Mediators of inflammation

Mediators

of Inflammation

By Terry L. Moore and Terry D. Weiss

T

process involves a comHE inflammatory of many cellular and plex interaction humoral elements. The primary purpose of this system is to protect the host from infectious agents and other noxious substances. However, inflammation is often involved in tissue injury sustained in the course of many acute and chronic diseases. Indeed, it plays a central role in the pathogenesis of these illnesses. It is the purpose of this discussion to review the humoral elements of the inflammatory process to facilitate an understanding of their role in disease states. The elements of the humoral systems reviewed are listed in Table 1. COMPLEMENT

The complement system is the main effector pathway of the humoral immune response.’ The system is made up of 18 plasma proteins that interact to produce a variety of effects.*-’ The system can be divided into two parts: (I) the activation portion that includes the “classic” and “alternative” pathways, and (2) a single final common pathway.2.5 A firm grasp of nomenclature is essential to understanding the complement system. The protein members of the classical and final common pathways are called “components.” Each component is designated by the letter “C” followed by the number of the particular component.6 The alternative pathway members are called “factors” and are represented by capital letters.’ Low-molecular weight fragments resulting from cleavage or activation of components are designated by lower case letters. The loss of a defined activity by a protein, when not associated with an alteration in the primary polypeptide structure, is denoted by the letter “i” following the protein’s symbol. When a protein loses a defined activity unaccompanied by fragmentation, its symbol is preceded by “i.“’ The individual polypeptide chains of complement proteins are labeled by Greek letters.’ A bar over a component’s or factor’s symbol indicates it is enzymatically active.’ The abbreviations used for control proteins6 are described below.

Classical Pathway Activation Activation of the classical pathway involves six components (Table 2, Fig l).” The inciting agents are aggregated immunoglobulins or immune complexes. These contain at least one IgM or at least two IgGl, IgG2, or IgG3 molecules though IgG2 fixes complement only weakIY.~ The Clq subcomponent (Fig 1) binds to the Fc region of the immunoglobulin molecule in the second constant domain of IgG or the fourth constant domain of IgM. Binding stimulates internal proteolysis of Cl and converts it to the active enzyme Ci. ‘O,’’ The CT macromolecule is composed of three glycoprotein subunits, Clq, Clr, and Cls, conjoined by calcium ions.‘* Clq is a collagen-like protein with a hexameric structure having six globular heads attached to six fibrillar stalks.6,‘3,‘4 C 1q undergoes conformational changes on binding two critically spaced Fc regionsI This induces steric changes in the proenzyme C 1r that is thereby activated.16 Activated CE then converts Cls to activated CE by cleavage of a peptide bond to produce Ci esterase.16 Active Cis next cleaves the fourth component, C4, by hydrolyzing a peptide bond into C4b that continues the reaction, and C4a,” which recently has been shown to have anaphylatoxic activity.” C4b can bind transiently to immune complexes

From the Division of Rheumatology, Departments of Internal Medicine and Pediatrics-Adolescent Medicine. St Louis University School of Medicine, St Louis. Terry L. Moore, MD: Associate Professor of Internal Medicine and Pediatrics-Adolescem Medicine and Director, Division of Rheumatology; and Terry D. Weiss, MD: Associate Clinical Professor of Internal Medicine, St Louis University School of Medicine, St Louis. Supported in part by grants from the National Institutes of Health. a Research Career Development award from rhe NIADDK (AM-01036). the Easter Seal Research Foundation, and the McDonnell-Douglas Corporation of St Louis. Address reprint requests to Terry L. Moore, MD. St Louis University School of Medicine. Division of Rheumatology, Room R215, Doisy Hall, 1402 S Grand Boulevard, St Louis, MO 63104. 0 I985 by Grune & Stratton, Inc. 0049-0172/85/l 404-0004$5.00/O

Seminars in Arthritis andRheumatism, Vol 14, No 4 (May), 1985: pp 247-262

247

MOORE

248

Table

1.

Humoral

Mediators

of the

AND

WEISS

Inflammatory

ReSPOllse Complement

system

Classical

pathway

Alternative

pathway

Membrane

attack

Control

complex

proteins

Hageman

factor

Hageman

system

factor

K~mns Clotting

factors

Control

protems

TISSW

Ftg 1.

host cell-dewed

actwity

Eosinophil

factor

chemotactlc

factor

Prostaglandins Thromboxanes Leukotnenes

and to complement receptors on many types of cells,” or interact with C2a in the presence of magnesium.” Activated C Is also cleaves another glycoprotein, C2, into an active fragment C2a and a smaller fragment C2b.‘” This reaction is enhanced by C4b. The resultant C2a in the presence of magnesium forms activated C4b.2a. the classic pathway C3 convertase. There are three controls inhibiting activation of the classical pathway (Table 3). First. activated Clr and Cls activity is controlled by a neuroaminoglycoprotein Ci inactivator (CT-In) that binds to Clr and Cls, irreversibly blocking their activities.” -*’ CT-In also regulates the activation of Cl .12 The control of Cls blocks the further cleavage of C4 and C2. A congenital deficiency in functionally active CT-In produces the syndrome hereditary angioneurotic edema (HANE).2J The kinin-like activity generated in HANE plasma may be derived in part from C4a.” Second, activated C4b,2a convertase is not stable at 37 “C and will decay rapidly, releasing inactive iC2a. C4b remains and is capable of

Table

2.

