Acute and Chronic Inflammation

DR. RENA NORMASARI

OVERVIEW OF INFLAMMATION Inflammation is a protective response against

pathogens To eliminate the initial cause of cell injury Then sets into motion the events that eventually heal and repair the sites of injury As the injurious agent is eliminated and antiinflammatory mechanisms become active If the injurious agent cannot be quickly eliminated, the result may be chronic inflammation.

Cardinal signs heat (calor), redness (rubor), swelling (tumor)

pain (dolor) loss of function (functio laesa),

ACUTE INFLAMMATION Rapid response to injury Lasting from a few minutes to as long as a few days Characterized by fluid and plasma protein exudation

and a predominantly neutrophilic leukocyte accumulation.

Acute inflammation has two major components: Vascular changes: Vasodilation Increased vascular permeability

Cellular events: Cellular recruitment and activation

Stimuli for Acute Inflammation Infections (bacterial, viral, fungal, parasitic) Trauma (blunt and penetrating) and physical and

chemical agents (thermal injury, e.g., burns or frostbite; irradiation) Tissue necrosis Foreign bodies (splinters, dirt, sutures) Immune reactions

Vascular Changes Arteriolar vasodilation occurs, increased blood flow Redness (erythema) and warmth characteristically seen in acute inflammation.

Increased vascular permeability protein-rich fluid moves into the extravascular tissues. increasing blood viscosity and slowing the circulation. Slowly flowing blood, stasis

Leukocytes begin to accumulate along the vascular

endothelial surface, margination.

In the early phase of inflammation, rise in intravascular hydrostatic pressure, movement of fluid from capillaries into the tissues

This fluid, called a transudate Increasing vascular permeability,movement of

protein-rich fluid and even cells (called an exudate) Reduces the intravascular osmotic pressure and increases the osmotic pressure of the interstitial fluid.

The net result is outflow of water and ions into the

extravascular tissues. Fluid accumulation in extravascular spaces is called edema; the fluid may be a transudate or exudate. Whereas exudates are typical of inflammation, transudates accumulate in various noninflammatory conditions

Normal homeostasis

Edema

Responses of Lymphatic Vessels Lymphatics also participate in the response. In inflammation, lymph flow is increased and helps

drain edema fluid from the extravascular space. Leukocytes and cell debris may also find their way into lymph. In severe inflammatory reactions, especially to microbes, the lymphatics may transport the offending agent.

Cellular Events: Leukocyte Recruitment and Activation To deliver leukocytes to the site of injury and to

activate them. Once activated, they may induce tissue damage and prolong inflammation Recruited and activated only when needed

Leukocyte RecruitmentThe sequence of events in the recruitment of leukocytes (1) margination, adhesion to endothelium, and rolling along the vessel wall; (2) firm adhesion to the endothelium; (3) transmigration between endothelial cells; and (4) migration in interstitial tissues toward a chemotactic stimulus

Margination and Rolling Leukocytes are pushed out, interact with lining

endothelial cells. This process of leukocyte accumulation at the periphery of vessels is called margination. Subsequently, leukocytes tumble on the endothelial surface, transiently sticking along the way, a process called rolling.

The weak and transient adhesions involved in rolling

are mediated by the selectin family of adhesion molecules Selectins are receptors expressed on leukocytes and endothelium The three members of this family are

E-selectin (also called CD62E), expressed on endothelial cells; P-selectin (CD62P), present on endothelium and platelets; and L-selectin (CD62L), on the surface of most leukocytes.

Adhesion and Transmigration The next step is firm adhesion to endothelial

surfaces. This adhesion is mediated by integrins expressed on leukocyte cell surfaces Integrins are normally expressed on leukocyte plasma membranes in a low-affinity form

Chemokines are chemoattractant cytokines secreted by many cells at sites of inflammation and are displayed bound to proteoglycans on the endothelial surface.

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

activate endothelial cells to increase their expression of ligands for integrins. Leukocytes migrate through the vessel wall primarily by squeezing between cells at intercellular junctions, diapedesis

Chemotaxis Leukocytes migrate toward sites of infection or

injury along a chemical gradient by a process called chemotaxis Both exogenous and endogenous substances can be chemotactic for leukocytes, including(1) bacterial products (2) cytokines (3) components of the complement system (4) products of the lipoxygenase pathway of arachidonic acid (AA) metabolism

In most forms of acute inflammation, neutrophils

predominate in the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours Neutrophils are more numerous in the blood They respond more rapidly to chemokines

Neutrophils are short-lived-they die by apoptosis

and disappear within 24 to 48 hours-while monocytes survive longer. There are exceptions:

In certain infections (e.g., those caused by Pseudomonas organisms) the cellular infiltrate is dominated by continuously recruited neutrophils for several days; in viral infections lymphocytes may be the first cells to arrive; and in some hypersensitivity reactions eosinophilic granulocytes may be the main cell type.

