chapter 2 - inflammation

8/3/2019 Chapter 2 - Inflammation

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CHAPTER 2

Inflammation

I. INTRODUCTION

Inflammation is a vascular response to injury.

A. Proc esses

y Exudation of fluid from vesselsy Attraction of leukocytes to the injury. Leukocytes engulf and destroy

bacteria, tissue debris, and other particulate material.

y Activation of chemical mediatorsy Proteolytic degradation of extracellular debrisy Restoration of injured tissue to its normal structure and function.

This is limited by the extent of tissue destruction and by the

regenerative capacity of the specific tissue.

B . Cardinal signs

y Rubor (redness caused by dilation of vessels)y Dolor (pain due to increased pressure exerted by the accumulation of

interstitial fluid and to mediators such as bradykinin)

y Calor (heat caused by increased blood flow)y Tumor (swelling due to an extravascular accumulation of fluid)y

Functio laesa (loss of function)

C. Causes

y Infectiony Traumay Physical injury from thermal extremes or from ionizing radiationy Chemical injuryy Immunologic injuryy Tissue death. Inflammatory changes occur in viable tissue adjacent to

necrotic areas.

II. ACUTE INFLAMMATION

A. Adhesion molecules

y General considerations


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o Adhesion molecules play an important role in acuteinflammation.

o They are divided into three families: selectins,immunoglobulin-family adhesion proteins, and integrins.

y Selectinso These molecules are induced by the cytokines

interleukin-1 (IL-1) and tumor necrosis factor (TNF).

o L-selectins are expressed on neutrophils and bind toendothelial mucin-like molecules such as GlyCam-1.

o E- and P-selectins are expressed on endothelial cells and bindto oligosaccharides such as sialyl-Lewis X on the surface of

leukocytes. P -selectins, stored in endothelial Weibel-Palade

bodies and platelet alpha granules, relocate to the plasma

membrane after stimulation by mediators such as histamine

and thrombin.

y Immunoglobulin -family adhesion proteins o Intercellular adhesion molecules 1 and 2 (ICAM-1 and ICAM-

2) are expressed on endothelial cells and bind to integrin

molecules on leukocytes.

o Vascular cell adhesion molecules (VCAMs) similarly areexpressed on endothelial cells and bind to integrin molecules

on leukocytes.

y Integrins. Examples include leukocyte LFA-1, MAC-1, and VLA-4,which bind to endothelial immunoglobulin-family adhesion proteins.

B . Vasoactive changes

y These changes begin with a brief period of vasoconstriction, followedshortly by dilation of arterioles, capillaries, and postcapillary

venules.

y The resultant marked increase in blood flow to the affected area isclinically manifest by redness and increased warmth of the affected

area.

C. In creased capillary permeabili ty

y This results in leakage of proteinaceous fluid, which causes edema.


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y Causes include endothelial changes that vary from contraction ofendothelial cells in postcapillary venules, with widening of

interendothelial gaps, to major endothelial damage involving

arterioles, capillaries, and venules.

D . Types of inflammatory cells

y Neutrophils are the most prominent inflammatory cells in foci ofacute inflammation during the first 24 hours. Important causes of

neutrophilia (increased neutrophils in the peripheral blood) include

bacterial infections and other causes of acute inflammation, such as

infarction. The early release of neutrophils into the peripheral blood

in acute inflammation is from the bone marrow postmitotic reserve

pool. There is often an increase in the proportion of less mature cells

such as band neutrophils (Figure 2-1).

y After 23 days, neutrophils are replaced mainly by monocytes-macrophages, which are capable of engulfing larger particles, are

longer-lived, and are capable of dividing and proliferating within the

inflamed tissue. Important causes ofmonocytosis (i.e., increased

number of monocytes in the peripheral blood) include tuberculosis,

brucellosis, typhus, and salmonella infection.

y Lymphocytes are the most prominent inflammatory cells in manyviral infections and, along with monocytes-macrophages and plasma

cells, are the most prominent cells in chronic inflammation.

Lymphocytosis (i.e., an increased number of lymphocytes in the

peripheral blood) is most often caused by viral infections such as

influenza, mumps, rubella, and infectious mononucleosis and certain

bacterial infections such as whooping cough and tuberculosis.

y Eosinophils are the predominant inflammatory cells in allergicreactions and parasitic infestations. The most important causes of

eosinophilia include allergies such as asthma, hay fever, and hives

and also parasitic infections. Other causes include polyarteritis

nodosa and Hodgkin lymphoma.

y Mast cells and basophils are sources of histamine. Important causesof basophilia include chronic myelogenous leukemia and other

myeloproliferative diseases.


