Chemical definition of serum anaphylatoxins has progressed rapidly in recent years. Structure-function studies are proposed here to further define the active site and mechanisms of action of these factors. Anaphylatoxins are low molecular weight polypeptides released from complement components in the course of activation. Complete primary structures of three human anaphylatoxins (e.g., C3a, C5a and C5a) have recently been elucidated in my laboratory. Quantitative data has also been collected regarding numerous biological activities associated with these purified anaphylatoxins in assays designed to assess their actions both in vitro and in vivo. An additional humoral factor, human C3e, will be examined both chemically and biologically. Recently it was suggested that C3e may be the C3-derived factor that inhibits mitogen-induced lymphocyte blastogenesis. If C3e proves to have immunoregulatory activities, in addition to leukocyte mobilizing activity, then this factor will be recognized as a very important factor in host defense. The anaphylatoxins have been shown to elicit acute responses in lung tissue. Severe lung injury involving complement activation fragments has never been examined in erms of chronic effects on pulmonary tissue. We now realize that introduction of anaphylatoxins to the airway side of lung tissue causes dramatic changes in the appearance of the lung's architecture. Complex lipid mediators are released as a direct result of anaphylatoxin action on pulmonary tissue. The C3a anaphylatoxin reportedly release vasoamines and prostaglandins while C5a is known to release vasoamines and leukotrienes. A main focus of this proposal is to examine the potential of anaphylatoxins for inducing chronic damage in pulmonary tissue from repeated insult. Purified anaphylatoxins will be administered repeatedly to both the airway and vascular sides of the lung tissue and both immediate and long-term effects will be assessed by histochemical and histological examination. Advantage will be taken of specific inhibitors of the anaphylatoxin inactivator (carboxypeptidase N), as well as antihistamines and inhibitors of the arachidonate pathways in estimating the role of anaphylatoxins in lung damage.
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