthesis of the CD18 β β subunit of the leukocyte integrins LFA-1 subunit of the leukocyte integrins LFA-1 and Mac-1 leads to impaired leukocyte adhesion to and migration and Mac-1 leads to impaired leukocyte adhesion to and migration through endothelium, and defective phagocytosis and generation through endothelium, and defective phagocytosis and generation of an oxidative burst.of an oxidative burst.

B. Leukocyte adhesion deficiency type 2 (LAD-2)B. Leukocyte adhesion deficiency type 2 (LAD-2)- Is caused by a defect in fucose metabolism resulting in the Is caused by a defect in fucose metabolism resulting in the

absence of sialyl-Lewis X, the oligosaccharide on leukocytes that absence of sialyl-Lewis X, the oligosaccharide on leukocytes that binds to selectins on activated endothelium.binds to selectins on activated endothelium.

- Its clinical manifestations are similar but milder than LAD1- Its clinical manifestations are similar but milder than LAD12. Defects in microbicidal activity2. Defects in microbicidal activity - An example is - An example is chronic granulomatous diseasechronic granulomatous disease,, a genetic a genetic

deficiency in one of the several components of the phagocyte oxidase deficiency in one of the several components of the phagocyte oxidase enzymeenzyme that is responsible for generating ROS, in these patients, that is responsible for generating ROS, in these patients, engulfment of bacteria does not result in activation of oxygen-engulfment of bacteria does not result in activation of oxygen-dependent killing mechanismsdependent killing mechanisms

- In an attempt to control these infections, the microbes are - In an attempt to control these infections, the microbes are surrounded by activated macrophages, forming the "granulomas” surrounded by activated macrophages, forming the "granulomas” 3.3.Defects in phagolysosome formation.Defects in phagolysosome formation. - Chédiak-Higashi syndrome,- Chédiak-Higashi syndrome, is an autosomal recessive disease that is an autosomal recessive disease that

results from disordered intracellular trafficking of organelles, ultimately results from disordered intracellular trafficking of organelles, ultimately impairing the fusion of lysosomes with phagosomes. impairing the fusion of lysosomes with phagosomes.

- The secretion of lytic secretory granules by cytotoxic T - The secretion of lytic secretory granules by cytotoxic T - - lymphocytes is lymphocytes is also affected, explaining the severe immunodeficiency also affected, explaining the severe immunodeficiency

4. M4. Mutations in genes encoding some components of the inflammasomeutations in genes encoding some components of the inflammasome , , one of which is called one of which is called cryopyrin,cryopyrin, are responsible for diseases called are responsible for diseases called cryopyrin-associated periodic fever syndromes (CAPSs), and d cryopyrin-associated periodic fever syndromes (CAPSs), and d respond well to treatment with IL-1 antagonists.respond well to treatment with IL-1 antagonists.

Outcomes of Acute Inflammation Outcomes of Acute Inflammation Acute inflammation generally has one of three outcomesAcute inflammation generally has one of three outcomes::1. Resolution:1. Resolution: Regeneration and repair. Regeneration and repair. - When the injury is limited or short-lived,- When the injury is limited or short-lived,- When there has been no or minimal tissue damage, and when the - When there has been no or minimal tissue damage, and when the

injured tissue is capable of regenerating, the usual outcome is injured tissue is capable of regenerating, the usual outcome is restoration to structural and functional normalcy. restoration to structural and functional normalcy.

- Before the process of resolution can start, the acute inflammatory - Before the process of resolution can start, the acute inflammatory response has to be terminated. response has to be terminated.

- This involves:- This involves:a. Neutralization, decay,or enzymatic degradation of the various a. Neutralization, decay,or enzymatic degradation of the various chemical mediators; chemical mediators; b. Normalization of vascular permeabilityb. Normalization of vascular permeability

cc. Cessation of leukocyte emigration, with subsequent death (by . Cessation of leukocyte emigration, with subsequent death (by apoptosis) of extravasated neutrophilsapoptosis) of extravasated neutrophils

d. Leukocytes begin to produce mediators that inhibitd. Leukocytes begin to produce mediators that inhibit in inflammation flammation thereby limiting the reaction thereby limiting the reaction

e. The necrotic debris, edema fluid, and inflammatory cells are e. The necrotic debris, edema fluid, and inflammatory cells are cleared by phagocytes and lymphatic drainage, eliminating the cleared by phagocytes and lymphatic drainage, eliminating the detritus from the battlefield.detritus from the battlefield.

2. Chronic inflammation2. Chronic inflammation - May follow acute inflammation if the offending agent is not - May follow acute inflammation if the offending agent is not

removed, or it may be present from the onset of injury (e.g., in removed, or it may be present from the onset of injury (e.g., in viral infections or immune responses to self-antigens).viral infections or immune responses to self-antigens).

Note:Note:- Depending on the extent of the initial and continuing tissue injury, as - Depending on the extent of the initial and continuing tissue injury, as

well as the capacity of the affected tissues to regrow, chronicwell as the capacity of the affected tissues to regrow, chronic

chronic inflammation may be followed by restoration of normal chronic inflammation may be followed by restoration of normal structure and function or lead to scarring.structure and function or lead to scarring.

3. Scarring3. Scarring : Is a type of repair after : : Is a type of repair after :a. Substantial tissue destruction (as in abscess formation, a. Substantial tissue destruction (as in abscess formation, b. Or when inflammation occurs in tissues that do not regenerate, in b. Or when inflammation occurs in tissues that do not regenerate, in

which the injured tissue is filled in by connective tissue.which the injured tissue is filled in by connective tissue.c. In organs in which extensive connective tissue c. In organs in which extensive connective tissue deposition occurs in attempts to heal the damage ordeposition occurs in attempts to heal the damage ord. consequence of chronic inflammation, the outcome is d. consequence of chronic inflammation, the outcome is fibrosis,fibrosis, a a

process that can significantly compromise function.process that can significantly compromise function.

MORPHOLOGIC PATTERNS OF ACUTE MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION INFLAMMATION

- The severity of the inflammatory response, its specific cause, and - The severity of the inflammatory response, its specific cause, and the particular tissue involved all can modify the basic morphology the particular tissue involved all can modify the basic morphology of acute inflammation, producing distinctive appearances and the of acute inflammation, producing distinctive appearances and the importance of recognizing these morphologic patterns is that they importance of recognizing these morphologic patterns is that they are often associated with different etiology and clinical situations.are often associated with different etiology and clinical situations.

1. Serous inflammation1. Serous inflammation : :

- Characterized by the outpouring of a watery, relatively protein-poor - Characterized by the outpouring of a watery, relatively protein-poor fluid that, depending on the site of injury, derives either from the fluid that, depending on the site of injury, derives either from the plasma or from the secretions of mesothelial cells lining the plasma or from the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities. peritoneal, pleural, and pericardial cavities.

- The skin blister resulting from a burn or viral infection is a good - The skin blister resulting from a burn or viral infection is a good example of the accumulation of a serous effusion either within orexample of the accumulation of a serous effusion either within or

immediately beneath the epidermis of the skin immediately beneath the epidermis of the skin - Fluid in a serous cavity is called an - Fluid in a serous cavity is called an effusion.effusion.

2. Fibrinous inflammation2. Fibrinous inflammation : :

- Occurs as a consequence of more severe injuries, resulting in - Occurs as a consequence of more severe injuries, resulting in greater vascular permeability that allows large molecules (such as greater vascular permeability that allows large molecules (such as fibrinogen) to pass the endothelial barrier.fibrinogen) to pass the endothelial barrier.

- Histologically, the accumulated extravascular fibrin appears as an - Histologically, the accumulated extravascular fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous eosinophilic meshwork of threads or sometimes as an amorphous coagulum coagulum

- A fibrinous exudate is characteristic of inflammation in the lining of - A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleurabody cavities, such as the meninges, pericardium, and pleura

- Such exudates: - Such exudates: a. May be degraded by fibrinolysis, and the accumulated debris may a. May be degraded by fibrinolysis, and the accumulated debris may

be removed by macrophages, resulting in restoration of the normalbe removed by macrophages, resulting in restoration of the normal

tissue structure tissue structure (resolution).(resolution).

b. However, extensive fibrin-rich exudates may not be completely b. However, extensive fibrin-rich exudates may not be completely removed, and are replaced by an ingrowth of fibroblasts and blood removed, and are replaced by an ingrowth of fibroblasts and blood vessels vessels (organization),(organization), leading ultimately to scarring that may leading ultimately to scarring that may have significant clinical consequences.have significant clinical consequences.