Component Clq Clr Cls

Classical

Activation

Pathway

MOlC%Xk%

Electrophoret,c

Weoght

Mob,l,ty

Components

95,000

35

85,000

c2

117,000

c3

185,000

complement

pathway

Elements of the alternative pathway lncludc factors B, D, and properdin (P): control protcinh I and H: and C7 (Table 4. Fig 2). The alternative pathway is activated when the complex surface polysaccharides of bacteria or yeasts come into contact with serum. but initiation in the fluid phase is a spontaneous event occurring continuously.l”.l’ C‘3b that is bound to ;I cell mcmbranc or in the fluid phase has a labile binding site b! which it bind5 to polysaccharidcs or immun<,globulins.” C3b binds to B reversibly in the presence of magnesium. B is the altcrnatlvc pathway homologue of CL The binding of C3b to B exposes a peptide bond in B that can be clca\zd by 6.” 6 is an active enzyme that acts only on B complexed with C3b. This allows formation 01 B is cleaved with Bb the C3b.B complex.” remaining bound to C3b to form the labile amplification C3 convertase, C3b,Bb.‘? The proteo3.

Control

Proteins

Approximate 70

200,000

classical

regenerating C4b,2a convertase activity. “Third, control of C4b,2a convertase is further accom plishcd by cleaving C4b into two inactive fragments, C4c and C4d. This takes place through the cooperative effect of the C4 binding protein (C4BP)‘- and the C3b inactivator (I).” The efficient binding of C4BP to cell-bound ( 4b renders it more susceptible to the proteol>tic activity of I.“ “’ This binding of C‘3BP displaces C3a from hpecitic binding sites on C’4b and le;~d\ to allosteric changes of C4b.‘”

Table

400,000

c4

by the

complexes.

mediators

Histamine Platelet

Activation

by immune

35 400 25 1,500

COlltrOl PKXe1fl ci-In I H C4BP

MCJltXUl~~

of the

Complement

Pathway %“Kl Concentrat,ru

Weight

kg/mL!

105.000

180

90,000 150,000 1.200.000

50 400 250

249

MEDIATORS OF INFLAMMATION

Table 4.

Alternative

Activation

Pathway

Complement

Factors Serum

Approximate Factor

Molecular

Electrophoretlc

Concentration

Welaht

Mobilitv

kl/mL)

B

95,000

D

25,000

Yz

P

149,000

;

c3

185,000

4,

250 2 25 1,500

lytic site for C3 cleavage resides on Bb and can only be expressed bound to C3b. Bb may be rapidly released at 37 oC.35 This intrinsic control can be reversed by P, a gamma globulin.36 In solution, P binds to polymeric C3b. With surface-bound C3b, P binds to more than one C3b in close proximity.37 P binds to C3b and stabilizes C3b,Bb,C3b, retarding the release of Bb and extending the half-life of C3b.35*37 P is not required for activation, but it does protect C3b from inactivation. In certain patients with hypocomplementemic glomerulonephritis38 and partial lipodystrophy,” a factor, C3 nephritic factor (C3NeF), is found in their sera that causes C3 cleavage in normal human serum by activation of the alternative been shown that pathway.40 It has recently C3NeF is an IgG immunoglobulin.4’A3 C3NeF acts by binding to and stabilizing the alternative pathway convertases C3b,B and C3b,Bb,44 thus protecting the convertases from the effects of I and H.45 Recent data have also demonstrated a non-IgG C3 activating factor (C3AF) isolated from the serum of a patient with membranoproliferative glomerulonephritis. It has been shown that C3AF activates the alternative pathway by interfering with H function.46 The alternative pathway is regulated by two proteins: H(PIH) and I (Table 3). H mediates

