LUNG VASCULAR & CELLULAR ACTIONS OF C3A, C5A, & FMLP

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The adult respiratory distress syndrome (ARDS) is characterized by pulmonary vasoconstriction as well as accumulation of cells and protein-rich fluid within the lung parenchyma. The mechanisms of these abnormalities are not understood. C3a and C5a, the anaphylatoxin products of complement activation, and formaylated oligopeptide bacterial products (e.g. formyl methionine-leucine-phenylalanine; fMLP) may be important in the development of these abnormalities. In this proposal we will investigate the actions of C3a, C5a, and fMLP on isolated pulmonary artery segments and pulmonary macrophages from rabbits. The specific aims of this project are: 1. To determine if C3a, C5a, their des arg derivatives, or fMLP constrict isolated rabbit pulmonary artery ring segments. We will construct dose- response curves, and evaluate tissue desensitization, synergism, and cross-reactivity between these peptides. 2. To determine through the use of pharmacologic inhibitors if the actions of these peptides are attributable to the release of histamine or arachidonic acid metabolities. 3. To determine the role of endothelium in the actions of these peptides on isolated pulmonary artery segments by testing their effects on segments which have undergone mechanical denuding of endothelium. 4. To identify receptors for these peptides in pulmonary tissues utilizing fluorescent probes for C3a, C5a, and fMLP. 5. To analyze physical parameters, ligand binding characteristics, and functional properties of pulmonary macrophages through the use of multiparameter flow cytometry. These studies will broaden our understanding of cellular and vascular responses to C3a, C5a, and fMLP, and may result in the development of more effective therapeutic modalities for ARDS.