Chapter 3 : Inflammation and Wound Healing

Figure 3.1

The sequence of events in the process of inflammation.

Figure 3.2

The five cardinal signs of acute inflammation.

Figure 3.3

Mast cell Fc receptor and degranulation. (A) Diagram of the high-affinity FcϵR on mast cells. The high-affinity FcϵR on mast cells (FcϵRI) is composed of six subunits (α1, α2, β1, β2, γ1, and γ2). The α subunits and β1 extend from the cell surface and bind to the CH2 and CH3 domains of the IgE molecule; the γ subunits (connected by a single disulfide bond) and the β2 subunit project through the cell membrane into the cytoplasm. (B) Postulated steps in mast cell degranulation. (1) Binding of antigen (allergen), cross-linking two IgE molecules on mast cell surface; (2) dimerization of IgE receptors; (3) alteration of methyltransferases; (4) conversion of membrane phospholipids to phosphatidylcholine; (5) opening of Ca²⁺ channel and influx of Ca²⁺ into cells; (6) activation of Ca²⁺-dependent protein phosphorylation; (7) enlargement of granules by protein kinases; (8) activation of phospholipase A₂ with formation of lysolecithin and arachidonic acid; (9) lysolecithin acts as “fusogen” causing granules to fuse with cell membranes with release of contents; (10) activation of granules is dependent on levels of cyclic AMP and cyclic GMP, which in turn are regulated by α- and β-adrenergic receptors (11).

Figure 3.4

Mast cell mediators and inflammation. (Modified from S. I. Wasserman and N. A. Solter, p. 192, in Advances in Allergy and Applied Immunology, Pergamon Press, Inc., Elmsford, N.Y., 1980.)

Figure 3.5

Arachidonic acid metabolism. (Modified from D. D. Metcalfe and M. Kaliner, p. 353, in J. J. Oppenheim, D. Rosenstreich, and M. Potter (ed.), Cellular Functions in Immunity and Inflammation, Elsevier Science Publishing, Inc., New York, N.Y., 1981.)

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Figure 3.6

General polypeptide structure of the integrins. Integrins are composed of two similar polypeptide chains (α and β) with an extracellular receptor for matrix proteins, a membrane domain, and a cytoplasmic “tail.” There is about 40 to 50% homology in amino acid sequence among the various α chains and among the three β chains but no homology between the α and β chains. The α subunit of each integrin has a matrix-binding domain, and binding to their respective ligands requires a divalent cation such as Ca²⁺ or Mg²⁺. About one-quarter of the β subunit consists of a repeating unit with a high cysteine content. Both subunits span the cell membrane and have a cytoplasmic COOH terminal that may provide a link between the extracellular matrix and the cytoskeleton. Phosphorylation of the cytoplasmic domain may regulate the binding functions of the receptors. The integrin phenotype expressed by a particular cell imparts specificity for binding to ligands on other cells or to different extracellular matrix components. (Modified from E. Ruoslahti, J. Clin. Investig. 87:1–5, 1991.)

Figure 3.7

Structure of selectin. Selectins have a similar overall structure: a cytoplasmic domain, a series of C3b-C4b-like domains, an EGF domain, and a lectin domain, and a signal peptide. L-selectin has only two C3b-C4b regulatory protein repeats; E-selectin has six, and P-selectin has nine. (Modified from B. I. Johnston, G. A. Bliss, P. J. Newman, and R. P. McEver, J. Biol. Chem. 265:21381, 1990.)

Figure 3.8

PMN-EC interactions during acute inflammation. Receptors on PMN interact with a series of cell adhesion molecules that are upregulated during the inflammatory process by mediators such as thrombin, histamine, IL-8, IL-1, and IFN.

Figure 3.9

Classical pathway of complement activation. Following reaction of antibody with antigen, a cascade reaction of complement components is activated. C1 functions as a recognition unit for the altered Fc of two IgG molecules or one IgM molecule; C2 and C4 act as an activation unit leading to cleavage of C3. C3 fragments have a number of biological activities: C3a is anaphylatoxin, and C3b is recognized by receptors on macrophages (opsonin). C3b also joins with fragments of C4 and C2 to form C3 convertase, which cleaves C5. C5 then reacts with C6 through C9 to form a membrane attack unit that produces a lesion in cell membranes, through which intracellular components may escape (lysis).

Figure 3.10

Details of the classical and alternate pathways of complement activation. For description, see text.

Figure 3.11

The binding and decay of C3.

Figure 3.12

The coagulation system and inflammation. Roman numerals designate the major components of the coagulation system; a roman numeral followed by the letter “a” indicates an active fragment of that factor. Coagulation is a cascading sequence of enzyme-driven activations. Coagulation products active in inflammation are fragments of Hageman factor (XIIa), thrombin (IIa), and fibrin split products. The coagulation system consists of three major parts: the extrinsic system, the intrinsic system, and the common thrombin-fibrin pathway. The extrinsic system is activated by the action of tissue thromboplastin on factor VII. The intrinsic system involves activation of a series of components beginning with factor XII (Hageman factor). The common pathway is the activation of factors X and V on platelets with the subsequent formation of thrombin and fibrin. Kallikrein, activated factor XI, and plasmin can all act to cleave activated factor XII to produce fragments that initiate fibrinolysis and kinin release and generate a plasma factor that enhances vascular permeability. Activated factor XII converts prekallikrein to kallikrein (see “The Kinin System” in the text) so that activation of the intrinsic coagulation system also generates inflammatory mediators.

