The complement anaphylatoxin peptides, C3a and C5a are well known mediators of inflammatory reactions in the lung. During the initial funding period of this research studies were begun into the cellular and molecular mechanisms of anaphylatoxin-induced injury using isolated lung tissues from both human and guinea pig. Evidence was obtained to show that contractile responses of isolated lung parenchymal strips induced by C5a and its metabolites C5adesArg are mediated by production of leukotrienes that constitute SRS-A and release of a small amount of histamine. C3a, in contrast, induces contractile responses by releasing cyclooxygenase metabolites but no detectable leukotrienes. Platelet-activating factor (PAF), an unusual phospholipid mediator released from inflammatory cells stimulated with C5a, also contracts lung parenchymal tissues from both human and guinea pig. PAF stimulates release of significant quantities of thromboxane from guinea pig lung, however indomethacin alone does not block contractile responses of the tissue. Evidence has recently been obtained indicating that PAF may act on parasympathetic neurons to release acetylcholine, and this may be a major component of tissue responses to this agonist. In this RCDA application studies are proposed to continue these investigations using the same general approach. Bioactive mediators released from lung by C3a and C5a will continue to be characterized. The contribution of these mediators to anaphylatoxin-mediated lung injury will be evaluated by studying the interactions of these mediators using in vitro assays. Investigations into the mechanism of PAF-induced activation of parasympathetic pathways in the lung will be expanded. Target cells for the anaphylatoxins will be identified and the role of the pulmonary vascular endothelium in binding, mediator release and degradation of the peptides will be evaluated. Finally, similar studies are planned using human lung tissues with the ultimate goal of understanding the mechanisms of anaphylatoxin induced pulmonary injury.
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