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E . Cellular response of leukocytes

y Emigration is the passage of inflammatory leukocytes between theendothelial cells into the adjacent interstitial tissue. Before

emigration, circulating leukocytes from the central blood flow move

toward the endothelial surface.

o Margination occurs as leukocytes localize to the outermargin of the blood flow adjacent to the vascular

endothelium.

o Pavementing occurs as leukocytes line the endothelial surface.o Rolling (or tumbling) is mediated by the action of endothelial

selectins loosely binding to leukocytes, producing a

characteristic "rolling" movement of the leukocytes along the

endothelial surface.o Adhesion occurs as leukocytes adhere to the endothelial

surface and is mediated by the interaction of integrins on

leukocytes binding to immunoglobulin-family adhesion

proteins on endothelium.

o Transmigration is the movement of leukocytes across theendothelium and is mediated by platelet endothelial cell

adhesion molecule-1 (PECAM-1) on both leukocytes and

endothelium.

y Chemotaxis o This is the process by which leukocytes are attracted to and

move toward an injury.

o Chemotaxis and other forms of cellular migration are measuredin an in vitro system (Boyden chamber technique) that assesses

the migration of cells from an upper chamber through a

microporous membrane to a lower chamber filled with a

chemoattractant.

o This process is mediated by diffusible chemical agents (Table2-1); movement of leukocytes occurs along a chemical

gradient.

o Chemotactic factors for neutrophils, produced at the site ofinjury, include:

Products from bacteria Complement components, especially C5a


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Arachidonic acid metabolites, especially leukotriene B 4 (LTB 4 ), hydroxyeicosatetraenoic acid (HETE), and

kallikrein

y Phagocytosis o Definition. Phagocytosis is the ingestion of particulate

material (e.g., tissue debris, living or dead bacteria, other

foreign cells) by phagocytic cells. Neutrophils and

monocytes -macrophages are the most important phagocytic

cells.

o Anatomic changes Phagocytosis is characterized morphologically

by internalization of the attached opsonized

particle by pseudopodial extensions from the

surface of the leukocyte, which enclose the

foreign particle, forming an internalized vesicle,

the phagosome.

Phagosomes fuse with cytoplasmic lysosomes and formphagolysosomes.

Phagolysosome formation is associated with leukocyticdegranulation.

o Opsonization This process facilitates phagocytosis. It is the coating

of particulate material by substances referred to as

opsonins, which immobilize the particles on the surface

of the phagocyte.

The most important opsonins are immunoglobulin G (IgG) subtypes and C3b, a complement component.

Fragments opsonized by IgG are bound to phagocyticcells by cell-surface receptors for the Fc portion of the

IgG molecule.

Fragments opsonized by C3b bind to cellular receptorsfor C3b.

y Intracellular microbial kill ing is mediated within phagocytic cells by oxygen-dependent and oxygen-independent mechanisms.

o Oxygen -dependent microbial killing is the most importantintracellular microbicidal process.


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Phagocytosis initiates activity of the hexosemonophosphate shunt, causing an oxidative burst and

supplying electrons to an NADPH oxidase in the

phagosomal membrane.

One of the products of the NADPH oxidase reaction issuperoxide anion (O 2

-), which is further converted to

hydrogen peroxide (H 2O2 ) by dismutation. H 2O2 may be

further converted to the activated hydroxyl radical

(OH).

In the presence of the leukocyte enzymemyeloperoxidase and a halide ion such as chloride,

H2 O2 oxidizes microbial proteins and disrupts cell

walls. This entire process is referred to as the

myeloperoxidase-halide system of bacterial killing.

o Oxygen - independent microbial killing This process is much less effective than oxygen-

dependent microbial killing.