Leukocyte Activation Stimuli for activation include microbes, products of

necrotic cells, and several mediators Leukocytes express on their surface different kinds of receptors that sense the presence of microbes.

These include Toll-like receptors (TLRs), which recognize endotoxin (LPS) and many other bacterial and viral products; Seven-transmembrane G-protein-coupled receptors, which recognize certain bacterial peptides and mediators produced in response to microbes

Leukocyte activation results in many enhanced functions: Phagocytosis of particles, Production of substances that destroy phagocytosed microbes and remove dead tissues

These leukocyte products include lysosomal enzymes and reactive oxygen and nitrogen species.

PhagocytosisPhagocytosis consists of three distinct but interrelated steps (1) recognition and attachment of the particle to the ingesting leukocyte; (2) engulfment, with subsequent formation of a phagocytic vacuole; and (3) killing and degradation of the ingested material.

Leukocytes bind and ingest most microorganisms

and dead cells via specific surface receptors Recognize either components of the microbes and dead cells, or host proteins, called opsonins The most important opsonins are

IgG class that bind to microbial surface antigens, breakdown products of the complement protein C3 Plasma carbohydrate-binding lectins called collectins

Binding of opsonized particles triggers engulfment; In engulfment, pseudopods are extended around the

object, eventually forming a phagocytic vacuole. The membrane of the vacuole then fuses with the membrane of a lysosomal granule, resulting in discharge of the granule's contents into the phagolysosome.

Killing and Degradation of Microbes The most important microbicidal substances are

reactive oxygen species (ROS) and lysosomal enzymes. Phagocytosis stimulates an oxidative burst

a sudden increase in oxygen consumption, glycogen catabolism (glycogenolysis), increased glucose oxidation, and production of ROS.

Rapid activation of a leukocyte NADPH oxidase

(phagocyte oxidase), which

oxidizes NADPH (reduced nicotinamide adenine dinucleotide phosphate) and, in the process, converts oxygen to superoxide ion Superoxide is then converted by spontaneous dismutation into hydrogen peroxide (H2O2)

These ROS act as free radicals and destroy microbes Lysosomes of neutrophils contain the enzyme

myeloperoxidase (MPO), and in the presence of a halide such as Cl-, MPO converts H2O2 to HOCl (hypochlorous radical). HOCl is a powerful oxidant and antimicrobial agent

After the oxygen burst, H2O2 is eventually broken

down to water and O2 by the actions of catalase Reactive nitrogen species, particularly NO, act in the same way as ROS. The dead microorganisms are then degraded by the action of lysosomal acid hydrolases

Several other constituents of leukocyte granules are capable of killing infectious pathogens

bactericidal permeability-increasing protein (causing phospholipase activation and membrane phospholipid degradation), lysozyme (causing degradation of bacterial coat oligosaccharides), major basic protein (an important eosinophil granule constituent that is cytotoxic for parasites), and defensins (peptides that kill microbes by creating holes in their membranes).

Leukocyte-Induced Tissue Injury

Lysosomal enzymes are released into the

extracellular space during phagocytosis

causing cell injury and matrix degradation

Activated leukocytes release reactive oxygen species

and products of arachidonic acid metabolism

can injure tissue and endothelial cells

Defects in Leukocyte Function Acquired and inherited Lead to increased susceptibility to infections, which

may be recurrent and life-threatening The most common causes of defective inflammation

bone marrow suppression caused by tumors and chemotherapy or radiation and metabolic diseases such as diabetes (causing abnormal leukocyte functions).

Defects in leukocyte adhesion. In leukocyte adhesion deficiency type 1 (LAD-1), impaired leukocyte adhesion to and migration through endothelium, and defective phagocytosis and generation of an oxidative burst. Leukocyte adhesion deficiency type 2 (LAD-2) is caused by a defect in binds to selectins on activated endothelium.