the release of Bb from C3b.45 H is the cofactor for I cleavage of fluid-phase C3b.45*47 H also directly inhibits C3b and directly inhibits activity of the alternative pathway convertases, C3b,B and C3b,Bb,P.45 I with cofactor H mediates inactivation of C3b by proteolytically degrading C3b into C3c and C3d in the fluid-phase, whereas the cellular membrane complement receptor for C3b (immune adherence receptor) (CRl), is the cofactor for I cleavage of fixed iC3b into fixed C3d,g and fluid-phase C~C.~‘,~’ Whether C3d,g is broken down in vivo is not yet studies have shown that C3 clear.49 Further fragments resulting from activation and breakdown by I have four distinct binding sites for B, H, CRl, CR2 (C3d receptor), CR3 (C3d,g receptor), and conglutinin.50 However, I cannot inactivate C3b that is complexed with Bb in the whereas surface-bound C3b is fluid-phase46 somewhat digestible.45 Thus, both H and I must be present simultaneously to prevent spontaneous activation of the alternative pathway.5’ Membrane Attack Complex (MAC) The sequence, the final common pathway, begins through the cleavage of C3 to C3a and C3b by either of the C3 convertases (C4b,2a or C3b,Bb) (Table 5, Fig 3). The resultant C3b provides a binding site for C5 and makes it available for action of the C5 convertases.52 Only surface-bound C3b participates in C5 cleavage and C3b must be free of ligands. In the alternative pathway at least two C3b molecules are required, one to interact with B and form the convertase for cleaving and the other to react with C5 and support the cleavage reaction.6V53 The cleavage of C5 produces a large fragment, CSb, and the anaphylatoxin, C5a.54 C5b then interacts with C6 to form the stable complex C5b,6. C5a is rapidly converted to a peptide

Table 5. Terminal

Attack Complement

Sequence

Components Serum

Approximate M0lelXlZ3r

Comoonent

Ampllllcation Loop Activation end amplification Fig 2. tive complement pathway.

Bbl

loop of the alterna-

Weight

Electrophwetic

Concentration

Mobilitv

(ualmLI

c3

185,000

01

c5

200,000

8,

1,500 85

C6

128,000

;:

75

c7

121,000

C8

151,000

c9

80,000

55 Y (Y

55 200

250

MOORE

Table

6.

Biologic

Effect

Mediators

Complement BEM

(BEM)

AND

as Products

WEISS

of

Activation ACtlWty

C3a

Anaphylatoxln:

C3b

Cell receptors

,mmunosuppresswe (Immune

adherence:

opsonua

VXl! C3d C3b.

Cell receptors Bb

Chemotaxln

C4a

Anaphylatoxfn

C5a

Anaphylatown;

chemotaxin,

modulate

rrnrnw~t~

responses C5.6 Fig

3.

membrane

The

final

complement

pathway

with

7

Chemotaxr

subsequent

damage.

B in normal chic\ Zrg by carboxypeptidasc activity serum.” C5a+, Arg lacks anaphylatoxic and is ineffective as a chemotaxin unless it binds to an anionic peptide that promotes its chemotactic properties.‘h The CSb,6 complex may reversibly bind to C3b on the membrane.” In the presence of C7, it forms the trimolecular complex, C5b,6,7.‘X This complex has hydrophobic regions enabling it to insert into the cell membrane preparing it for hemolysis.59 C5b,6,7 decays rapidly if it does not encounter a membrane. The presence of C5b,6,7 on the membrane permits binding to C8 that is relatively hydrophobic.h” The final component to react is C9.h’ It is proposed that protein micelle formation occurs at the C5b,6,7 stage of assembly; dissociation of these micelles on binding of C8 facilitate the dimerization of C5b,6.7.8,9 and thus MAC formation.h2 The MAC may then mediate increased membrane permeability by protein channel formation in addition to lipid reorientation.“’ The MAC assembly includes the process of poly C9 formation and the typical ultrastructural mcmbrane lesions caused by complement are the image of poly C9 formed by membrane-bound C5b-8.h4 By-products

of the Complemrnt

Cascade

Complement activation produces a number of by-products that mediate the inflammatory process (Table 6). The cleavage fragments produced during activation may effect the target complex as a whole with opsonization and cytolysis. They may produce vascular permeability and migration of leukocytes into the area. Being chemotactic, they also promote leukocyte migration with the resultant possible release of lysosomal

cnqmex. Overall. 3 \ystcmatic etrcct iiu~ be generated. Changes in vascular permeability have been attributed to the cleavage of C4 and (‘2 b! (‘1, The formation of C3a with kinin-like activity might explain the edema associated with C I -In deficicncq .I’:“ (‘3b coated complexes ma\ be bound b! diil‘crcnt cells. nameI> crythrocytcs. neutrophils. monocytes. macrophages. and B lymphocytes that have C3b membrane reccpturx (CRI). The binding of C3b ma) result III enhanced phagocytosis. secretion. and dilt’erentiation.’ The rate and extent of phagocqtosih ot IgG-containing complexes are greatly incrcascd by the presence of C3b on the complex.h‘ Reccptars for C‘3d (CR?) are also present on human monocytes and B lymphocytes.“” The releaac 01‘ lysosomal enzymes by neutrophils appears tc~ bc mediated mainlk by Ig(;-containing immune complexes. but (‘3b may increase IgCi stimulation as well as increasing neutrophil oxidativc metabolism.“Fluid-phase C3b has allro been shown to stimulate release of lymphokines bk R Iymphoqtcs.“” C3b plays a central role in enhancing immune adherence and phagucyti)sis.“” The active enzyme C3b,Bb also has chemotactic properties.-” The IOU molecular weight cleavage prc)ducl\ of C3 and C5 are anaphylatoxic peptides. C’~:I-’ 7, and CSa. The) are capable of increasing va~ular permeability by inducing the secretion 01‘ histamine b> mast cells and basophils.” Both also stimulate smooth muscle contraction. Their anaphylatoxic activities are blocked by a magnesium dependent enzyme. carboxypcptidasc I%“ The C3a fragment has. also, b;en found to have immunosuppressive properties by acting on helper T cells.“ C3a can also inhibit T l>mph
251