- - For example, organization of a fibrinous pericardial exudate forms For example, organization of a fibrinous pericardial exudate forms dense fibrous scar tissue that bridges or obliterates the pericardial dense fibrous scar tissue that bridges or obliterates the pericardial space and restricts myocardial function.space and restricts myocardial function.

33. Suppurative (purulent) inflammation and abscess formation. Suppurative (purulent) inflammation and abscess formation These are manifested by the collection of large amounts of These are manifested by the collection of large amounts of purulent exudate (pus) consisting of neutrophils, necrotic cells, and purulent exudate (pus) consisting of neutrophils, necrotic cells, and edema fluid. edema fluid.

- - Certain organisms (e.g., staphylococci) are more likely to induce Certain organisms (e.g., staphylococci) are more likely to induce such localized suppuration and are therefore referred to as such localized suppuration and are therefore referred to as pyogenic (pus-forming pyogenic (pus-forming

Serous inflammationSerous inflammation

AbscessesAbscesses : :

- Are focal collections of pus that may be caused by seeding of - Are focal collections of pus that may be caused by seeding of pyogenic organisms into a tissue or by secondary infections of pyogenic organisms into a tissue or by secondary infections of necrotic foci.necrotic foci.

- Abscesses typically have a central, largely necrotic region Abscesses typically have a central, largely necrotic region rimmed by a layer of preserved neutrophils with a rimmed by a layer of preserved neutrophils with a surrounding zone of dilated vessels and fibroblast proliferation surrounding zone of dilated vessels and fibroblast proliferation indicative of attempted repair. indicative of attempted repair.

• Chemical Mediators of Chemical Mediators of inflammationinflammation1. 1. Mediators may be produced:Mediators may be produced:

a. Locally by cells at the site of inflammation, or a. Locally by cells at the site of inflammation, or b. May be derived from circulating inactive precursors (typically b. May be derived from circulating inactive precursors (typically

synthesized by the liver) that are activated at the site of synthesized by the liver) that are activated at the site of inflammation inflammation

Fibrinous pericarditisFibrinous pericarditis

Duodenal ulcerDuodenal ulcer

NOTES:NOTES:- Complement regulatory proteins block complement activation. - Complement regulatory proteins block complement activation. - Cell-derived mediators are normally sequestered in intracellular - Cell-derived mediators are normally sequestered in intracellular

granules and are rapidly secreted upon cellularactivation (e.g., granules and are rapidly secreted upon cellularactivation (e.g., histamine in mast cells) or are synthesized de novo in response to histamine in mast cells) or are synthesized de novo in response to a stimulus (e.g., prostaglandins and cytokines produced by a stimulus (e.g., prostaglandins and cytokines produced by leukocytes and other cells). leukocytes and other cells).

- Plasma protein-derived mediators (complement proteins, kinins) - Plasma protein-derived mediators (complement proteins, kinins) circulate in an inactive form and undergo proteolytic cleavage to circulate in an inactive form and undergo proteolytic cleavage to acquire their biologic activitiesacquire their biologic activities..

2. Most mediators act by binding to specific receptors on different 2. Most mediators act by binding to specific receptors on different target cells.target cells.

-. -. Such mediators may act on only one or a very few cell types, or Such mediators may act on only one or a very few cell types, or they may have diverse actions they may have diverse actions

- Other mediators (lysosomal proteases, ROS) have direct enzymatic - Other mediators (lysosomal proteases, ROS) have direct enzymatic activities that do not require binding to specific receptors.activities that do not require binding to specific receptors.

3. The actions of most mediators are tightly regulated and short-lived.3. The actions of most mediators are tightly regulated and short-lived.

- Once activated and released from the cell,- Once activated and released from the cell,a. Some mediators quickly decay (e.g., arachidonic acid metabolites)a. Some mediators quickly decay (e.g., arachidonic acid metabolites) b. Some are inactivated by enzymes (e.g., kininase inactivates b. Some are inactivated by enzymes (e.g., kininase inactivates

bradykininbradykininc. Some are eliminated (e.g., antioxidants scavenge toxic oxygen c. Some are eliminated (e.g., antioxidants scavenge toxic oxygen

metabolites), metabolites), d. Or are inhibited (e.g.,d. Or are inhibited (e.g., I. Cell-Derived MediatorsI. Cell-Derived Mediators

- Tissue macrophages, mast cells, and endothelial cells at the site of - Tissue macrophages, mast cells, and endothelial cells at the site of inflammation, as well as leukocytes that are recruited to the site inflammation, as well as leukocytes that are recruited to the site of inflammation from blood all are capable of producing mediatorsof inflammation from blood all are capable of producing mediators

1. 1. Vasoactive Amines Vasoactive Amines : histamine and serotonin,: histamine and serotonin,- Are stored as preformed molecules in mast cells and- re among - Are stored as preformed molecules in mast cells and- re among

the first mediators to be released in acute inflammatory reactions. the first mediators to be released in acute inflammatory reactions. a. Histamine:a. Histamine:

- P- Produced mainly by mast cells and basophils and plateletsroduced mainly by mast cells and basophils and platelets- Preformed histamine is released from mast cell granules in - Preformed histamine is released from mast cell granules in

response to a variety of stimuli:response to a variety of stimuli:1. Physical injury such as trauma or heat;1. Physical injury such as trauma or heat;2. Immune reactions involving binding of IgE antibodies to Fc 2. Immune reactions involving binding of IgE antibodies to Fc

receptors on mast cellsreceptors on mast cells3. C3a and C5a fragments of complement, the so-called 3. C3a and C5a fragments of complement, the so-called

anaphylatoxins anaphylatoxins 5. Neuropeptides (e.g., substance P)5. Neuropeptides (e.g., substance P)6. Cytokines like IL-1 and IL-8 6. Cytokines like IL-1 and IL-8

- In humans, histamine causes :- In humans, histamine causes :a. Arteriolar dilation anda. Arteriolar dilation andb. Rapidly increases vascular permeability b. Rapidly increases vascular permeability - Histamine is inactivated by histaminase. - Histamine is inactivated by histaminase. 2. Arachidonic Acid Metabolites:2. Arachidonic Acid Metabolites:

- - Products derived from the metabolism of AA affect a variety of Products derived from the metabolism of AA affect a variety of biologic processes, including inflammation and hemostasis. biologic processes, including inflammation and hemostasis.

- AA metabolites, also called - AA metabolites, also called eicosanoidseicosanoids (because they are derived (because they are derived from 20-carbon fatty acids-Greek from 20-carbon fatty acids-Greek eicosaeicosa, "twenty"),, "twenty"),

- Their synthesis is increased at sites of inflammatory response, and - Their synthesis is increased at sites of inflammatory response, and agents that inhibit their synthesis also diminish inflammationagents that inhibit their synthesis also diminish inflammation

- Leukocytes, mast cells, endothelial cells, and platelets are the - Leukocytes, mast cells, endothelial cells, and platelets are the major sources of AA metabolites in inflammationmajor sources of AA metabolites in inflammation

- AA-derived mediators act locally at the site of generation and then - AA-derived mediators act locally at the site of generation and then decay spontaneously or are enzymatically destroyed.decay spontaneously or are enzymatically destroyed.

- AA is a 20-carbon polyunsaturated fatty acid produced primarily - AA is a 20-carbon polyunsaturated fatty acid produced primarily from dietary linoleic acid and present in the body mainly in its from dietary linoleic acid and present in the body mainly in its esterified form as a component of cell membrane phospholipidsesterified form as a component of cell membrane phospholipids

- It is released from these phospholipids through the action of - It is released from these phospholipids through the action of cellular phospholipases that have been activated by mechanical, cellular phospholipases that have been activated by mechanical, chemical, or physical stimuli, or by inflammatory mediators such as chemical, or physical stimuli, or by inflammatory mediators such as C5a. C5a.

