A differential effect of C5a and C5a des Arg in the induction of pulmonary inflammation.

Earlier studies have shown that C5 fragments induce an inflammatory reaction when instilled into the rabbit lung. Because C5a is rapidly converted to C5a des Arg in vivo, experiments were performed to determine which fragment was most effective in producing pulmonary inflammation in this animal model. C5a des Arg consistently produced marked inflammation. This was characterized by neutrophil accumulation, edema, hemorrhage, fibrin formation, and damage to alveolar epithelium. The time course of the inflammatory reaction initiated by C5a des Arg showed pulmonary vascular sequestration of neutrophils with no intra-alveolar migration at 30 minutes after injection. By 2 hours, interstitial and alveolar neutrophils were numerous, with the accumulation of neutrophils in the alveoli increasing to a maximum at 6 hours. At 24 and 48 hours, the predominant cells were mononuclear (macrophages). By 120 hours, the lesions were resolving. In contrast, at all doses examined, a similar instillation of C5a induced either no inflammation or a milder, more focal response than C5a des Arg. This inability of C5a to initiate inflammation was not apparently due to the generation of inhibitors, since mixtures of C5a and C5a des Arg were phlogistic. A prolonged, intrapulmonary infusion of C5a (20 minutes), in contrast to a bolus instillation (1 minute), did initiate an inflammatory response, which may reflect the conversion of the C5a to C5a des Arg in the lung. This study points out the inflammatory potential of products of complement activation, particularly of the C5 fragment C5a des Arg, when applied to the airway side of the lungs. This inflammatory response raises the possibility that cleavage of intrapulmonary C5 may play an important role in the initiation of pulmonary inflammation.