MEDIATORS OF INFLAMMATION

chemotactic capabilities of C3a are questionable at this time.76 C5a is the primary chemotactic factor produced by the complement system.” It attracts neutrophils, monocytes, and eosinophils, and in high concentration induces secretion of neutrophi1 lysosomal enzymes.” When C5a is broken down it loses its anaphylatoxic activity, but retains the chemotactic properties by binding to an anionic peptide. C5a has also recently been shown to modulate both specific and nonspecific human immune responses.79 The in vitro action of C5a appears to involve helper T cells.79 The inactivated trimolecular complex C5,6,7, is chemotactic for neutrophils and eosinophils.” Hereditary Dejiciencies of Complement Deficiencies of the complement system provide experiments in nature that are instructive in the biologic significance of most of the complement components, factors, and inhibitors. Hereditary deficiencies have been described for all 11 of the classical components, factors B and P in the alternative pathway, and for the inhibitors CT-In, H, and I (Table 7).5,8’ These are briefly reviewed below. Two types of abnormalities of Clq have been reported including several cases of a complete absence of C 1q.82-84 One was a child with skin lesions and recurrent sepsis.82 The other cases have been patients with a lupus-like syndrome without the typical serologic findings.83,84 A patient has also been reported who had an abnormal C 1q gene. The gene codes for the production of an antigenically deficient, nonfunctioning molecule, and is expressed as a codominant allele.85 The child had a lupus-like syndrome with glomerulonephritis. The other report described two brothers with a functionally abnormal Clq that did not react with Clr or Cls or bind to the Fc regions of immunoglobulins.86 Multiple cases of Clr deficiency have been reported in three families.87~88 One patient had glomerulonephritis and the others had a lupuslike syndrome.87.88 A few cases have been reported with deficiencies of Cls, all with symptoms and serologic studies compatible with systemic lupus erythematosus (SLE).“.” Cases of a complete C4 deficiency have been described as a lupus-like syndrome9h92 but in only two patients was there serologic evidence of

Table 7. Diseases Associated Deficiencies Component

With Hereditary

of Complement Disease

Clq

Lupus-like syndrome; skin disease; sepsis;

Clr

Lupus-like syndrome; glomerulonephritis

Cls

SLE

c4

SLE

c2

None; SLE; discoid lupus; polymyositis;

glomerulonephritis

glomerulonephritis; Henoch-Scholeim purpura: vasculitis; JA c3

Lupus-like syndrome; recurrent bacterial in-

c5

None; Neisserial infections: SLE

fection C6

Neisserial infections: lupus-like syndrome

C7

Raynaud; Neisserial infections: lupus-like syn-

C6

SLE; Neisserial infections

c9

None

ci-1” I B

HANE; SLE; discoid lupus

P

Neisserial infections

H

Hemolytic-uremic syndrome

drome

Recurrent bacterial infections Recurrent bacterial infections

SLE.92 The C4 deficiency was inherited by a doubly deficient C4 haplotype from both parents in one patient” and in autosomal recessive mode in another.” The genes for the C4 molecule are limited to the major histocompatibility complex.” C2 is the most commonly described complement deficiency.” The prevalence of homozygous C2 deficiency has been estimated at one in 20,000 persons, while heterozygous C2 deficiency is found in 1% to 2%.93 It is inherited as an autosomal codominant. Multiple homozygous cases of C2 deficiency have been described with about 40% having no symptoms.” However, heterozygous C2 deficiency has been associated with many diseases, particularly patients with SLE and juvenile arthritis (JA).93 In SLE patients, it has been associated in particular with the presence of anti-R0 (SS-A) antibodies.94 C2 deficiency was the first component of complement to be linked to an HLA locus9’ and has subsequently been found to be in linkage dysequilibrium with HLA-A25 or HLA-AlO, B18, Dw2, and factor B.95-97 Multiple cases of C3 deficiency have been described. One family had four members with a lupus-like syndrome and vasculitis9’ Another family had two sisters with a lupus-like syndrome99 but both had negative serology for SLE.