- AA metabolism proceeds along one of two major pathways : - AA metabolism proceeds along one of two major pathways : A. Cyclooxygenase stimulates the synthesis of prostaglandins and A. Cyclooxygenase stimulates the synthesis of prostaglandins and

thromboxanesthromboxanesB. Lipoxygenase is responsible for production of leukotrienes and B. Lipoxygenase is responsible for production of leukotrienes and

lipoxinslipoxins

A. Prostaglandins and thromboxanesA. Prostaglandins and thromboxanes

- Products of the cyclooxygenase pathway include :. - Products of the cyclooxygenase pathway include :. 1. Prostaglandins E1. Prostaglandins E22 (PGE (PGE22), PGD), PGD22, PGF, PGF2α2α, PGI, PGI22

2. And thromboxane A2. And thromboxane A22 (TXA (TXA22),),

- Each derived by the action of a specific enzyme on an intermediate. - Each derived by the action of a specific enzyme on an intermediate. - Some of these enzymes have a restricted tissue distribution- Some of these enzymes have a restricted tissue distributiona. For example, platelets contain the enzyme a. For example, platelets contain the enzyme thromboxane thromboxane

synthase,synthase, and hence and hence TXATXA22 which is: which is:

1. A potent platelet-aggregating agent 1. A potent platelet-aggregating agent 2. And vasoconstrictor,2. And vasoconstrictor,b. Endothelial cells, on the other hand, lack thromboxane synthase b. Endothelial cells, on the other hand, lack thromboxane synthase

but contain prostacyclin synthase, responsible for the formation but contain prostacyclin synthase, responsible for the formation of of PGIPGI22,which is :,which is :

1. A vasodilator and 1. A vasodilator and 2. A potent inhibitor of platelet aggregation.2. A potent inhibitor of platelet aggregation.c. Mast cellsc. Mast cells- PGD- PGD22 is the major metabolite of the cyclooxygenase pathway in is the major metabolite of the cyclooxygenase pathway in

mast cells; and along with PGEmast cells; and along with PGE22 and PGF2 it causes and PGF2 it causes vasodilatoion and potentiates edema formationvasodilatoion and potentiates edema formation

NoteNote

- PGE2 contributes to the pain and fever in acute inflammation- PGE2 contributes to the pain and fever in acute inflammation

B. Leukotrienes:B. Leukotrienes:

- Are produced by the action of 5-lipoxygenase, the major AA-- Are produced by the action of 5-lipoxygenase, the major AA-metabolizing enzyme in neutrophilsmetabolizing enzyme in neutrophils..

- The synthesis of leukotrienes involves multiple steps- The synthesis of leukotrienes involves multiple steps- The first step generates leukotriene A- The first step generates leukotriene A44 (LTA (LTA44), which in turn gives ), which in turn gives

rise to LTBrise to LTB44 or LTC or LTC44

1. LTB1. LTB44 is produced by neutrophils and is a potent chemotactic is produced by neutrophils and is a potent chemotactic agent for neutrophilsagent for neutrophils

2. LTC2. LTC44 and its subsequent metabolites, LTD and its subsequent metabolites, LTD44 and LTE and LTE44, are , are produced mainly in mast cells and cause:produced mainly in mast cells and cause:

a. Bronchoconstrictiona. Bronchoconstriction b. And increased vascular permeabilityb. And increased vascular permeabilityC. Lipoxins.C. Lipoxins. - Once leukocytes enter tissues, they gradually change their major - Once leukocytes enter tissues, they gradually change their major

lipoxygenase-derived AA products from leukotrienes to anti-lipoxygenase-derived AA products from leukotrienes to anti-inflammatory mediators called lipoxins, which inhibit neutrophil inflammatory mediators called lipoxins, which inhibit neutrophil chemotaxis and adhesion to endothelium and thus serve as chemotaxis and adhesion to endothelium and thus serve as endogenous antagonists of leukotrienes.endogenous antagonists of leukotrienes.

- Platelets that are activated and adherent to leukocytes also are - Platelets that are activated and adherent to leukocytes also are important sources of lipoxinsimportant sources of lipoxins 6565

Anti-inflammatory Drugs That Block Prostaglandin Production Anti-inflammatory Drugs That Block Prostaglandin Production

- Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin - Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, inhibit cyclooxygenase activity, thereby blocking alland ibuprofen, inhibit cyclooxygenase activity, thereby blocking all

prostaglandin synthesis (are efficacy in treating pain and fever)prostaglandin synthesis (are efficacy in treating pain and fever) • There are two forms of the cyclooxygenase enzyme, COX-1 and There are two forms of the cyclooxygenase enzyme, COX-1 and

COX-2.COX-2.a. COX-1 is produced in response to inflammatory stimuli and also is a. COX-1 is produced in response to inflammatory stimuli and also is

constitutively expressed in most tissues, where it stimulates the constitutively expressed in most tissues, where it stimulates the production of prostaglandins that serve a homeostatic function production of prostaglandins that serve a homeostatic function (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract). the gastrointestinal tract).

b. By contrast, COX-2 is induced by inflammatory stimuli but it is b. By contrast, COX-2 is induced by inflammatory stimuli but it is absent from most normal tissues. absent from most normal tissues.

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Note:Note:- Therefore, COX-2 inhibitors have been developed with the - Therefore, COX-2 inhibitors have been developed with the

expectation that they will inhibit harmful inflammation but will not expectation that they will inhibit harmful inflammation but will not block the protective effects of constitutively produced block the protective effects of constitutively produced prostaglandins. prostaglandins.

- COX-2 inhibitors may increase the risk for cardiovascular and - COX-2 inhibitors may increase the risk for cardiovascular and cerebrovascular events, possibly because they impair endothelial cerebrovascular events, possibly because they impair endothelial

cell production of prostacyclin (PGIcell production of prostacyclin (PGI22), an inhibitor of platelet ), an inhibitor of platelet aggregation, but leave intact the COX-1-mediated production by aggregation, but leave intact the COX-1-mediated production by platelets of TXAplatelets of TXA22, a mediator of platelet aggregation. , a mediator of platelet aggregation.

c. Glucocorticoids, which are powerful anti-inflammatory agents, act c. Glucocorticoids, which are powerful anti-inflammatory agents, act in part by inhibiting the activity of phospholipase Ain part by inhibiting the activity of phospholipase A22 and thus the and thus the release of AA from membrane lipids. release of AA from membrane lipids.

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3. Cytokines 3. Cytokines

- Are polypeptide products of many cell types that function as - Are polypeptide products of many cell types that function as mediators of inflammation and immune responses mediators of inflammation and immune responses

- Some cytokines stimulate bone marrow precursors to produce - Some cytokines stimulate bone marrow precursors to produce more leukocytes, thus replacing the ones that are consumed more leukocytes, thus replacing the ones that are consumed during inflammation and immune responsesduring inflammation and immune responses

- The major cytokines in acute inflammation are TNF, IL-1, IL-6, and - The major cytokines in acute inflammation are TNF, IL-1, IL-6, and chemokineschemokines

- Cytokines important in chronic inflammation include interferon-γ - Cytokines important in chronic inflammation include interferon-γ (IFN-γ) and IL-12(IFN-γ) and IL-12

A. Tumor necrosis factor and IL-1A. Tumor necrosis factor and IL-1- Their secretion is stimulated by bacterial endotoxin, immune - Their secretion is stimulated by bacterial endotoxin, immune complexes and products of T lymphocytes generated during complexes and products of T lymphocytes generated during

adaptive immune responses.adaptive immune responses.

- IL-1 is also the cytokine induced by activation of the - IL-1 is also the cytokine induced by activation of the inflammasome. inflammasome.

- The principal role of these cytokines in inflammation is in - The principal role of these cytokines in inflammation is in endothelial activationendothelial activation

Both TNF and IL-1:Both TNF and IL-1:a. Stimulate the expression of adhesion molecules onendothelial a. Stimulate the expression of adhesion molecules onendothelial

cellscellsb. Enhance the production of additional cytokines notably b. Enhance the production of additional cytokines notably

chemokines) and eicosanoidschemokines) and eicosanoidsc. They may enter the circulation and act at distant sites to induce c. They may enter the circulation and act at distant sites to induce

the systemic acute-phase reactionthe systemic acute-phase reactiond. TNF increases the thrombogenicity of endotheliumd. TNF increases the thrombogenicity of endotheliume. IL-1 activates tissue fibroblasts, resulting in increased e. IL-1 activates tissue fibroblasts, resulting in increased

proliferation and production of ECM. proliferation and production of ECM. 7070

B. Chemokines B. Chemokines - Act primarily as chemoattractants for different subsets of - Act primarily as chemoattractants for different subsets of

leukocytes leukocytes - The two main functions of chemokines are:- The two main functions of chemokines are:1. To recruit leukocytes to the site of inflammation 1. To recruit leukocytes to the site of inflammation - Combinations of chemokines that are produced transiently in - Combinations of chemokines that are produced transiently in

response to inflammatory stimuli recruit particular cell populations response to inflammatory stimuli recruit particular cell populations (e.g., neutrophils, lymphocytes or eosinophils) to sites of (e.g., neutrophils, lymphocytes or eosinophils) to sites of inflammation inflammation