Figure 3.13

Mechanism of the generalized Shwartzman reaction induced by endotoxin. The classic generalized Shwartzman reaction is elicited by giving rabbits two doses of endotoxin 24 h apart. The primary effect of the first (preparatory) dose of endotoxin is to cause release of platelet thromboplastin. Most of this thromboplastin is cleared by reticuloendothelial system (RES). Some thrombin triggers conversion of fibrinogen to fibrin, but again, most of this fibrin is cleared by the RES. If an animal is examined after one dose of endotoxin (preparative dose), a few fibrin thrombi are found in vessels of the liver, lungs, and spleen. These thrombi appear to be removed quickly by fibrinolysis, with no damage to the treated rabbit. However, because of the action of the RES in clearing thromboplastin and fibrin, blockade of the RES occurs. This blockade permits a second dose of endotoxin to produce severe intravascular coagulation. The second dose (provocative dose) initiates the same release of platelet thromboplastin as did the first dose, but with the RES blockaded, this thromboplastin is not cleared; most goes on to form thrombin and initiate conversion of fibrinogen to fibrin. This fibrin cannot be cleared by the blockaded RES, and most becomes lodged in capillaries, particularly capillaries of renal glomeruli. The fibrinolytic system may not be capable of overcoming large amounts of fibrin formed in a short period of time. The end result may be fatal renal cortical necrosis.

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Figure 3.14

The kinin system.

Figure 3.15

Interrelationships of inflammatory cells and systems in acute inflammation. Products of the complement, kinin, coagulation, and mast cell systems produce vasoactive and chemotactic mediators of acute inflammation. The major mediators are highlighted by boxes.

Figure 3.16

Adhesion and emigration cascade of lymphocytes during the early stages of chronic inflammation. The sequence includes four stages: (i) weak binding to endothelial cells through selectin molecules, (ii) an activation signal to upregulate integrin expression, (iii) strong integrin-mediated adhesion, and (iv) migration through the vessel wall. MIP-1β, a member of the intercrine family, increases the adhesiveness of the α₄β₁-integrin VLA-4 on CD8⁺ T_CTL cells to VCAM-1. HA, hyaluronate. (Modified from Y. Shimizu, W. Newman, Y. Tanaka, and S. Shaw, Immunol. Today 13:106, 1992.)

Figure 3.17

Phagocytosis. Foreign material is ingested into a phagosome. The phagosome fuses with a primary lysosome (formed by a Golgi body), which contains enzymes to digest ingested material. The resulting fusion vacuole is termed a secondary lysosome. When digestion is ended, some material may remain in the residual body or be eliminated from the cell by cell defecation. (Modified from C. de Duve, Sci. Am. 208:64, 1963.)

Figure 3.18

Schematic drawing of steps in phagocytosis. (1) Opsonization: aggregated Fc of antibody, activation of C3b. (2) Recognition through receptors and patching of receptors. (3) Ingestion: cation influx stimulates transduction of hexosemonophosphate shunt and conversion of O₂ to H₂O₂. (4) Fusion of lysosome and phagosome to form phagolysosome involving microtubules. (5) Digestion of bacteria in phagolysosome. (6) Exocytosis of remnants.

Figure 3.19

Nonspecific macrophage activation. Macrophages may acquire an increased capacity to destroy infective organisms or target cells after treatment with a variety of agents. BCG acts upon a T_DTH cell, which produces soluble factors that affect macrophages. Endotoxins and polynucleotides act directly on macrophages. The mechanism of action of these agents is not understood, but as a result of macrophage activation, a laboratory animal will resist a normally infectious challenge dose of an infectious agent.

Figure 3.20

Models of coreceptor (CCR5 and CXCR4) usage and inhibition of HIV binding by coreceptor ligands. Entry of M-tropic strains of HIV is blocked by CCR5 ligands MIP-1α, MIP-1β, and RANTES. Entry of T-tropic strains is blocked by the CXCR4 ligand SDF-1. (From A. S. Fauci, Nature 384:529, 1996.)

Figure 3.21

Apoptosis. Activation of the death signal may be mediated by growth factor withdrawal (reduction of Bcl-2 expression), DNA damage (p53 activation), metabolic alterations (lack of oxygen), or activation of specific death receptors by TNF or Fas ligand. Binding of the death receptor by ligand leads to trimerization of the receptor and binding of FSf ADD. The FADD-receptor complex is internalized, and in the cytosol FADD binds and activates caspase 8, initiating the caspase activation cascade. Caspase activation is amplified by granzyme B if the cell is targeted by T_CTL cells. The threshold of caspase activation is controlled by Bcl-2, which blocks activation and promotes cell survival. The activity of Bcl-2, in turn, is blocked by Bax, which forms inactive heterodimers with Bcl-2. Caspases cause DNA fragmentation (endonucleases), cell surface alterations (blebbing), and cytoskeletal reorganization (shrinking), leading to cell death and phagocytosis. (Modified from C. B. Thompson, p. 813–829, in W. E. Paul, ed., Fundamental Immunology, 4th ed., Lippincott-Raven, Philadelphia, Pa., 1999.)

Figure 3.22

Schematic model of binding of a cellular integrin and cell surface proteoglycan to the extracellular matrix. Both the α and β chains of the cell adhesion molecule integrin bind to the cytoskeleton and extend through the cell membrane to attach to proteoglycans in the extracellular matrix, involving Ca²⁺ and the RGD sequence. Cell surface proteoglycans, such as heparan sulfate/chrondroitin sulfate proteoglycan, bind to basic amino acid sequences in fibronectin through the heparan sulfate side chains. (Modified from E. Ruoslahti, J. Biol. Chem. 264:13369, 1989.)

Figure 3.23

Summary of the roles of mediators in the process of inflammation. PGE, prostaglandin E; PGD, prostaglandin D; VIP, vasoactive intestinal polypeptide; LTB, leukotriene B; LTD, leukotriene D; PAF, platelet-activating factor; IFN, interferon; IL-1, interleukin-1.