252

Because C3 is pivotal in both the classical and alternative pathways, the deficiency has been associated with marked increased susceptibility to infection by encapsulated bacteria. A decreased number of leukocytes in areas of inflammation occurs with these infections.x’ This indicates a possible role for C3 in directing circulating WBCs.‘“” Many patients with C5 deficiency have had clinical and serologic findings compatible with SLE.“‘.‘“’ A study of a large kindred with a heritable deficiency of C5 showed that the deticiency may be present in healthy individuals but may also be associated with repeated gonococcemia.‘“’ Cases of C6 deficiency have been described. most with pedigrees compatible with an autosomal codominant inheritance. Affected patients suffer recurrent Neisseria infections.“‘4.‘“’ One patient had a lupus-like syndrome and was not unusually subject to infection.‘nh C7 deficiency has been associated with Raynaud phenomenon, sclerodactyly, and chronic meningococcemia presenting as vasculitis.“‘7.“‘X All have demonstrated a pattern of inheritance consistent with autosomal codominance.“‘” Patients with homozygous C8 deticiencics have been studied, some with SLE”” and the others with Neisseria infections.“” Recently. two forms of CS abnormalities have been noted. In the first, the serum of affected homozygotes lacks antigenic material reactive with antiserum to human C8 as well as C8 functional activity.“’ The patients are deficient in C8 cy-chains.“’ In the other form, the serum lacks C8 function.“’ It is deficient in the P-subunit of C8 and defines a second common genetic polymorphism in this protein.“’ C9 deficiency has been described in two patients who have had no symptoms of autoimmune disease or recurrent infections.“3,“J Family studies indicated the deficiency was inherited as an autosomal codominant allele.“‘The studies also have shown serum without C9 can kill Neisseria.“4 Thus, C5, C6, C7. and C8 deficiencies have been associated with recurrent or disseminated Neisseria infections, but not C9.‘li Relatives of patients with C5 through C8 deficiencies also have been associated with Neisserial infections. These associations indicate that the MAC and subsequent bacterial lysis has a

MOORE

AND

WEISS

critical role in host defcnsc. especially for Rleisseria infections.‘“” Cl-In deficiencies have been associated with HANE.‘j SLE with clinical and serologic manifestations has also been found associated with Cl-In deficiency.“” Two forms of c‘l -In deticiency have been recognized, both autosomal dominant. Eighty-five percent of patients have markedly reduced serum levels: but 15”; have normal or high levels of a dysfunctional (‘I-ln protein.Y’ These patients demonstrate lou lcvcls of c‘4 and CI! secondary to the spontaneous and unimpeded cleavage by C I .“’ Five cases of I deficiency have been described.“’ Four patients have had rcpeatcd bacterial infections and one was clinicall!, normal. Studies have shown an autosomal dominant transmission.“. Two patients with homojygoux H deficiency have been observed. one patient having a hemolytic-uremic syndrome.“’ On1y two defects have been noted in the altsrnatc pathway. Two patients have been reported who have had a partial deficiency of B resulting in ;I functional abnormalitv oF the ajternatlve pathway.‘“’ Both were also c:! deticient and had scvcre sqatcmic symptoms and bacteremia Three men in ;I large family have shown ;I selective deticiency of P with one dying of Nie~ascria meningitis.“”

Transplant studies have indicated that OO’+ 01‘ the circulating C?. c‘6. C8, and B arc \ynthcsiyed in the Iivcr.Y” Other studies suggest eutrahcpatic synthesis of Cl. C4. C?. (‘3. CS. B. ,lnd -I’/ D and indicate that local production 01‘ complement proteins by cells of the monocc_tcrnacrophage series may play a role in the initial phase of inflammation.“”

The complement proteins have hemolctlc capability. Therefore. the standard methods of measuring the total complement pathwa! 111 serum or synovial fluids is the CH50 or C‘H 100: ic. the ability for a test specimen to lyse 50”s or lOOR&of a standard suspension of sheep red blood cells (SRBCs) coated with rabbit antibody to SRBC.“? The CH50 or CHIOO is ;I useful screening procedure in trying to rule out ;I complement deficiency or to evaluate the amount

253

MEDIATORS OF INFLAMMATION

of complement fixation in a very ill patient with immune complex disease. Concentration of individual complement components may also be measured by hemolytic assays but these are usually only research tools.‘23 Routine testing is performed by immunodiffusion or nephelometry of the individual complement components, most often C3 or C4. Unfortunately, there are problems associated with these tests. Immunodiffusion has a range of error of approximately 10% and there are no international standards. Therefore, each laboratory must determine its own normal range and this range is usually rather wide. A base line level on a patient during a healthy period is important for interpretation of a test performed during illness. This is especially helpful if the latter result is in the normal range so that it might be distinguished as being depressed as compared to the base line level. C3 has a much wider range of normal concentration than C4. C4 is, therefore, more sensitive to minor episodes of complement activation.* For complement screening, C3 and C4 performed by nephelometry and total hemolytic activity by CH50 and CHlOO is recommended. HAGEMAN

FACTOR SYSTEM

Activation of the Hageman factor (HF) pathways result in kinin formation, stimulation of the intrinsic clotting system, fibrinolysis, and inflammatory reactions.‘24 These pathways involve four molecules: HF, high molecular weight kininogen (HMWK), prekallikrein, and factor XI (Fig 4).‘25 Activation of these systems occurs when these plasma proteins contact negatively charged particles such as silicon dioxide, dextran sulfate, and crystals of sodium urate and calcium pyro-

Fig 4.