2. To control the normal anatomic organization of cells in lymphoid 2. To control the normal anatomic organization of cells in lymphoid and other tissues:Some chemokines are produced constitutively and other tissues:Some chemokines are produced constitutively in tissues and are responsible for the anatomic segregation of in tissues and are responsible for the anatomic segregation of different cell populations in tissues (e.g., the segregation of T and different cell populations in tissues (e.g., the segregation of T and B lymphocytes in different areas of lymph nodes and spleenB lymphocytes in different areas of lymph nodes and spleen

c. Activate leukocytes; one consequence of such activation, is increased c. Activate leukocytes; one consequence of such activation, is increased affinity of leukocyte integrins for their ligands on endothelial cells affinity of leukocyte integrins for their ligands on endothelial cells

d. Two of these chemokine receptors (called CXCR4 and CCR5) are d. Two of these chemokine receptors (called CXCR4 and CCR5) are important coreceptors for the binding and entry of the human important coreceptors for the binding and entry of the human immunodeficiency virus into lymphocytes immunodeficiency virus into lymphocytes

- Chemokines are classified into four groups - Chemokines are classified into four groups - The two major groups are the CXC and CC- The two major groups are the CXC and CCa. CXC chemokines:a. CXC chemokines:

- Have one amino acid separating the conserved cysteines - Have one amino acid separating the conserved cysteines - And act primarily on neutrophils and IL-8 is typical of this group- And act primarily on neutrophils and IL-8 is typical of this group

b. CC chemokinesb. CC chemokines : : - Have adjacent cysteine residues and include :- Have adjacent cysteine residues and include :

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A. Monocyte chemoattractant protein-1 (MCP-1A. Monocyte chemoattractant protein-1 (MCP-1B. Macrophage inflammatory protein-1α (MIP-1α) B. Macrophage inflammatory protein-1α (MIP-1α) - Both (a&b) chemotactic predominantly for monocytes),- Both (a&b) chemotactic predominantly for monocytes),C. Eotaxin (chemotactic for eosinophils C. Eotaxin (chemotactic for eosinophils 4. Reactive Oxygen Species 4. Reactive Oxygen Species ::- ROS are synthesized via the NADPH oxidase (phagocyte - ROS are synthesized via the NADPH oxidase (phagocyte

oxidase) pathway and are released from neutrophils and oxidase) pathway and are released from neutrophils and macrophagesmacrophages

Functions:Functions:a. When produced within lysosomes they function to destroy a. When produced within lysosomes they function to destroy

phagocytosed microbes and necrotic cells. phagocytosed microbes and necrotic cells. b. When secreted at low levels, ROS can increase chemokine, b. When secreted at low levels, ROS can increase chemokine,

cytokine, and adhesion molecule expression, thus amplifying the cytokine, and adhesion molecule expression, thus amplifying the cascade of inflammatory mediators. cascade of inflammatory mediators. 7373

c. At higher levels, these mediators are responsible for tissue injury c. At higher levels, these mediators are responsible for tissue injury by several mechanisms, including 1.Endothelial damage and by several mechanisms, including 1.Endothelial damage and increased permeabilityincreased permeability

2. Protease activation and antiprotease inactivation, with a net 2. Protease activation and antiprotease inactivation, with a net increase in breakdown of the ECM; and Direct injury to other cell increase in breakdown of the ECM; and Direct injury to other cell types (e.g., tumor cells, red cells, parenchymal cells types (e.g., tumor cells, red cells, parenchymal cells

Note:- Fortunately, various antioxidant protective mechanisms(e.g., Note:- Fortunately, various antioxidant protective mechanisms(e.g., mediated by catalase, superoxide dismutase, and glutathione) mediated by catalase, superoxide dismutase, and glutathione) present in tissues and blood minimize the toxicity of the oxygen present in tissues and blood minimize the toxicity of the oxygen metabolites . metabolites .

5.Nitric Oxide(5.Nitric Oxide( NO) NO)- Is a short-lived, soluble, free radical gas produced by many cell - Is a short-lived, soluble, free radical gas produced by many cell

types and capable of mediating a variety of functions that includetypes and capable of mediating a variety of functions that include

Functions: Functions: a. In the central nervous system it regulates neurotransmitter release a. In the central nervous system it regulates neurotransmitter release

as well as blood flowas well as blood flow. b. Macrophages use it as a cytotoxic agent for killing microbes and . b. Macrophages use it as a cytotoxic agent for killing microbes and

tumor cellstumor cellsc. When produced by endothelial cells it relaxes vascular smooth c. When produced by endothelial cells it relaxes vascular smooth

muscle and causes vasodilation. muscle and causes vasodilation. --NO is synthesized de novo from L-arginine, and NADPH by the --NO is synthesized de novo from L-arginine, and NADPH by the

enzyme nitric oxide synthase (NOS).here are three isoforms of enzyme nitric oxide synthase (NOS).here are three isoforms of NOS, NOS,

a. Type I, neuronal NOS (nNOS), is constitutively expressed a. Type I, neuronal NOS (nNOS), is constitutively expressed in neurons, and does not play a significant role in inflammationin neurons, and does not play a significant role in inflammationb. Type II, inducible NOS (iNOS), Is induced in macrophages and b. Type II, inducible NOS (iNOS), Is induced in macrophages and

endothelial cells by a number of inflammatory cytokinesendothelial cells by a number of inflammatory cytokines

and mediators, most notably by IL-1, TNF, and IFN-γ, and by and mediators, most notably by IL-1, TNF, and IFN-γ, and by bacterial endotoxin,bacterial endotoxin,

- Is responsible for production of NO in inflammatory reactions- Is responsible for production of NO in inflammatory reactions - This inducible form is also present in hepatocytes, cardiac - This inducible form is also present in hepatocytes, cardiac

myocytes, and respiratory epithelial cells myocytes, and respiratory epithelial cells c. Type III, endothelial NOS, (eNOS), is constitutively synthesized c. Type III, endothelial NOS, (eNOS), is constitutively synthesized

primarily (but not exclusively) in endothelium.primarily (but not exclusively) in endothelium.- An important function of NO is as a microbicidal (cytotoxic) agent - An important function of NO is as a microbicidal (cytotoxic) agent

in activated macrophages in activated macrophages - NO plays other roles in inflammation, including:- NO plays other roles in inflammation, including:a. Vasodilationa. Vasodilationb. Antagonism of all stages of platelet activation (adhesion, b. Antagonism of all stages of platelet activation (adhesion,

aggregation, and degranulation),aggregation, and degranulation),c. And reduction of leukocyte recruitment at inflammatory sitesc. And reduction of leukocyte recruitment at inflammatory sites 7676

5. Lysosomal Enzymes of Leukocytes 5. Lysosomal Enzymes of Leukocytes

- The lysosomal granules of neutrophils and monocytes contain - The lysosomal granules of neutrophils and monocytes contain many enzymes that destroy phagocytosed substances and are many enzymes that destroy phagocytosed substances and are capable of causing tissue damage.capable of causing tissue damage.

- Acid proteases generally are active only in the low-pH - Acid proteases generally are active only in the low-pH - - environment of phagolysosomes, environment of phagolysosomes,

- Neutral proteases, including elastase, collagenase, and cathepsin, - Neutral proteases, including elastase, collagenase, and cathepsin, are active in extracellular locations and cause tissue injury by are active in extracellular locations and cause tissue injury by degrading elastin, collagen, basement membrane, and other degrading elastin, collagen, basement membrane, and other matrix proteins. matrix proteins.

- Neutral proteases can cleave the complement proteins C3 and C5 - Neutral proteases can cleave the complement proteins C3 and C5 directly togenerate the vasoactive mediators C3a and C5a and can directly togenerate the vasoactive mediators C3a and C5a and can generate bradykinin-like peptides from kininogengenerate bradykinin-like peptides from kininogen

- The potentially damaging effects of lysosomal enzymes are limited - The potentially damaging effects of lysosomal enzymes are limited by antiproteases present in the plasma and tissue fluidsby antiproteases present in the plasma and tissue fluids

- These include αThese include α11-antitrypsin, the major inhibitor of neutrophil -antitrypsin, the major inhibitor of neutrophil elastase, and αelastase, and α22-macroglobulin -macroglobulin

--. . Deficiencies of these inhibitors may result in sustained activation of Deficiencies of these inhibitors may result in sustained activation of leukocyte proteases, resulting in tissue destruction at sites of leukocyte proteases, resulting in tissue destruction at sites of leukocyte accumulation leukocyte accumulation

NeuropeptidesNeuropeptides- these are small proteins, such as substance P, that transmit pain these are small proteins, such as substance P, that transmit pain

signals, regulate vessel tone, and modulate vascular permeability. signals, regulate vessel tone, and modulate vascular permeability. Nerve fibers that secrete neuropeptides are especially prominent Nerve fibers that secrete neuropeptides are especially prominent in the lung and gastrointestinain the lung and gastrointestina

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Il. Il. Plasma Protein-Derived Mediators Plasma Protein-Derived Mediators

- Circulating proteins of three interrelated systems-the complement, - Circulating proteins of three interrelated systems-the complement, kinin, and coagulation systems-are involved in several aspects of kinin, and coagulation systems-are involved in several aspects of the inflammatory reaction.the inflammatory reaction.

