Plasma-type platelet-activating factor acetylhydrolase is a distinct Ca+2- independent phospholipase A2 enzyme specific for the inactivation of platelet-activating factor (PAF) and PAF- like phospholipids. Thus, PAF acetylhydrolase plays a crucial role in inactivating a potent inflammatory mediator implicated in the initiation and propagation of acute lung injury. This anti- inflammatory property of PAF acetylhydrolase has lead to the therapeutic investigation of PAF acetylhydrolase in a wide range of inflammatory diseases including asthma, Adult Respiratory Distress Syndrome, diabetes, pancreatitis, and vascular and heart disease. The objective of the proposed research is to investigate the cellular and molecular mechanisms involved in the expression and regulation of PAF acetylhydrolase in rat models of acute lung injury. Lung tissue PAF acetylhydrolase expression is dramatically increased in response to in vivo inflammatory challenge. Three closely related Specific Aims will lead to the localization and characterization of PAF acetylhydrolase- expressing cells; the elucidation of the mechanisms involved in PAF acetylhydrolase up-regulation; and the determination of the physiological consequences of increased PAF acetylhydrolase in resolving and limiting lung injury. First, a detailed localization and characterization of PAF acetylhydrolase in normal lung and in response to lung injury will be performed. These experiments in whole animals will explore the differential expression of PAF acetylhydrolase in resident lung macrophages and granulocytes. Granulocytes, predominately comprised of neutrophils, appear to have the capacity to deliver this potent anti-inflammatory agent to sites of inflammation. Second, the involvement of PAF, the PAF receptor, and STAT transcription factors in PAF acetylhydrolase up-regulation will be examined. These experiments will determine the effects on PAF acetylhydrolase expression resulting from the administration of PAF and PAF receptor antagonists and in mice genetically lacking the PAF receptor. Third, the physiological consequences of up- regulated PAF acetylhydrolase expression in lung injury will be investigated by assessing the in vivo PAF-degrading capacity of the compromised lung and determining the effects on the lung inflammatory sequelae in response to exogenous PAF acetylhydrolase administration. Through the logical design of the proposed studies, novel and important information will be gained that will significantly advance our understanding of the cell biology of this important anti-inflammatory enzyme.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Biology and Pathology Study Section (LBPA)
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Harabin, Andrea L
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University of Texas Health Science Center San Antonio
Other Domestic Higher Education
San Antonio
United States
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