Anaphylatoxin smooth muscle contraction

Vascular Effects of Complement Activation. During complement activation a number of complement fragments (anaphylatoxins), which are polypeptides with inflammatory properties, are released. The anaphylatoxins C3a and C5a induce smooth muscle contraction and enhance vascular permeability (H31). The most pronounced activation of complement with the formation of anaphylatoxins and terminal C5-9 complexes has been observed in septic shock (B29, B30, P2). Studies indicate that there is a relation between high concentrations of anaphylatoxins and C5-9 complexes and the development of ARDS or MODS in patients with sepsis (H10). 

C5-derived peptide in serum. This molecule lacks anaphylatoxin activity (i.e. it cannot cause smooth muscle contraction), and its ability to cause che-motaxis in neutrophils is about 10-20 times lower than that of C5a. However, human serum also contains a heat-stable, anionic protein termed co-chemotaxin (relative molecular mass = 60 kDa), which acts in a concentration-dependent manner to permit C5a des Arg to act as a chemoattractant for neutrophils. Thus, C5a des Arg plus cochemotaxin working together probably account for most of the neutrophil chemoattractant activity in vivo following complement activation. The mechanism of action of cochemotaxin is unknown, but it may form a physical complex by attaching to a sialic acid residue on the oligosaccharide chain of C5a des Arg. Deglycosylation of C5a des Arg increases its chemoattractant activity more than 10-fold, and its dependency upon cochemotaxin is decreased. 

Being an anaphylatoxin, however, C5a also expresses many proinflammatory activities. These include its potent chemotactic activities for the recruitment of inflammatory cells to sites of tissue injury and infection (Shin et al., 1968), its ability to induce smooth muscle contraction (Hugh et al., 1987), increase vascular permeability (Hugh and Muher-Eberhard, 1978 Hugh, 1981, 1990), and induce the release of a variety of secondary inflammatory mediators such as histamine, lysosomal enzymes, and vasoacdve eicosanoids from responsive cells such as mast cells, neutrophils, eosinophils, and macrophages (Drapeau etal., 1993 Johnson et al., 1975 Goldstein and Weissmann, 1974 Schorlemmer et al., 1976 Lundberg et al., 1987). 

Anaphylatoxins The family of peptides C3a, C4a, C5a, and C5a des-arginine produced in the serum during complement activation. They produce smooth muscle contraction, mast cell histamine release, affect platelet aggregation, and act as mediators of the local inflammatory process. The order of anaphylatoxin activity from strongest to weakest is C5a, C3a, C4a, and C5a des-arginine. The latter is the so-called "classical" anaphylatoxin but shows no spasmogenic activity though it contains some chemotactic ability, [nih]... 

Anaphylatoxins and Chemotactic Factors (cf, reference 5 for extensive review of this area) - There are two complement-associated anaphylatoxlc factors which effect smooth muscle contraction and increase vascular permeability. The first of these, a polypeptide of molecular weight approximately 7,000, C3a, arises from the cleavage of C3 in the following reactions ... 

Another possible function of C2 is in relation to the liberation of a kinin mediator (C-kinin) in the serum of patients with HANE (Donaldson et aL, 1969, 1970). It was found that HANE results from a severe deficiency of the Cl-INH protein or from structurally abnormal and functionally inactive Cl-INH (Donaldson et aL, 1963 Harpel et al, 1975). Thus activated Cl is increased in the serum of these patients, and on incubation a dialyzable and heat-stable mediator is released which increases vascular permeability and contracts smooth muscle without causing tachyphylaxis. The activity was inactivated by carboxypeptidase B and, unlike bradykinin, by trypsin, suggesting that the active principle is a polypeptide distinct from bradykinin, C3a and C5a anaphylatoxins (Donaldson et al, 1969). The liberation of this activity required Ci, C4, and C2 and was inhibited by added Cl-INH or antiserum to C4 or C2 but not by anti-C3 (Donaldson et al, 1969, 1970). In addition, the active principle was detected in the incubation mixture of refined ( s, C4, and C2 (Klemperer et al, 1969). Intradermal injection of active Cls increased vascular permeability in normal but not in C2-deficient patients (Klem-... 

Many biological functions have been attributed to C3a anaphylatoxin. It has the ability to release histamine from mast cells and thereby to increase vascular permeability, cause an intradermal wheal and erythema, and contract smooth muscle with tachyphylaxis (Dias Da Silva and Lepow, 1967 Bodammer and Vogt, 1970 Lepow et al., 1970 Wuep-per et al., 1972 Bokisch et al., 1969). Whether it has a direct effect on smooth muscle is somewhat uncertain. Recent studies have shown that the smooth muscle activity resides in a smaller fragment (Erickson et al., 1977). 

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