This process is mediated by proteins, such as lysozyme,lactoferrin, major basic protein of eosinophils, and

cationic proteins, such as bactericidal permeability-

increasing protein and defensins.

table 2-1 Chemotactic Factors

Factor Description Chemotactic For

Formylated

peptides

Bacterial products ofEscherichia coli Neutrophils

C5a Activated complement component Neutrophils

HETE,

LTB4

Leukotrienes Neutrophils

Kallikrein Product of factor XIIa-mediatedconversion

of prekallikrein

Neutrophils

Fibrinogen Plasma protein Neutrophils


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PAF AGEPC; from basophils, mast cells, and

other cells

Eosinophils

PDGF From platelets, monocytes-macrophages,

smooth muscle cells, and endothelialcells

Neutrophils and macrophages

TGF- From platelets, neutrophils, macrophages,lymphocytes, and fibroblasts

Macrophages and fibroblasts

Fibronectin Extracellular matrix protein Fibroblasts and endothelial cells

PAF, platelet-activating factor; PDGF, platelet-derived growth factor; AGEPC, acetyl-glyceryl-ether phosphortransforming growth factor-.

F. Exogenous and endogenous mediators of acute inflammation

These mediators influence chemotaxis, vasomotor phenomena, vascular

permeability, pain, and other aspects of the inflammatory process (Table 2-

2).

y Exogenous mediators are most often of microbial origin(e.g., formylated peptides of Escherichia coli, which are

chemotactic for neutrophils).

y Endogenous mediators are of host origin.o Vasoactive amines

H istamine mediates the increase in capillarypermeability associated with the contraction of

endothelial cells in postcapillary venules that occurs

with mild injuries.

Histamine is liberated from basophils , mastcells , and platelets.

(b) Basophils and mast cells. Histamine isliberated by degranulation triggered by the

following stimuli:

Binding of specific antigen to basophiland mast cell membrane-bound IgE

(complement is not involved)


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Binding of complement fragments C3a andC5a, anaphylatoxins, to specific cell-

surface receptors on basophils and mast

cells (specific antigen and IgE antibodies

are not involved)

Physical stimuli such as heat and cold Cytokine IL-1 Factors from neutrophils, monocytes, and

platelets

Platelets. Histamine is liberated from plateletsby platelet aggregation and the release reaction,

which can be triggered by endothelial injury and

thrombosis or by platelet-activating factor (PAF).

PAF is derived from the granules ofbasophil s and mast cells and from

endothelial cells, macrophages,

neutrophils, and eosinophils. PAF is

acetyl-glyceryl-ether phosphorylcholine,

also known as AGEPC.

PAF activates and aggregates platelets,with the release of histamine and

serotonin; causes vasoactive and

bronchospastic effects; and activates

arachidonic acid metabolism.

Serotonin (5 -hydroxytryptamine) This substance acts similarly to histamine. It is derived from platelets. It is liberated from

platelets, along with histamine, during the

release reaction.

o Arachidonic acid metabolites. Phospholipase A2 stimulatesthe release of arachidonic acid from membrane phospholipids.

The metabolism of arachidonic acid proceeds along two

pathways:

The cyclooxygenase (cyclic endoperoxide) pathway iscatalyzed by two enzymic isoforms, referred to as

cyclooxygenase-1 (COX-1) and cyclooxygenase-2

(COX-2).


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This pathway is inhibited by aspirin andother anti-inflammatory drugs.

It yields thromboxanes and prostaglandins:thromboxane A2 (TxA2 ) in platelets , prostacyclin

(PGI2 ) in endothelial cells, and other

prostaglandins in other tissues.

Platelet TxA2 is a powerfulvasoconstrictor and platelet aggregant.

Endothelial PGI2 is a powerfulvasodilator and inhibitor of platelet

aggregation.

The lipoxygenase pathway yieldshydroperoxyeicosatetraenoic acid (HPETE) and its

derivatives, 12 -HPETE in platelets, and 5-HPETE and

15 -HPETE in leukocytes.

5 -HPETE in turn gives rise to HETE, achemotactic factor for neutrophils.

5 -HPETE also gives rise to leukotrienes: LTB 4, a chemotactic factor for neutrophils LTC 4, LTD4 , and LTE4 , potent

vasoconstrictors, bronchoconstrictors, and

mediators of increased capillary

permeability, which are sometimes jointly

referred to as the slow-reacting substance

of anaphylaxis

5 -HPETE also indirectly gives rise to l ipoxins.LXA4 and LXB 4 inhibit polymorphonuclear

neutrophils and eosinophils and also activate

monocytes and macrophages. It is proposed that

these lipoxins are involved in resolving

inflammation and are potential anti-inflammatory

mediators that may have therapeutic value.

o Cytokines. These soluble proteins are secreted by severaltypes of cells. They can act as effector molecules that

influence the behavior of other cells.


