Immunopharmacology of Anaphylatoxin-Induced Bronchoconstrictor Responses

Abstract

The complement anaphylatoxin peptides, C3a and C5a, are potential mediators of immediate hypersensitivity reactions, eliciting many of the same actions on isolated tissue and cell preparations as specific antigen. Instilled intratracheally in experimental animals, the peptides induce acute bronchospasms and are sometimes lethal. In vitro, they cause dosedependent contraction of isolated lung tissue preparations, a response which correlates well with bronchospasms observed in vivo, and our current understanding of the cellular and molecular mechanisms of this action are reviewed here. C5a and its catabolic derivative, C5a (des Arg), stimulate contraction of isolated guinea pig lung parenchymal strips in part by production of leukotrienes that constitute SRS-A, and by release of histamine. Leukotrienes in turn release thromboxane from lung tissue, and evidence indicates that at least part of the spasmogenic activity of these peptidolipids is mediated by this effect. C3a is considerably less potent than C5a in contracting lung tissues and appears to act primarily by causing the release of spasmogenic cyclooxygenase metabolites. Both peptides may additionally have direct action on contractile cells within the tissue. Platelet-activating factor (PAF), an unusual phospholipid mediator released from inflammatory cells stimulated with C5a and other agents, also contracts isolated lung parenchymal tissues. PAF stimulates release of significant quantities of thromboxane from guinea pig lung; however, indomethacin does not block contractile responses of the tissue. Recent evidence indicates that PAF may act on parasympathetic neurons in lung to release endogenous acetylcholine, and this action may be a major component of tissue responses to this mediator. Thus the complement anaphylatoxins stimulate release of many of the same mediators from lung tissues as are released by antigen challenge of sensitized tissue, and may, therefore, play an important role in the pathogenesis of allergic bronchospasms.

Expression of the Complement Anaphylatoxin C3a and C5a Receptors on Bronchial Epithelial and Smooth Muscle Cells in Models of Sepsis and Asthma

“…Synthetic peptides, based on the carboxyl-terminal sequence of C3a, can also mimic these properties (53), and the addition of inhibitors to carboxypeptidase N potentiates the respiratory distress stimulated by instillation of C3a and C5a (54,55). Previous studies have suggested that these properties may be mediated in part by expression of leukotrienes, histamine, or plateletactivating factor (55,56). Whether the pulmonary changes are the direct result of C3a or C5a or are controlled through mediators regulated by these anaphylatoxins remains to be fully determined.…”

Cutting Edge: Guinea Pigs with a Natural C3a-Receptor Defect Exhibit Decreased Bronchoconstriction in Allergic Airway Disease: Evidence for an Involvement of the C3a Anaphylatoxin in the Pathogenesis of Asthma

“…It promotes multifarious in vitro reactions that include bronchoconstriction (8,9), edema formation, as well as attraction and activation of mast cells (10,11) and eosinophils (12,13); but it has no effect on neutrophil chemotaxis. C3a binds to a single ligand-specific receptor, the C3aR, which has only recently been cloned from several species including man, mouse, rat, and guinea pig (14 -19).…”

“…Consequently, these animals have also been used to analyze C3a-induced bronchoconstriction, which can be antagonized by cyclooxygenase inhibitors but not antihistamines (8) similar to the situation in humans. Although an inbred guinea pig strain, called C2BB/R Ϫ , has been described that is nonresponsive to C3a in platelet-based assays (22), the molecular nature of this defect remained obscure and few animal studies have been performed with this strain (23).…”

Prostacyclin biosynthesis and reduced 5‐HT uptake after complement‐induced endothelial injury in the dog isolated lung

“…It did not accumulate in plasma unless the carboxypeptidase inhibitor EACA was present. These are all characteristics of CSa of most species (Vogt, 1974;Stimler, 1986 could explain the gradual differences between YAP and ZAP, in which soluble yeast products were absent.…”

“…Local release of an autacoid with this spectrum of activities is beneficial, e.g. by reducing endotoxin-induced lung injury (Ikeda et al, 1983), but systemic effects of PGI2 appear to be detrimental (Bult et al, 1980;Rie et al, 1983;Bult & Herman, 1985;Slotman et al, 1985;1986).…”