Defects in microbicidal activity. chronic granulomatous disease engulfment of bacteria does not result in activation of oxygendependent killing mechanisms the microbes are surrounded by activated macrophages, forming the "granulomas" Defects in phagolysosome formation. Chdiak-Higashi syndrome, is an autosomal recessive disease, impairing the fusion of lysosomes with phagosomes.

Outcome Resolution.

no or minimal tissue damage, capable of replacing any irreversibly injured cells, decay or enzymatic degradation of the various chemical mediators, normalization of vascular permeability, and cessation of leukocyte emigrat

Termination of the acute inflammatory response

Leukocytes begin to produce mediators that inhibit

inflammation Efforts of lymphatic drainage and macrophage ingestion of necrotic debris

Progression to chronic inflammation may follow acute inflammation if the offending agent is not removed.

Scarring or fibrosis substantial tissue destruction or when inflammation occurs in tissues that do not regenerate Abscesses may form in the setting of extensive neutrophilic infiltrates or in certain bacterial or fungal infections (pyogenic).

MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION Serous inflammation characterized by the outpouring of a watery, relatively proteinpoor fluid derives either from the serum or from the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities. Fluid in a serous cavity is called an effusion.

Fibrinous inflammation occurs as a consequence of more severe injuries, A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura

Suppurative (purulent) inflammation the presence of large amounts of purulent exudate (pus) consisting of neutrophils, necrotic cells, and edema fluid. Abscesses are focal collections of pus that may be caused by seeding of pyogenic organisms into a tissue or by secondary infections of necrotic foci. Ulcer a local defect, or excavation, of the surface of an organ or tissue inflammatory necrosis of the mucosa of the mouth, stomach, intestines, or genitourinary tract; and tissue necrosis and subcutaneous inflammation of the lower extremities

CHEMICAL MEDIATORS OF INFLAMMATION Mediators may be produced locally or circulating in

the plasma Most mediators induce their effects by binding to specific receptors on target cells Mediators may stimulate target cells to release secondary effector molecules.

Cell-Derived Mediators Histamine produced by many cell types mast cells,circulating basophils and platelets. causes arteriolar dilation and increased vascular permeability after its release, histamine is inactivated by histaminase Serotonin effects similar to those of histamine. released during platelet aggregation

Arachidonic Acid (AA) Metabolites: Prostaglandins, Leukotrienes, and Lipoxins AA metabolites (eicosanoids) can mediate virtually

every step of inflammation released from these phospholipids via cellular phospholipases AA metabolism proceeds along one of two major enzymatic pathways:

Cyclooxygenase stimulates the synthesis of prostaglandins and thromboxanes, and lipoxygenase is responsible for production of leukotrienes and lipoxins

Cyclooxygenase pathway Products of this pathway include prostaglandin E2

(PGE2), PGD2, PGF2, PGI2 (prostacyclin), and thromboxane A2 (TXA2) platelets contain the enzyme thromboxane synthase, and hence TXA2,

a potent platelet-aggregating agent and vasoconstrictor

Endothelial cells, lack thromboxane synthase but

contain prostacyclin synthase (PGI2)

a vasodilator and a potent inhibitor of platelet aggregation.

Lipoxygenase pathway Is the predominant AA-metabolizing enzyme in

neutrophils. Leukotrien cause vasoconstriction, bronchospasm, and increased vascular permeability. lipoxins, inhibit neutrophil chemotaxis and adhesion to endothelium

Platelet-Activating Factor vasodilation and increased vascular permeability increased WBC adhesion (incr integrin binding) chemotaxis

platelet aggregation

Cytokines Mediators of inflammation and immune responses Molecularly characterized cytokines are called

interleukins major cytokines in acute inflammation are TNF and IL-1 a group of chemoattractant cytokines called chemokines Cytokines in chronic inflammation include interferon- (IFN-) and IL-12.

Tumor Necrosis Factor and Interleukin-1 TNF and IL-1 are produced by activated macrophages Their secretion is stimulated by microbial products,

such as bacterial endotoxin, immune complexes, and products of T lymphocytes The principal role of these cytokines in inflammation is in endothelial activation. Both TNF and IL-1 stimulate the expression of adhesion molecules on endothelial cells

Chemokines The chemokines are proteins that act primarily as

chemoattractants for different subsets of leukocytes. The two main functions of chemokines are in leukocyte recruitment in inflammation and in the normal anatomic organization of cells in lymphoid and other tissues. Chemokines also activate leukocytes

Reactive Oxygen Species ROS are synthesized via the NADPH oxidase

(phagocyte oxidase) pathway destroy phagocytosed microbes and necrotic cells When secreted at low levels, ROS can increase chemokine, cytokine, and adhesion molecule expression At higher levels, these mediators are responsible for tissue injury

Nitric Oxide NO is a short-lived, soluble, free-radical gas

produced by many cell types In the central nervous system it regulates neurotransmitter release Macrophages use it as a cytotoxic metabolite for killing microbes and tumor cells. When produced by endothelial cells cause smooth muscle relaxation and vasodilation.