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Cytokines are mediators of immunologic response (e.g.,interferon- [produced by T cells and natural killer

cells] activates monocytes).

The cytokines IL-1 and TNF are secreted by monocytes-macrophages and other cells and have several effects on

inflammation.

IL-1 and TNF induce acute phase responses, such as Systemic effects of inflammation, including

fever and leukocytosis

Hepatic synthesis of acute phase proteins, suchas C-reactive protein, serum amyloidassociated

protein, complement components, fibrinogen,

prothrombin, 1-antitrypsin, 2-macroglobulin,

ferritin, and ceruloplasmin

Synthesis of adhesion molecules Neutrophil degranulation

IL-1 and TNF reduce the thromboresistant properties ofendothelium, thus promoting thrombosis.

o Kinin system. The kinin system is initiated by activatedHageman factor (factor XIIa). Factor XIIa also activates the

intrinsic pathway of coagulation and the plasminogen

(fibrinolytic) system. Activation of this system in turn

activates the complement cascade. Thus, factor XIIa links the

kinin, coagulation, plasminogen, and complement systems.

This system converts prekallikrein to kallikrein (achemotactic factor).

It results in the cleavage, by kallikrein, of high-molecular-weight kininogen t o bradykinin, which is a

peptide that is nine amino acids in length that mediates

vascular permeability, arteriolar dilation, and pain.

o Complement system. The complement system consists of agroup of plasma proteins that participate in immune lysis of

cells and play a significant role in inflammation.

C3a and C5a (anaphylatoxins) mediate degranulation ofbasophils and mast cells with the release of histamine.

C5a is chemotactic, mediates the release of histamine

from platelet-dense granules, induces expression of


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leukocyte adhesion molecules, and activates the

lipoxygenase pathway of arachidonic acid metabolism.

C3b is an opsonin. C5b -9 , the membrane attack complex, is a lytic agent

for bacteria and other cells.

o Nitric oxide (formerly known as endothelium-derived relaxingfactor)

This is produced by endothelial cells. It stimulates relaxation of smooth muscle, thus playing

a role in controlling vascular tone.

It inhibits platelet aggregation, contributing toendothelial thromboresistance.

G . Outcome of acute inflammation

y Resolution of tissue structure and function often occurs if theinjurious agent is eliminated.

y Tissue destruction and persistent acute inflammation o Abscess. This is a cavity filled with pus (neutrophils,

monocytes, and liquefied cellular debris).

It is often walled off by fibrous tissue and is relativelyinaccessible to the circulation.

It results from tissue destruction by lysosomal productsand other degradative enzymes.

It is usually caused by bacterial infections, often bystaphylococci.

o Ulcer This is the loss of surface epithelium. This can be caused by acute inflammation of epithelial

surfaces (e.g., peptic ulcer, ulcers of the skin).

o Fistula. This is an abnormal communication between twoorgans or between an organ and a surface.

o Scar. This is the final result of tissue destruction, withresultant distortion of structure and, in some cases, altered

function.

y Conversion to chronic inflammation


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o This change is marked by the replacement of neutrophils andmonocytes with lymphocytes, plasma cells, and macrophages.

o It often includes proliferation of fibroblasts and new vessels,with resultant scarring and distortion of architecture.

H. Hereditary defects that impair the acute inflammatory response

y Deficiency of complement components o This defect manifests clinically as increased susceptibility to

infection.

o Notable deficiencies include C2, C3, and C5.y Defects in neutrophils

o Chronic granulomatous disease of childhood This disease is most commonly an X - linked disorder

character ized b y deficient activity ofone of the

enzymes involved in NADPH oxidase activity and the

oxidative burst. Autosomal recessive variants also

occur.

The disease is marked by phagocytic cells that ingestbut do not kill certain microorganisms.

Catalase-positive organisms are ingested but notkilled. These organisms (e.g., Staphylococcus aureus)

can destroy H 2 O2 generated by bacterial metabolism.

Because enzyme-deficient neutrophils cannot produce

H2 O2 and bacterial H2O2 is destroyed by bacterial

catalase, H2 O2 is not available as a substrate for

myeloperoxidase. Thus, the myeloperoxidase-halide

system of bacterial killing fails.