I. The complement system: Consists of plasma proteins that Upon I. The complement system: Consists of plasma proteins that Upon activation, different complement proteins:activation, different complement proteins:

a. Coat (opsonize) particles for phagocytosis and destruction,a. Coat (opsonize) particles for phagocytosis and destruction,b. Contribute to the inflammatory response by increasing vascular b. Contribute to the inflammatory response by increasing vascular

permeability and leukocyte chemotaxis. permeability and leukocyte chemotaxis. c. Complement activation ultimately generates a porelike membrane c. Complement activation ultimately generates a porelike membrane

attack complex (MAC) that punches holes in the membranes of attack complex (MAC) that punches holes in the membranes of invading microbes. invading microbes.

- The complement-derived factors way contribute to a variety of - The complement-derived factors way contribute to a variety of phenomena in acute inflammation phenomena in acute inflammation

11. Vascular effects.. Vascular effects.

- C3a and C5a:- C3a and C5a:a. Increase vascular permeability a. Increase vascular permeability b. Cause vasodilation by inducing mast cells to release histamine b. Cause vasodilation by inducing mast cells to release histamine c. These complement products are also called anaphylatoxins c. These complement products are also called anaphylatoxins

because their actions mimic those of mast cells, which main because their actions mimic those of mast cells, which main cellular effectors of the severe allergic reaction called anaphylaxis cellular effectors of the severe allergic reaction called anaphylaxis

2. Leukocyte activation, adhesion, and chemotaxis.2. Leukocyte activation, adhesion, and chemotaxis. - C5a, and to lesser extent, C3a and C4a, activate leukocytes - C5a, and to lesser extent, C3a and C4a, activate leukocytes

increasing their adhesion to endothelium, and is a potent. increasing their adhesion to endothelium, and is a potent. chemotactic agent for neutrophils, monocytes, eosinophils, and chemotactic agent for neutrophils, monocytes, eosinophils, and basophilsbasophils

3. Phagocytosis.3. Phagocytosis.

- - When fixed to a microbial surface, C3b and its inactive proteolytic. When fixed to a microbial surface, C3b and its inactive proteolytic. neutrophils and macrophages, which express receptors for these neutrophils and macrophages, which express receptors for these complement products complement products

- Product iC3b act as opsonins, augmenting phagocytosis by- Product iC3b act as opsonins, augmenting phagocytosis by- The MAC, which is made up of multiple copies of the final - The MAC, which is made up of multiple copies of the final

omponent C9, kills some bacteria (especially thin-walled omponent C9, kills some bacteria (especially thin-walled eisseriaeisseria) ) by creating pores that disrupt osmotic balance.by creating pores that disrupt osmotic balance.

NOTENOTE

- The activation of complement is tightly controlled by cell-- The activation of complement is tightly controlled by cell-associated and circulating regulatory proteinsassociated and circulating regulatory proteins

- The presence of these inhibitors in host cell membranes protects - The presence of these inhibitors in host cell membranes protects normal cells from inappropriate damage during protective normal cells from inappropriate damage during protective

reactions against microbes reactions against microbes 8181

- Inherited deficiencies of these regulatory proteins lead to - Inherited deficiencies of these regulatory proteins lead to spontaneous complement activation: spontaneous complement activation:

1. A protein called 1. A protein called C1 inhibitorC1 inhibitor blocks activation of C1, and its blocks activation of C1, and its inherited deficiency causes a disease called inherited deficiency causes a disease called hereditary hereditary angioedemaangioedema, in which excessive to complement activation , in which excessive to complement activation results in edema in multiple tissues, including the larynx.results in edema in multiple tissues, including the larynx.

2. 2. decay-accelerating factordecay-accelerating factor (DAF) (DAF)- In a disease called - In a disease called paroxysmal nocturnal hemoglobinuria,paroxysmal nocturnal hemoglobinuria, there is there is

an acquired deficiency of DAF that results in complement-an acquired deficiency of DAF that results in complement-mediated lysis of red cells (which are more sensitive to lysis than mediated lysis of red cells (which are more sensitive to lysis than most nucleated cells)most nucleated cells)

3. Factor H3. Factor H : called the : called the hemolytic uremic syndromehemolytic uremic syndrome as well as as well as spontaneous vascular permeability in spontaneous vascular permeability in macular degenerationmacular degeneration of of the eye.the eye.

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Role of mediators in different reactions of Role of mediators in different reactions of inflammationinflammation

vasodilationvasodilation ProstaglandinsProstaglandins

Nitric oxideNitric oxide

histaminehistamine

Increased vascular permeabilityIncreased vascular permeability Histamine and serotoninHistamine and serotonin

C3a and C5aC3a and C5a

BradykininBradykinin

Leukotriens C, D4,E4Leukotriens C, D4,E4

Leukoyte recruitment and activationLeukoyte recruitment and activation TNF,IL-1TNF,IL-1

Chemokines(IL-8)Chemokines(IL-8)

C3a C5aC3a C5a

LTB4LTB4

Bacterial productsBacterial products

feverfever IL-1, TNFIL-1, TNF

Prostaglandin E2Prostaglandin E2

painpain Prostaglandins E2Prostaglandins E2

BradykininBradykinin

neurppeptidesneurppeptides

Tissue damageTissue damage Lysosomal enzymes of leukocytesLysosomal enzymes of leukocytes

Reactive oxygen speciesReactive oxygen species

Nitric oxideNitric oxide

B. Coagulation and Kinin Systems B. Coagulation and Kinin Systems - Hageman factor- Hageman factor (also known as (also known as factor XII of the intrinsic factor XII of the intrinsic

coagulation cascadecoagulation cascade) is synthesized by the liver circulating in an ) is synthesized by the liver circulating in an in an inactive form until it encounters collagen, or activated in an inactive form until it encounters collagen, or activated platelets (e.g., at a site of endothelial injury). platelets (e.g., at a site of endothelial injury).

- Activated Hageman factor (factor XIIa) initiates four systems that - Activated Hageman factor (factor XIIa) initiates four systems that may contribute to the inflammatory response: may contribute to the inflammatory response:

1. The kinin system 1. The kinin system 2. The clotting system2. The clotting system3. The fibrinolytic system,3. The fibrinolytic system,1. 1. Kinin systemKinin system- Its activation leads to the formation of bradykininand it causes- Its activation leads to the formation of bradykininand it causesa. Increased vascular permeabilitya. Increased vascular permeabilityb. Arteriolar dilationb. Arteriolar dilation 8484

c. Bronchial smooth muscle contractionc. Bronchial smooth muscle contractiond. It causes pain when injected into the skind. It causes pain when injected into the skinNote : Actions of bradykinin are short –lived because are it is rapidly Note : Actions of bradykinin are short –lived because are it is rapidly

degraded by kininases present in the plasma degraded by kininases present in the plasma2. Clotting system2. Clotting system- The proteolytic cascade leads to formation of thrombin , which - The proteolytic cascade leads to formation of thrombin , which

cleaves soluble fibrinogen to generate insoluble fibrin clotcleaves soluble fibrinogen to generate insoluble fibrin clota. Factor Xa: Causes increased vascular permeabilitya. Factor Xa: Causes increased vascular permeabilityB. Thrombin by binding to receptors on platelets and endothelial B. Thrombin by binding to receptors on platelets and endothelial

cells leads to activation of endothelial cells and enhance cells leads to activation of endothelial cells and enhance leukocyte adehesionleukocyte adehesion

3. Fibrinopeptides generated by thrombin cleavages of fibrinogen 3. Fibrinopeptides generated by thrombin cleavages of fibrinogen causes increased vascular permeability and are chemotactic causes increased vascular permeability and are chemotactic factors for leukocytesfactors for leukocytes

Anti-inflammatory Anti-inflammatory Mechanisms Mechanisms - - Inflammatory reactions subside because:Inflammatory reactions subside because:

a. Many of the mediators are short-lived and destroyed by a. Many of the mediators are short-lived and destroyed by degradative degradative enzymesenzymes..

b. here are several mechanisms that counteract inflammatory b. here are several mechanisms that counteract inflammatory mediators and function to limit or terminate the inflammatory mediators and function to limit or terminate the inflammatory response. response.