Hageman factor pathways.

phosphate.‘26 Bacterial lipopolysaccharides and immune complexes have been implicated in the activation of HF.‘25 However, no specific combination of elements of connective tissue has been identified that would activate the systems.‘25 Hageman Factor At the center of the HF system is HF, a &globulin with a molecular weight of 80,000.‘27 Three different molecules, HF, prekallikrein, and HMWK, are assembled on a negatively charged surface to generate rapidly activated HF (HFa). The activation of HF occurs in two steps. The first consists of cleavage of HF by HFa (autodigestion)‘*’ or by kallikrein that yields the enzyme (H Fa) ‘29,‘30with a molecular weight of 80,000. HFa is composed of two chains, a heavy chain of 52,000 linked by a disulfide bond to a light chain of molecular weight 28,000.‘28 As autodigestion proceeds, HFa is further digested to a major active product of molecular weight 40,000, a minor product of 70,000 and HF fragment (HFf) that appears as two closely related molecular species of 28,000 and 30,000’3’ each of which has an active site.‘*’ HF digestion by kallikrein is more rapid, but the active species formed are greatly reduced.13’ They are mainly formed by autodigestion. The addition of HMWK increases the rate of HFa and HFf formation as well as the extent of the autodigestion.‘*’ Further studies have demonstrated that on reduction of HFf and the 40,000-dalton moiety each possesses a heavy chain of 28,000, but the 40,000-dalton enzyme has a light chain of 15,000; whereas, the 30,000 dalton-form of HFf has a light chain of 2,000.‘32 These data indicate that digestion of native HF to form HFa precedes formation of any of the activated forms of HF and demonstrate that HFf is a two-chain enzyme.13* The plasma enzyme primarily responsible for cleavage and activation of HF in the solid fluid phase is plasma kallikrein.‘33 Activation by kallikrein occurs more rapidly than autodigestion.‘** The active products are almost exclusively HFa and HFf; however, in prekallikrein-deficient plasma the active intermediate 40,000-dalton moiety is as prominent as HFf.‘28 Thus, HF and prekallikrein appear to activate each other by specific proteolytic cleavage both in the fluid and surface phase steps.‘34 The kinetics of prekalli-

MOORE

254

krein activation and the effects of inhibitors provide evidence that the amidolytic and proteolytic activities of HF reside in the activated forms derived by limited proteolysis of the native molecule.“’ HMWK has been found to enhance the function and formation of HFa.“X.‘15 The combination of prekallikrein, factor XI, and HF on the surface is directed by HMWK, functioning as a nonenzymatic cofactor.‘34.‘3’ The HM WK molecule possesses binding sites for the negativelq charged surface, prekallikrein, and factor XI.‘“’ Prekallikrein and factor Xl circulate complexed to HMWK.“’ When the HMWK-prekallikrein complex binds to the surface near H Fa, prekalliKallikrein can then activate krein is activated.“’ numerous surface-bound H F molecules.“” H Fa may itself also cause release of kinin by proteolytic cleavage of HMWK.“’ Overall. the main effect of HMWK is to bind HF substrates on negatively charged surfaces in optimal positions so as to interact with HF.‘“” Plasmin and activated factor XI also activate HF in the fluid phase. but are one tenth as potent.“’ The activation of HF by factor XI is augmented bq HMWK; no effect is seen with plasmin.‘J’ Surface-bound HFa initiates the intrinsic coagulation pathway by cleaving and activating factor XI molecules brought into close proximit] by HMWK.““,“” In the initiation of the extrinsic coagulation pathway, HFa cleaves and activates factor VII.“” Factor VII then activates factor X and this is potentiated in the presence of thromboplastin.“’ HFa may function as a weak plasminogen activator.‘“’ However, most data indicate that prekallikrein is the prime plasminogen activator with factor Xl as a second activator and HFa or HFf as contributors.“” Recent studies indicate that activated B of the alternative pathway cleaves and activates plasminogen.‘J”

AND

WEISS

with HM WK 11) form bradykintn and plahmlnogcn to form plasmin.“Recent studies have demonstrated ~hc rn \~tro IgE-mediated release of prekallikrein activator from human Iung.“” The lung prekallikrein activator differs from the other known physiologic activators of kallikrein. Its role is not clear bul it does represent ;t lirst and important interface between IgE-mediated reactions and the IHFdependent pathways of the inflammatorL response. “’

Two molecular forms of kininogen c:xIst tn plasma. namely low molecular weight kininogen (l.MWK) and HMWK forms. Purification of HMWK and l.MWK shows them to bc Gngle Their substrate conccntr;ichain molecules.“” tions may play ;I role in determining the rate 211 which tissue kallikreins release kinins from k~ninogen either in the circulation or extravascuweight <)I lar~~.‘i’J H MWK has ;I molecular 1~0.000 bv sodium dodeck sulfate gel electrophorcsis. ‘- It i\ digested by plasma kallikrein 10 form bradqkinin ;tnd other peptides that ha\c not been isolated’ “’ ;ind there ib no Io\a of coagulant aclivit>.“” Human platelet> contain and \‘,in hccrctc HMW K that may participate in plasma coagulation reactions.“’