Catalase-negative organisms are ingested and killed.These organisms (e.g., streptococci) produce sufficient

H2 O2 to permit oxygen-dependent microbicidal

mechanisms to proceed. In effect, the substrate for

myeloperoxidase is produced by the bacteria, and the

bacteria in a sense kill themselves.

o Myeloperoxidase deficiency This defect is rarely associated with recurrent bacterial

infections but often has little clinical consequence.


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In some instances, this defect has been associated witha marked increase in susceptibility to infections with

Candida albicans.

o Chdiak-Higashi syndrome This autosomal recessive disorder is characterized by

neutropenia, albinism, cranial and peripheral

neuropathy, and a tendency to develop repeated

infections.

It is marked by the presence of abnormal white bloodcells, which are characterized as follows:

Functionally, by abnormal microtubuleformation, affecting movement, with

impaired chemotaxis and migration

Morphologically, by large cytoplasmic granules(representing abnormal lysosomes) in

granulocytes, lymphocytes, and monocytes and

by large abnormal melanosomes in melanocytes,

all caused by impaired membrane fusion of

lysosomes

o Leukocyte adhesion deficiency (LAD) types 1 and 2 LAD type 1 deficiency is associated with recurrent

bacterial infections and is caused by deficiency of 2-

integrins.

LAD type 2 deficiency is also associated with recurrentbacterial infections and results from mutations in the

gene that codes for fucosyltransferase, required for the

synthesis of sialyl-Lewis X on neutrophils.

III. CHRONIC INFLAMMATION

A . General considerations

y Chronic inflammation can occur when the inciting injury is persistentor recurrent or when the inflammatory reaction is insufficient to

completely degrade the agent (e.g., bacteria, tissue debris, foreign

bodies) that incites the inflammatory reaction.

y It often occurs de novo, without a preceding acute inflammatoryreaction.


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y It occurs in two major patterns: chronic nonspecific inflammation andgranulomatous inflammation.

B . Chronic nonspecific inflammation (Figure 2-2)

y A cellular reaction with a preponderance ofmononuclear (round)cells (macrophages, lymphocytes, and plasma cells), often with a

proliferation of fibroblasts and new vessels. Scarring and

distortion of tissue architecture is characteristic.

y This type of inflammation is mediated by the interaction ofmonocytes-macrophages with lymphocytes.

y Monocytes are recruited from the circulation by variouschemotactic factors.

y Cytokines derived from monocytes-macrophages activatelymphocytes. The activated lymphocytes, in turn, are the source of

additional cytokines that activate monocytes-macrophages.

y B lymphocyte activation by macrophage-presented antigen results inthe formation of antibody-producing plasma cells.

table 2-2 Vasoactive Mediators

Activity Mediator

Vasoconstriction TxA2

LTC4, LTD4, LTE4

PAF

Vasodilation PGI2

PGD2, PGE2, PGF2

Bradykinin

PAF


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Nitric oxide

Increased vascular permeability Histamine

Serotonin

PGD2, PGE2, PGF2

LTC4, LTD4, LTE4

Bradykinin

PAF

LTC4, leukotriene C4; LTD4, leukotriene D4; LTE4, leukotriene E4; TxA2, thromboxane A2; PAF, platelet-activa

prostacyclin (prostaglandin I2); PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGF2, prostaglandin F2.

C. Granulomatous inflammation (Figures 2-3 and 2-4)

y This type of inflammation is characterized by granulomas, which arenodular collections of specialized macrophages referred to as

epithelioid cells. Granulomas are usually surrounded by a rim of

lymphocytes.

y Activation of macrophages by interactions with T lymphocytes isinvolved. Poorly digestible antigen is presented by macrophages to

CD4+ lymphocytes. Interaction with the antigen-specific T-cell

receptor of these cells triggers the release of cytokines (especially

interferon-), which mediate the transformation of monocytes and

macrophages to epithelioid cells and giant cells.

y Caseous necrosis is often characteristic (especially in tuberculosis),resulting from the killing of mycobacteria-laden macrophages by T

lymphocytes and possibly by cytokines or sensitized macrophages.