NO plays many roles in inflammation including

(1) relaxation of vascular smooth muscle (vasodilation), (2) antagonism of all stages of platelet activation (adhesion, aggregation, and degranulation), (3) reduction of leukocyte recruitment at inflammatory sites, and (4) action as a microbicidal (cytotoxic) agent

Plasma Protein-Derived Mediators Complement present in plasma in inactive forms Vascular effects. C3a and C5a increase vascular permeability and cause vasodilation by inducing mast cells to release histamine Leukocyte activation, adhesion, and chemotaxis Coagulation proteins Activated factor XII triggers the clotting, kinin and complement cascades, and activates the fibrinolytic system Kinin system bradykinin causes increased vascular permeability, arteriolar dilation, and bronchial smooth muscle contraction

CHRONIC INFLAMMATION Inflammation of prolonged duration (weeks to

months to years) Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells Tissue destruction, largely induced by the products of the inflammatory cells Repair, involving new vessel proliferation (angiogenesis) and fibrosis

Chronic inflammation arises in the following settings Viral infection Persistent infections Immune-mediated inflammatory diseases (hypersensitivity diseases). Prolonged exposure to potentially toxic agents.

Chronic Inflammatory Cells and Mediators Macrophages from circulating blood monocytes liver (Kupffer cells), spleen and lymph nodes (sinus histiocytes), central nervous system (microglial cells), and lungs (alveolar macrophages). Together these cells comprise the so-called mononuclear phagocyte system, also known by the older name of reticuloendothelial system.

Lymphocytes Lymphocytes and macrophages play an important role in chronic inflammation Macrophages display antigens to T cells, express membrane molecules and produce cytokines (IL-12) that stimulate T-cell responses Activated T lymphocytes, produce cytokines Plasma cells develop from activated B lymphocytes and produce antibodies

Eosinophils found in inflammatory sites around parasitic infections or as part of immune reactions mediated by IgE (allergies). Mast cells Widely distributed in connective tissues throughout the body In atopic individuals (allergic reactions), mast cells are "armed" with IgE antibody specific for certain environmental antigens. release histamines and AA metabolites that elicit the early vascular changes of acute inflammation. IgE-armed mast cells are central players in allergic reactions, including anaphylactic shock

SYSTEMIC EFFECTS OF INFLAMMATION Viral illness Acute-phase reaction, or the systemic inflammatory

response syndrome TNF, IL-1, and IL-6

Several clinical and pathologic changes Fever is produced in response to substances called pyrogens Bacterial products, such as lipopolysaccharide (LPS; exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (endogenous pyrogens) increase the levels of cyclooxygenases that convert AA into prostaglandins. In the hypothalamus the PGs, especially PGE2, stimulate the production of neurotransmitters, which function to reset the temperature set point at a higher level.

Elevated plasma levels of acute-phase proteins C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) Synthesis of these molecules by hepatocytes is up-regulated by cytokines, especially IL-6. CRP and SAA, bind to microbial cell walls, and they may act as opsonins Fibrinogen binds to erythrocytes and causes them to form stacks (rouleaux)

Leukocytosis accelerated release of cells from the bone marrow (caused by cytokines, including TNF and IL-1) a rise in the number of more immature neutrophils in the blood (shift to the left). Most bacterial infections induce an increase in the blood neutrophil count, neutrophilia Viral infections, increased numbers of lymphocytes (lymphocytosis).

Bronchial asthma, hay fever, and parasite infestations all involve an increase in the absolute number of eosinophils, creating an eosinophilia. Certain infections, decreased number of circulating white cells (leukopenia), likely because of cytokine-induced sequestration of lymphocytes in lymph nodes.

How is the inflammation terminated? Vascular permeability/dilation is back to normal Edema fluid is drained into lymphatic vessels or by

macrophage pinocytosis Necrotic debris are engulfed by macrophages Phagocytosis by apoptotic neutrophils Removal of macrophages