We perceive that aggregating agents fall into 3 categories: 1) agents which transiently aggregate neutrophils (PMN) (e.g., C5a and synthetic oligopeptides [FMLP]), cause equally transient neutropenia and evanescent mild lung dysfunction; 2) agents which transiently aggregate PMN and platelets (PL) (e.g., platelet activating factor [PAF]) cause equally transient neutropenia and thrombocytopenia and severe lung dysfunction; 3) agents which aggregate PMN and PL irreversibly (e.g., phorbol myristate acetate [PMA]) cause prolonged (greater than 3 hr) neutropenia, thrombocytopenia, and lung dysfunction. We propose that C5a, FMLP, PAF, BUT NOT PMA are active in vivo because they trigger the generation of arachidonate metabolites which mediate cytopenias and lung dysfunction. We will test this hypothesis by measuring blood levels of two arachidonate metabolites (e.g. PGE2 and TXB2), following intravenous administration of the various stimuli; by assessing the effects of arachidonate antimetabolites on the in vivo actions of C5a, FMLP, PAF, and PMA; by determining if PMN of PL obtained from treated rabbits are insensitive (i.e., are desensitized) to stimulation by C5a, FMLP, PAF, LTB4, or PMA; by determining if certain arachidonate metabolites can mimic the actions of the stimuli; and, where possible, by determining if these bioactive arachidonate metabolites circulate in the blood of treated rabbits. In addition, we will explore the role of endogenous C5a, PAF, and arachidonate metabolism on the syndrome of endotoxin shock, a syndrome that also involves neutropenia, thrombocytopenia, and lung dysfunction. In these pursuits our aim is to find evidence supporting the hypothesis that various endogenously formed aggregating agents (e.g., products of arachidonate metabolism or PAF) mediate various syndromes which associate cytopenia with lung dysfunction. Finally, we will examine the effects of these mediators on lung function and structure when administered to animals over prolonged periods (i.e., days to months). These studies may uncover possible etiologies for acute or chronic lung disease and fibrosis.

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National Heart, Lung, and Blood Institute (NHLBI)
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Pathology A Study Section (PTHA)
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Wake Forest University Health Sciences
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