Noncaseating pulmonary granulomatous disease is caused most

often by sarcoidosis.

y The presence ofmultinucleated giant cells derived frommacrophages is also characteristic. The Langhans giant cell


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has nuclei arranged in a horseshoe-shaped pattern about the

periphery of the cell and is particularly characteristic of, but

not specific for, the granulomatous inflammation of

tuberculosis. The foreign body giant cell has scattered

nuclei.

y Granulomatous inflammation is the characteristic form ofinflammation associated with a number of diverse etiologic agents,

including:

o Infectious agents Mycobacterium tuberculosis and M. leprae B las tomyces derma ti tidis, Histoplasma capsulatum,

Coccidioides immitis, and many other fungi

Treponema pallidum The bacterium of cat-scratch disease

o Foreign bodies o Unknown etiology, including sarcoidosis

IV . TISSUE REPAIR

A. Restoration of normal structure.

This occurs when the connective tissue infrastructure remains relatively

intact. It requires that the surviving affected parenchymal cells have the

capacity to regenerate.

y Labile cellso These cells divide actively throughout life to replace lost

cells.

o They are capable of regeneration after injury.o They include cells of the epidermis and gastrointestinal

mucosa, cells lining the surface of the genitourinary tract, and

hematopoietic cells of the bone marrow.

y Stable cells o Characteristically, these cells undergo few divisions but are

capable of division when activated; that is, they can regenerate

from G0 cells when needed.

o They are also capable of regeneration following injury.o They include hepatocytes, renal tubular cells, parenchymal

cells of many glands, and numerous mesenchymal cells (e.g.,


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smooth muscle, cartilage, connective tissue, endothelium,

osteoblasts) .

y Permanent cells o These cells have been considered to be incapable of division

and regeneration (a view challenged by recent provocative new

evidence involving stem cells).

o They include neurons and myocardial cells.o They are replaced by scar tissue (typically fibrosis; gliosis in

the central nervous system) after irreversible injury and cell

loss.

B . Cellular proliferation.

This process is mediated by an assemblage of growth factors.

y Platelet -derived growth factor (PDGF ) is a competence factor thatpromotes the proliferative response of fibroblasts and smooth muscle

cells on concurrent stimulation by progression factors (e.g., other

growth factors). Indirectly in this manner, PDGF promotes the

synthesis of collagen.

o PDGF is synthesized by platelets and several other cells.o PDGF promotes the chemotactic migration of fibroblasts and

smooth muscle cells.

o PDGF is chemotactic for monocytes.o PDGF reacts with specific cell-surface receptors. Generally,

growth factor receptors are transmembrane proteins that

respond to ligand interaction by conformational changes that

induce tyrosine kinase activity in their intracellular domains.

y Epidermal g rowth factor (EGF) is a progression factor thatpromotes the growth of endothelial cells and fibroblasts, as well as

epithelial cells.

y Fibroblast growth factors (FGFs) promote the synthesis ofextracellular matrix protein (including fibronectin) by fibroblasts,

endothelial cells, monocytes, and other cells. Fibronectin is a

glycoprotein with the following characteristics:

o It is chemotactic for fibroblasts and endothelial cells.o It promotes angiogenesis (new vessel formation).


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o It links other extracellular matrix components (e.g., collagen,proteoglycans) and macromolecules (e.g., fibrin, heparin) to

cell-surface integrins. Integrins mediate interactions between

cells and extracellular matrix.

y Transforming growth factors (TGFs) o TGF- functions similarly to EGF.o TGF- is a growth inhibitor for many cell types and may aid

in modulating the repair process; it is also a chemotactic factor

for macrophages and fibroblasts.

y Macrophage-derived growth factors (IL-1 and TNF) promote theproliferation of fibroblasts, smooth muscle cells, and endothelial

cells.

C. The repair process

y Removal of debris begins in the early stages of inflammation and isinitiated by liquefaction and removal of dead cellular material and

other debris.

y Formation of granulation tissue o Granulation tissue is highly vascular, newly formed connective

tissue consisting ofcapillaries and fibroblasts; it fills defects

created by liquefaction of cellular debris.

o Granulation tissue is not related to granulomas orgranulomatous inflammation.

y Scarringo Collagen is produced by fibroblasts. As the amount of

collagen in granulation tissue progressively increases, the

tissue becomes gradually less vascular and less cellular.

o Progressive contraction of the wound also occurs, oftenresulting in a deformity of the original structure.

D. Factors that delay or impede repair

y Retention of debrisy Impaired circulationy Persistent infectiony Metabolic disorders, such as diabetes mellitus (associated with both

susceptibility to infection and impaired circulation)


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y Dietary deficiency of ascorbic acid or protein, which arerequired for collagen formation.

chapter 2 - inflammation

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