- a. Some of these, such as lipoxins, and complement regulatory - a. Some of these, such as lipoxins, and complement regulatory proteins proteins

b. IL-10: down-regulate the responses of activated macrophages, b. IL-10: down-regulate the responses of activated macrophages, thus providing a negative feedback loop. In a rare inherited thus providing a negative feedback loop. In a rare inherited disease in which IL-10 receptors are mutated, affected patients disease in which IL-10 receptors are mutated, affected patients develop severe colitis in infancy. develop severe colitis in infancy.

c..Other anti-inflammatory cytokines include:TGF-β and tyrosine c..Other anti-inflammatory cytokines include:TGF-β and tyrosine

CHRONIC INFLAMMATION CHRONIC INFLAMMATION - Is inflammation of prolonged duration (weeks to years) - Is inflammation of prolonged duration (weeks to years) - In which continuing inflammation, tissue injury, and healingby - In which continuing inflammation, tissue injury, and healingby

fibrosis, proceed simultaneously fibrosis, proceed simultaneously - In contrast with acute inflammation, which is distinguished by - In contrast with acute inflammation, which is distinguished by

vascular changes, edema, and a predominantly neutrophilic vascular changes, edema, and a predominantly neutrophilic infiltrate, chronic inflammation is characterized by a different set of infiltrate, chronic inflammation is characterized by a different set of reactions : reactions :

a. a. Infiltration with mononuclear cellsInfiltration with mononuclear cells,, including macrophages, including macrophages, lymphocytes, and plasma cellslymphocytes, and plasma cells

b. Repair involving new vessel formation and fibrosis b. Repair involving new vessel formation and fibrosis NoteNote: Acute inflammation may progress to chronic inflammation if the : Acute inflammation may progress to chronic inflammation if the

acute response cannot be resolved, either: acute response cannot be resolved, either:

a. Because of the persistence of the injurious agent a. Because of the persistence of the injurious agent b. Because of interference with the normal process of healing, - b. Because of interference with the normal process of healing, -

For example, a peptic ulcer of the duodenum initially shows acute For example, a peptic ulcer of the duodenum initially shows acute inflammation followed by the beginning stages of resolution inflammation followed by the beginning stages of resolution However, recurrent bouts of duodenal epithelial injury interrupt However, recurrent bouts of duodenal epithelial injury interrupt this process, resulting in a lesion characterized by both acute and this process, resulting in a lesion characterized by both acute and chronic inflammation.chronic inflammation.

c. Alternatively, some forms of injury (e.g., immunologic reactions, c. Alternatively, some forms of injury (e.g., immunologic reactions, some viral infections) engender a chronic inflammatory response some viral infections) engender a chronic inflammatory response from the outsetfrom the outset

- Chronic inflammation may arise in the following settings- Chronic inflammation may arise in the following settings:: 1. Persistent infections1. Persistent infections by microbes that are difficult to eradicate. by microbes that are difficult to eradicate. - These include - These include Mycobacterium tuberculosisMycobacterium tuberculosis, , Treponema pallidumTreponema pallidum

(cause syphilis), and certain viruses and fungi all of which(cause syphilis), and certain viruses and fungi all of which

tend to establish persistent infections and elicit a T lymphocyte-tend to establish persistent infections and elicit a T lymphocyte-mediated immune response called mediated immune response called delayed-type hypersensitivitydelayed-type hypersensitivity

2. Immune-mediated inflammatory diseases (hypersensitivity 2. Immune-mediated inflammatory diseases (hypersensitivity diseases:diseases: immune reactions develop immune reactions develop against the affected against the affected person's own tissues, leading to person's own tissues, leading to autoimmune diseases a autoimmune diseases a reaction reaction that results in tissue damage and persistent inflammationthat results in tissue damage and persistent inflammation

- Autoimmunity plays an important role in several common chronic - Autoimmunity plays an important role in several common chronic inflammatory diseases, such as rheumatoid arthritis and psoriasisinflammatory diseases, such as rheumatoid arthritis and psoriasis

- Immune responses against common environmental substances - Immune responses against common environmental substances are the cause of are the cause of allergic diseases,allergic diseases, such asbronchial asthma such asbronchial asthma

Note:Note:- Immune-mediated diseases may show morphologic patterns of - Immune-mediated diseases may show morphologic patterns of

mixed acute and chronic inflammation because mixed acute and chronic inflammation because they arethey are characterized by repeated boutscharacterized by repeated bouts of inflammation of inflammation

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- In most cases, the eliciting antigens cannot be eliminated, these - In most cases, the eliciting antigens cannot be eliminated, these disorders tend to be chronic and intractabledisorders tend to be chronic and intractable

3. Prolonged exposure to potentially toxic agents.3. Prolonged exposure to potentially toxic agents. a. Exogenous materials such as inhaled silica a. Exogenous materials such as inhaled silica b. Endogenous agents such as cholesterol which may contribute to b. Endogenous agents such as cholesterol which may contribute to

atherosclerosisatherosclerosis4. Mild forms of chronic inflammation may be important in the 4. Mild forms of chronic inflammation may be important in the

pathogenesis of many diseases that are not conventionally thought pathogenesis of many diseases that are not conventionally thought of as inflammatory disorders. Such diseases include as Alzheimer of as inflammatory disorders. Such diseases include as Alzheimer disease, atherosclerosis, type 2 diabetes.disease, atherosclerosis, type 2 diabetes.

Chronic Inflammatory Cells and MediatorsChronic Inflammatory Cells and Mediators

1. 1. MacrophagesMacrophages- Are the dominant cells of chronic inflammation- Are the dominant cells of chronic inflammation- Are tissue cells derived from circulating blood monocytes- Are tissue cells derived from circulating blood monocytes

after their emigration from the bloodstream. after their emigration from the bloodstream. - Are normally diffusely scattered in most connective tissues and - Are normally diffusely scattered in most connective tissues and

are also found in organs such as are also found in organs such as a. The liver ( called Kupffer a. The liver ( called Kupffer cells),cells),b. b. Spleen and lymph nodes (where they are called sinus histiocytes)Spleen and lymph nodes (where they are called sinus histiocytes)c. Central nervous system (microglial cells), c. Central nervous system (microglial cells), d. and lungs (alveolar macrophages) d. and lungs (alveolar macrophages) - Together these cells constitute the so-called - Together these cells constitute the so-called mononuclear mononuclear

phagocyte system,phagocyte system, also known by the older name of also known by the older name of reticuloendothelial systemreticuloendothelial system

- Macrophages act as filters for particulate matter, microbes as well - Macrophages act as filters for particulate matter, microbes as well as the effector cells that eliminate microbes in cellular and humoral as the effector cells that eliminate microbes in cellular and humoral immune responsesimmune responses

- Monocytes arise from precursors in the bone marrow and circulate - Monocytes arise from precursors in the bone marrow and circulate in the blood in the blood for only about a day and ufor only about a day and under the influence of nder the influence of adhesion molecules and chemokines, they migrate to a site of adhesion molecules and chemokines, they migrate to a site of injury within 24 to 48 hours after the onset of acute inflammation injury within 24 to 48 hours after the onset of acute inflammation

- When monocytes reach the extravascular tissue, they undergo - When monocytes reach the extravascular tissue, they undergo transformation into macrophages, which are somewhat larger and transformation into macrophages, which are somewhat larger and have a longer lifespan and a greater capacity for phagocytosis have a longer lifespan and a greater capacity for phagocytosis than do blood monocytes than do blood monocytes

- Two major pathways of macrophage activation- Two major pathways of macrophage activation 1. Classical macrophage activation:1. Classical macrophage activation:

- Is induced by microbial products such as endotoxin, by T cell-- Is induced by microbial products such as endotoxin, by T cell-derived signals mainly the cytokine IFN-γ, and by foreign derived signals mainly the cytokine IFN-γ, and by foreign substances including crystalssubstances including crystals

- Classically activated macrophages produce lysosomal enzymes, - Classically activated macrophages produce lysosomal enzymes, NO, and ROS, all of which enhance theirNO, and ROS, all of which enhance their ability to kill ingested ability to kill ingested organisms, and secrete cytokines that stimulate inflammation organisms, and secrete cytokines that stimulate inflammation

2. 2. Alternative macrophage activationAlternative macrophage activation

- - Is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, Is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes .produced by T lymphocytes .

- Alternatively activated macrophages are not actively microbicidal; - Alternatively activated macrophages are not actively microbicidal; instead, their role is in tissue repair. instead, their role is in tissue repair.

