Activation of the complement cascade by immune or nonimmune stimuli generates the anaphylatoxins C3a and C5a, which are primary mediators of acute inflammation. These peptides stimulate the contraction of smooth muscle by two mechanisms. Contraction occurs when histamine is released from mast cells stimulated by binding of C3a or C5a to specific cell surface receptors. Histamine-independent contraction of vascular smooth muscle and increase in vascular permeability occurs when the anaphylatoxins bind at or near alpha-adrenergic receptors. C5a is a chemotactic agent that directs the migration of leucocytes, including neutrophils, basophils, eosinophils, monocytes, and macrophages, toward the site of inflammation. Each of these mechanisms is important for initiation and amplification of the inflammatory response in the lung. We have developed synthetic peptides that exhibit the anaphylatoxic activities of human C3a and others that specifically inhibit these activities. This project will explore the mechanisms of action and the metabolic fates of these anaphylatoxin agonists and antagonists in the lung. In addition, a series of radiolabeled peptides will be prepared by solid-phase peptide synthesis that are agonists and antagonists of human C3a and C5a anaphylatoxin and the related leucotactic factors. Peptide analogues will be prepared that are resistant to serum anaphylatoxin inactivator, which will greatly facilitate patho-physiological studies of lung tissue and perfused lung. Anaphylatoxin analogues will also be synthesized for covalent affinity labeling and isolation of the cellular receptor sites for C3a and C5a.