Factor >(I 15 ;I ;-globulin with a molecular weight of 158.000 b! sodium dodccyl sulfate gci clcctrophorcsis.“‘ Factor XI circulates conplexed HM W K augmenting its conversion to activated factor XI.‘” ‘Ii The rate of formation of activated tlictor Xl IS dependent on prckallikrein. “.“’ tlouever. prekallikrein circulates cotnplexed to ;I HMWK different from that 01 factor XI. “’

Prekallikrein

Prekallikrein has fast y-globulin mobility. By sodium dodecyl sulfate gel electrophoresis, two molecular variants of 85,000 and 88,000 molecular weight have been identified.“’ HFf activates prekallikrein to kallikrein by limited proteolytic digestion of each of the two Kallikrein then interacts molecular forms.“’

Plasma markedly inhibits the binding ot‘ HE 10 surfaces.“! This has been attributed to man! plasma fractions and is nonspecitic.“’ The I~JOI inhibitor of HFa“’ and HFf”’ is Cl-In. (‘!-In binds

and irreversibly

inactivates

HFf.“”

Anti-

thrombin III may also inactivate HF.“. In CCN~tradistinction, HFf also can activate the classical

255

MEDIATORS OF INFLAMMATION

pathway of complement in serum or platelet-poor plasma.“’ The activation appears to be due to direct interaction of HFf with macromolecular Cl, converting to Cl r or Cir. Cls is then activated primarily by Cir and to a lesser degree by HFf.15’ The major inhibitor of plasma kallikrein is also Cir-In that binds the active site of the enzyme inhibiting all esterase and proteolytic activibinding site for CT-In is ties.‘59 The functional localized in the light chain of kallikrein.16’ Neither the heavy-chain region of kallikrein nor HMWK is significantly involved in its inactivais inhibited by tion by Ci-In.‘60~‘6’ Kallikrein CT-In (52%) with further inhibition by ayzmacroglobulin (35%), and antithrombin III, LY,antitrypsin, and a,-antiplasmin (1 3%).‘6’ Alpha, macroglobulin also inhibits kallikrein16* by forming a complex with kallikrein.16’ Two inhibitors have been found for activated factor XI. The main inhibitor is Ci-In,‘54 with cu,-antitrypsin inhibiting to a lesser degree.16* Alpha, antiplasmin is the major inactivator of plasmin.’ Only when excess plasmin is produced does inhibition take place with (YemacroIII can also inhibit globulin.‘64 Antithrombin plasmin in the presence of heparin. Antithrombin III can inhibit activated factor XI and plasmin kallikrein in the same manner.‘65 TISSUE MAST CELL-DERIVED MEDIATORS

Mediators derived from mast cells are produced by IgE-dependent mechanisms or secondarily by products of the complement pathway, C3a, C4a, C5a, Hageman factor-dependency pathways, and bradykinin. These mediators include histamine, platelet activating factor (PAF), eosinophilic chemotactic factors (ECF), prostaglandins (PG), thromboxanes (TX) and leukotrienes (LT). Histamine Histamine is one of a group of diverse substances released from tissues during injury or inflammatory reactions.‘66,‘67 Histamine is formed by the decarboxylation of histidine by the cytoplasmic enzyme 1-histidine decarboxylase. It is stored within intracellular granules of mast cells or basophils’66 from which it is released on stimulation by IgE or other stimuli-causing

degranulation.16’ Histamine can also be released from basophils by a noncytotoxic and calciumindependent mechanism, by stimulation by platelet factor 4 (PF4).16’ This may represent the direct ionic displacement of histamine from the basophil granules by PF4.16’ The biologic effects of histamine are mediated through two classes of receptors termed HI and H2.‘66 These receptors are found in a nonrandom distribution on immunocytes.‘69 Histamine via HI actions causes bronchial and intestinal smooth muscle contraction, increases vascular permeability, induces pulmonary vasoconstriction, raises intracellular cyclic GMP levels, enhances eosinophil and neutrophil chemotaxis, and stimulates the production of PGF2m, PGE,, PGD,, TX, and prostacyclin (PG12).‘66S’67.‘7S’72 Stimulation of H, receptors by histamine increases airway mucus production and tissue levels of cyclic CAMP (CAMP), inhibits eosinophi1 and neutrophil chemotaxis, lymphocytotoxicity, IgE-mediated basophil and skin mast cell mediator release, and causes bronchodilatation in opposition to H, effects.‘67~‘69-‘7’~‘73 Thus, histamine may play a prominent role in the inflammatory model. Platelet Activating Factor PAF is a low molecular weight phospholipid which causes platelets to change shape, aggregate, and release their granule content.‘74 It is produced by macrophages, neutrophils, eosinophils, and possibly by mast cells and basophils.I’5~I” PAF is very active in small quantities (lo-” M), but is inactivated if the acetate group is removed or it is sequentially demethylated.‘67 PAF is the most potent compound known to cause aggregation of platelets.“’ In addition, it sequesters platelets in tissues, increases vascular permeability, promotes vasoconstriction, and bronchoconstriction, and induces neutrophilia, basopenia, and thrombocytopenia.‘67~‘79-‘80 The degranulation of platelets also involves the release of serotonin and other platelet amines that cause local vasodilatation, thus providing a means for serotonin to modulate or amplify the inflammatory response.‘74 PAF induces plasma TX and PG formation and release from platelets.“’ PAF in the fluid phase is an intermediary of WBC-platelet interaction and this interaction