- So they secrete growth factors that promote angiogenesis, activate - So they secrete growth factors that promote angiogenesis, activate fibroblasts and stimulate collagen synthesisfibroblasts and stimulate collagen synthesis

NOTE:- In response to most injurious stimuli, macrophages are NOTE:- In response to most injurious stimuli, macrophages are initially activated by the classical pathway, designed to destroy theinitially activated by the classical pathway, designed to destroy the offending agents, and this is followed by alternative activation, offending agents, and this is followed by alternative activation, which initiates tissue repairwhich initiates tissue repair

- - Roles of macrophages includeRoles of macrophages include::1. Macrophages, similar to neutrophils, 1. Macrophages, similar to neutrophils, ingest and eliminate ingest and eliminate

microbes and dead tissuesmicrobes and dead tissues , because they respond to activating , because they respond to activating signals from T-lymphocytes , they are considered as the most signals from T-lymphocytes , they are considered as the most important phagocytes in the cell-mediated arm of adaptive immune important phagocytes in the cell-mediated arm of adaptive immune responsesresponses

2. Initiate the process of tissue repair and are involved in scar 2. Initiate the process of tissue repair and are involved in scar formation and fibrosisformation and fibrosis

3. 3. Secrete mediators of inflammationSecrete mediators of inflammation, such as cytokines (TNF, IL-1, , such as cytokines (TNF, IL-1, chemokines, and eicosanoids. These cells are therefore central to chemokines, and eicosanoids. These cells are therefore central to the initiation and propagation of all inflammatory responses.the initiation and propagation of all inflammatory responses.

4. 4. Display antigens Display antigens to T lymphocytes and respond to signals from T to T lymphocytes and respond to signals from T cells,cells, thus setting up a feedback loop that is essential for defense thus setting up a feedback loop that is essential for defense against many microbes by cell-mediated immune responses against many microbes by cell-mediated immune responses

B. Lymphocytes B. Lymphocytes

- Are mobilized in the setting of infections as well as non-immune-- Are mobilized in the setting of infections as well as non-immune-mediated inflammation ( due to ischemic necrosis or trauma), and mediated inflammation ( due to ischemic necrosis or trauma), and are the major drivers of inflammation in many autoimmune and are the major drivers of inflammation in many autoimmune and other chronic inflammatory diseases other chronic inflammatory diseases

- The activation of T and B lymphocytes is part of the adaptive - The activation of T and B lymphocytes is part of the adaptive immune response in infections and immunologic diseasesimmune response in infections and immunologic diseases

- In the tissues, B lymphocytes may develop into - In the tissues, B lymphocytes may develop into plasma cells,plasma cells, which which secrete antibodies, and CD4+ T lymphocytes are activated to secrete antibodies, and CD4+ T lymphocytes are activated to secrete cytokinessecrete cytokines

- Due to cytokine secretion, CD4+ T lymphocytes- Due to cytokine secretion, CD4+ T lymphocytes promote promote inflammation and influence the nature of the inflammatory reactioninflammation and influence the nature of the inflammatory reaction

- - There are three subsets of CD4+ helper T cells that secrete There are three subsets of CD4+ helper T cells that secrete

different sets of cytokines and elicit different types of inflammationdifferent sets of cytokines and elicit different types of inflammation1. T1. THH1 cells produce the cytokine IFN-γ, which activates.1 cells produce the cytokine IFN-γ, which activates. . .

macrophages in the classical pathway macrophages in the classical pathway 2. T2. THH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate 2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate

eosinophils and are responsible for the alternativeeosinophils and are responsible for the alternative--. pathway of . pathway of macrophage activationmacrophage activation

3. T3. THH17 cells secrete IL-17 and other cytokines that induce the 17 cells secrete IL-17 and other cytokines that induce the secretion of chemokines responsible for recruiting neutrophils and secretion of chemokines responsible for recruiting neutrophils and monocytes into the reaction. monocytes into the reaction.

- Both T- Both THH1 and T1 and THH17 cells are involved in defense against many 17 cells are involved in defense against many types of bacteria and viruses and in autoimmune diseasestypes of bacteria and viruses and in autoimmune diseases

- T- THH2 cells are important in defense against helminthic parasites and 2 cells are important in defense against helminthic parasites and in allergic inflammation.in allergic inflammation.

- Lymphocytes and macrophages interact in a bidirectional way, and- Lymphocytes and macrophages interact in a bidirectional way, and

so, they play an important role in propagating chronic inflammationso, they play an important role in propagating chronic inflammation- Macrophages display antigens to T cells, express membrane - Macrophages display antigens to T cells, express membrane

molecules and produce cytokines (IL-12 and others) that stimulate molecules and produce cytokines (IL-12 and others) that stimulate T cell responses and activated T lymphocytes, in turn, produce T cell responses and activated T lymphocytes, in turn, produce cytokines, which recruit and activate macrophages and thus cytokines, which recruit and activate macrophages and thus promote more antigen presentation and cytokine secretion, and promote more antigen presentation and cytokine secretion, and The result is a cycle of cellular reactions that fuel and sustain The result is a cycle of cellular reactions that fuel and sustain chronic inflammation. chronic inflammation.

Eosinophils:Eosinophils:

- Are characteristically in parasitic infections and as part of immune - Are characteristically in parasitic infections and as part of immune reactions mediated by IgE, ed with allergies.reactions mediated by IgE, ed with allergies.

- Their recruitment is driven by adhesion molecules similar to those - Their recruitment is driven by adhesion molecules similar to those used by neutrophils, and by specific chemokines (e.g., eotaxin) used by neutrophils, and by specific chemokines (e.g., eotaxin) derived from leukocytes and epithelial cellsderived from leukocytes and epithelial cells

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- Eosinophil granules contain major basic protein, a highly charged - Eosinophil granules contain major basic protein, a highly charged cationic protein that is toxic to parasites but also causes epithelial cationic protein that is toxic to parasites but also causes epithelial cell necrosis. cell necrosis.

D. Mast cellD. Mast cells:s:

- A- Are widely distributed in connective tissues throughout the bodyre widely distributed in connective tissues throughout the body- They can participate in both acute and chronic inflammatory - They can participate in both acute and chronic inflammatory

responses and important in allergic reactions),to environmental responses and important in allergic reactions),to environmental antigens.antigens.

NOTENOTE: : Although the presence of neutrophils is the hallmark of acute Although the presence of neutrophils is the hallmark of acute inflammation, many forms of chronic inflammation may continue to inflammation, many forms of chronic inflammation may continue to show extensive neutrophilic infiltrates,show extensive neutrophilic infiltrates, as a result of either as a result of either persistent microbes or necrotic cells, or mediators elaborated by persistent microbes or necrotic cells, or mediators elaborated by macrophages. Such inflammatory lesions are sometimes called macrophages. Such inflammatory lesions are sometimes called "acute on chronic"-for example, in inflammation of bones "acute on chronic"-for example, in inflammation of bones (osteomyelitis(osteomyelitis

Granulomatous inflammationGranulomatous inflammation- Is a distinctive pattern of chronic inflammation characterized by - Is a distinctive pattern of chronic inflammation characterized by

aggregates of activated macrophages with scattered lymphocytes. aggregates of activated macrophages with scattered lymphocytes. - Granulomas are characteristic of certain specific pathologic states;- Granulomas are characteristic of certain specific pathologic states;- Consequently, recognition of the granulomatous pattern is important - Consequently, recognition of the granulomatous pattern is important

because of the limited number of conditions (some life-threatening) because of the limited number of conditions (some life-threatening) that cause it and causes of granulomas are: that cause it and causes of granulomas are:

A. Infections: A. Infections: With persistent T-cell responses to certain microbes With persistent T-cell responses to certain microbes (such as(such as Mycobacterium tuberculosis, T. pallidum, Mycobacterium tuberculosis, T. pallidum, or fungi), and or fungi), and Tuberculosis is the prototype of a granulomatous disease caused Tuberculosis is the prototype of a granulomatous disease caused By infection and should always be excluded as the cause when By infection and should always be excluded as the cause when granulomas are identifiedgranulomas are identified

B. Immune mediated Inflammatory disorders like B. Immune mediated Inflammatory disorders like Crohn diseaseCrohn disease C. SarcoidosisC. Sarcoidosis: a disease of unknown etiology : a disease of unknown etiology

D. Foreign Bodies: D. Foreign Bodies: Granulomas in response to relatively inert foreign Granulomas in response to relatively inert foreign bodies ( suture, forming so-called bodies ( suture, forming so-called foreign body granulomasforeign body granulomas

NOTE:NOTE:- The formation of a granuloma effectively "walls off" the offending - The formation of a granuloma effectively "walls off" the offending agent and is therefore a useful defense mechanism agent and is therefore a useful defense mechanism

- Granuloma formation does not always lead to eradication of the - Granuloma formation does not always lead to eradication of the causal agent, which is frequently resistant to killing causal agent, which is frequently resistant to killing - Granulomatous inflammation with subsequent fibrosis may even be the - Granulomatous inflammation with subsequent fibrosis may even be the

major cause of organ dysfunction in some diseases, such as major cause of organ dysfunction in some diseases, such as tuberculosistuberculosis