MOORE

256

may play a role in the deposition of immune complexes in blood vessels and tissue.“’ This may also play a part in the pulmonary and cardiovascular effects seen in IgE-induced anaphylaxis in rabbits.‘*’ Plasma rapidly deacylates PAF to generate the inactive ~~so-PAF;‘~” whereas, platelets degrade PAF to a new breakdown product termed PX.“’ Eosinophil

Chemotactic

Phospholipase

AND

WEISS

AZ

Factors

Mast cells secrete several distinct substances capable of attracting eosinophils.‘xh Histamine, oxidative products of arachidonic acid metabolism, some low molecular weight compounds (600 to 1,000 daltons), and the ECF are released after anaphylactic activation of mast cells or basophils.‘86 These ECF are highly acidic, tetrapeptides and have been shown to mediate human eosinophil chemotaxis.“’ Another low molecular weight factor identified in cold urticaria also is chemotactic for eosinophils and like ECF-tetrapeptides also deactivates these cells to subsequent chemotactic activation.‘xx They both have little activity for monocytes or neutrophils.‘x” However, a higher molecular weight ECF isolated has been shown to possess a prominent secondary chemotactic specificity for monocytes.lxx Prostaglandins, Thromboxanes, and Leukotrienes Arachidonic acid is liberated from phospholipids by phospholipase AI and is rapidly metabolized by cyclooxygenase to form PC and TX or by lipoxygenase to form hydroxy fatty acids and LT (Fig 5).‘2h.‘X9Cyclooxygenase converts the precursor fatty acids into intermediate compounds (endoperoxides) which have a half-life of about five minutes.“’ The endoperoxides cause aggregation of platelets and effect smooth muscle organs.“’ The endoperoxides are converted into primary PC (PGD2, PGE,, PGF?,,, PG12, and TX).“’ PGE2. PGD,, and PGF?,, are stable but are rapidly hydrolyzed to inactive metabolites. Their mechanism of action is by working via receptors on the cell membrane and as a result raise intracellular CAMP levels that inhibit platelet and neutrophil aggregation.“’ They are also vasodilators. PG12 inhibits platelet aggrega-

Fig

5.

thromboxanes.

Metabolites and

of arachidonic

acid:

prostaglandms.

leukotrienes.

lion. induces vasodilation, and increases CAMP levels in various cells even more potently than PGE,. etc.“” In contrast. TXA: is a potent \‘asoconstrictor and platelet aggregator.“” PG I, and PGE2 primarily are mediatorx of’ the inflammatory process by their vasodilatory properties and by increasing vascular permeability that induces vascular leakage at the postcapiltarl and collecting venules.“h They cause edema b) producing the anaphylatoxin C5a.“” In contraat. in certain cases PG may have antiinflamrnatc)~~ properties by elevating CAMP lcvets.‘h” I”’ Therefore. the overall etfect of PG in certain cases 13 to promote inflammation and in others to modif! the inflammatory response.‘“’ The lipoxygenase pathway begins by substltuting hydroperoxy groups into arachidonic acid (Fig 5). SLipoxygenase action produces 5-h\dropcroxy-6,X, I I. 14eicosatetrancoic :icid (HPETE). which may be reduced to the monohydroxy fatty acid 5-hydroxyeicosatetraenoic acid (SHETE).‘“” Alternatively, HPETE ma\ be broken down into the unstable l.TA, which ih rapidly transformed into 5.12 dihydroxycicosatetraenoic acid (LTB,), a potent chemotaxin. or LTC,.‘“’ LTC, may be transformed into LTD, by the removal of a terminal glutamine residue by the action of gamma glutamyt transpeptidase and then to LTE, by the removal of a glycyl residue by different peptidases.“” LTB, ib a potent inflammatory stimulus mediating Its

MEDIATORS

257

OF INFLAMMATION

effect through neutrophils. It has no direct effect on blood vessels or on tissues.‘89 LTC,, LTD4, and LTE, comprise what were originally called slow reaction substances of anaphylaxis’99 that are generated by IgE-dependent mechanisms from

human lung mast cells.200These substances are capable of causing bronchoconstriction and capillary damage by direct effect on receptors for LT on the smooth muscle of bronchi and blood vesse1s.‘67*‘89

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