MORPHOLOGY MORPHOLOGY :In the usual H&E preparations::In the usual H&E preparations:a. The activated macrophages in granulomas have pink, granular a. The activated macrophages in granulomas have pink, granular

cytoplasm with indistinct cell boundaries; called cytoplasm with indistinct cell boundaries; called epithelioid cellsepithelioid cells

b. The aggregates of epithelioid macrophages are surrounded by a collar b. The aggregates of epithelioid macrophages are surrounded by a collar of lymphocytes of lymphocytes

c. Older granulomas may have a rim of fibroblasts and connective c. Older granulomas may have a rim of fibroblasts and connective tissue tissue

d. Frequently, multinucleate d. Frequently, multinucleate giant cellsgiant cells 40 to 50μm in diameter are 40 to 50μm in diameter are found in granulomas.andSuch cells consist of a large mass of found in granulomas.andSuch cells consist of a large mass of cytoplasm and many nuclei, and they derive from the fusion of cytoplasm and many nuclei, and they derive from the fusion of multiple activated macrophagesmultiple activated macrophages

- In granulomas associated with certain infectious organisms - In granulomas associated with certain infectious organisms ( tubercle bacillus), a combination of hypoxia and free radical ( tubercle bacillus), a combination of hypoxia and free radical injury leads to a central zone of necrosis and injury leads to a central zone of necrosis and On gross On gross examination:examination: This has cheesy appearance called This has cheesy appearance called caseous caseous necrosisnecrosis

- The granulomas associated with Crohn disease, sarcoidosis, tend - The granulomas associated with Crohn disease, sarcoidosis, tend to be "noncaseating."to be "noncaseating."

GranulomaGranuloma

SYSTEMIC EFFECTS OF SYSTEMIC EFFECTS OF INFLAMMATION INFLAMMATION

Called the Called the acute-phase reaction,acute-phase reaction,

- - The cytokines TNF, IL-1, and IL-6 The cytokines TNF, IL-1, and IL-6 are the most important mediators of are the most important mediators of

the acute-phase reaction These the acute-phase reaction These cytokines are released systemically.cytokines are released systemically.

Note: Note: - TNF and IL-1 have similar biologic actions, although these may - TNF and IL-1 have similar biologic actions, although these may

differ in subtle ways .differ in subtle ways .- IL-6 stimulates the hepatic synthesis of a number of plasma - IL-6 stimulates the hepatic synthesis of a number of plasma

proteins. proteins. The acute-phase response consists of several clinical and pathologic The acute-phase response consists of several clinical and pathologic

changes:changes:a. Fevera. Fever,:,:- Characterized by an elevation of body temperature, - Characterized by an elevation of body temperature, - Is produced in response to substances called pyrogens that act by Is produced in response to substances called pyrogens that act by

stimulating prostaglandin synthesis in the vascular and stimulating prostaglandin synthesis in the vascular and perivascular cells of the hypothalamusperivascular cells of the hypothalamus

- Bacterial products, such as lipopolysaccharide (LPS) (called Bacterial products, such as lipopolysaccharide (LPS) (called exogenous pyrogensexogenous pyrogens), stimulate leukocytes to release cytokines), stimulate leukocytes to release cytokines

- - such as IL-1 and TNF (called such as IL-1 and TNF (called endogenous pyrogensendogenous pyrogens), which increase ), which increase the levels of cyclooxygenases that convert AA into prostaglandins. the levels of cyclooxygenases that convert AA into prostaglandins.

- In the hypothalamus the prostaglandins, especially PGE- In the hypothalamus the prostaglandins, especially PGE22, stimulate , stimulate the production of neurotransmitters, which function to reset the the production of neurotransmitters, which function to reset the temperature set point at a higher level temperature set point at a higher level

- NSAIDs, including aspirin, reduce fever by inhibiting NSAIDs, including aspirin, reduce fever by inhibiting cyclooxygenase and thus blocking prostaglandin synthesis cyclooxygenase and thus blocking prostaglandin synthesis

b. b. Elevated plasma levels of acute-phase proteins.Elevated plasma levels of acute-phase proteins. - These plasma proteins are mostly synthesized in the liver, and in These plasma proteins are mostly synthesized in the liver, and in

the setting of acute inflammation, their concentrations may the setting of acute inflammation, their concentrations may increase several hundred-foldincrease several hundred-fold

Three of the best known of these proteins are :Three of the best known of these proteins are :1. C-reactive protein (CRP)1. C-reactive protein (CRP)2. Fibrinogen, 2. Fibrinogen, 3. Serum amyloid A (SAA) protein 3. Serum amyloid A (SAA) protein

- Synthesis of these molecules by hepatocytes is stimulated by - Synthesis of these molecules by hepatocytes is stimulated by cytokines, especially IL-6cytokines, especially IL-6

- CRP and SAA, bind to microbial cell walls, and they may act as - CRP and SAA, bind to microbial cell walls, and they may act as opsonins and fix complement, thus promoting the elimination of opsonins and fix complement, thus promoting the elimination of the microbes the microbes

- Fibrinogen binds to erythrocytes and causes them to form stacks - Fibrinogen binds to erythrocytes and causes them to form stacks (rouleaux) that sediment more rapidly at unit gravity than (rouleaux) that sediment more rapidly at unit gravity than individual erythrocytes and this is the basis for measuring the individual erythrocytes and this is the basis for measuring the erythrocyte sedimentation rate (ESR) as a erythrocyte sedimentation rate (ESR) as a - - simple test for the simple test for the systemic inflammatory response, caused by any number of systemic inflammatory response, caused by any number of stimuli, including LPS stimuli, including LPS

- Serial measurements of ESR and CRP are used to assess - Serial measurements of ESR and CRP are used to assess therapeutic responses in patients with inflammatory disorders therapeutic responses in patients with inflammatory disorders such as rheumatoid arthritis. such as rheumatoid arthritis.

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- Elevated serum levels of CRP are now used as a marker for - Elevated serum levels of CRP are now used as a marker for increased risk of myocardial infarction or stroke in patients with increased risk of myocardial infarction or stroke in patients with atherosclerotic vascular disease. It is believed that inflammation atherosclerotic vascular disease. It is believed that inflammation is involved in the development of atherosclerosis , and increased is involved in the development of atherosclerosis , and increased CRP is a measure of inflammation.CRP is a measure of inflammation.

c. Leukocytosisc. Leukocytosis::- - Is a common feature of inflammatory reactions, especially those Is a common feature of inflammatory reactions, especially those

induced by bacterial infection induced by bacterial infection - The leukocyte count usually climbs to 15,000 to 20,000 cells/mL, - The leukocyte count usually climbs to 15,000 to 20,000 cells/mL,

but in some extraordinary cases it may reach 40,000 to 100,000 but in some extraordinary cases it may reach 40,000 to 100,000 cells/mL. cells/mL.

- These extreme elevations are referred to as - These extreme elevations are referred to as leukemoid reactionsleukemoid reactions - The leukocytosis occurs initially because of accelerated release - The leukocytosis occurs initially because of accelerated release

of cells (under the influence of cytokines, including TNF and IL-1) of cells (under the influence of cytokines, including TNF and IL-1) from the bone marrow postmitotic reserve poolfrom the bone marrow postmitotic reserve pool. .

- Prolonged infection also stimulates production of colony-stimulating- Prolonged infection also stimulates production of colony-stimulating factors (CSFs), which increase the bone marrow output of factors (CSFs), which increase the bone marrow output of leukocytes, thus compensating for the consumption of these cells inleukocytes, thus compensating for the consumption of these cells in the inflammatory reactionthe inflammatory reaction- Most bacterial infections induce an increase in the blood neutrophil - Most bacterial infections induce an increase in the blood neutrophil

count, called neutrophiliacount, called neutrophilia- Viral infections, such as infectious mononucleosis, mumps - Viral infections, such as infectious mononucleosis, mumps

associated with increase numbers of lymphocytes associated with increase numbers of lymphocytes (lymphocytosis).(lymphocytosis).

- Bronchial asthma and parasite infestations all involve an increase - Bronchial asthma and parasite infestations all involve an increase in the absolute number of eosinophils, creating an eosinophiliain the absolute number of eosinophils, creating an eosinophilia

- Typhoid fever , rickettsiae, and certain protozoa) are associated - Typhoid fever , rickettsiae, and certain protozoa) are associated with a decreased number of circulating white cells (leukopenia)with a decreased number of circulating white cells (leukopenia)

- Rigors (shivering)and chills Chills (perception of being cold - Rigors (shivering)and chills Chills (perception of being cold