PROSTAGLANDIN G/H SYNTHASE 1 AND 2 LUNG INJURY

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Products of the prostaglandin G2/H2 synthase/cyclooxygenase (PGH synthase) pathway of arachidonic metabolism play fundamentally important roles in modulating inflammation of lung and other tissues. There are two genes that encode for two similar enzymatic isoforms, but the PGH synthase 1 and the pGH synthase 2 genes contain unique features, suggesting specific roles for each of the proteins in modulating cellular functions. We find that PGH synthase 2 expression is specifically increased in endotoxin-primed rabbit alveolar macrophages, rabbit lung, human polymorphonuclear neutrophils (PMN), THP-1 promonocytic cells, and human alveolar macrophages. PGH synthase 1 can be induced in THP-1 cells by phorbol myristate acetate. The objective of this proposal is to investigate pGH synthase 1 and 2 gene expression in human leukocytes. Aim 1 will test the hypothesis that PGH synthase 1 and 2 genes are differentially regulated in human blood leukocytes, THP-1 cells, and human alveolar macrophages, and that post- transcriptional processes play a major role in regulating the expression of the pGH synthase 2 gene. We will compare rates of synthesis, and degradation of pGH 1 and 2 synthase mRNA's and translation of the two genes under basal conditions and following stimulation with various agonists. We also will determine the effects of adrenocorticosteroids on expression of the two genes. We will further assess whether differential expression of the genes alters the capacity for total eicosanoid synthesis in the different cells, using negative ion chemical ionization gas chromatographic mass spectroscopy. Aim 2 will test the hypothesis that pGH synthase 2 is the predominant cyclooxygenase involved in regulating inflammatory responses associated with certain types of lung injury. We will define the expression of PGH synthase 1 and 2 in blood leukocytes and alveolar leukocytes obtained from patients with acute burn injury, the Adult Respiratory Distress Syndrome (ARDS), and the late asthmatic response of patients with atopic forms of asthma. Longer-term goals will address the signal transduction processes associated with the molecular regulation of PGH synthase 1 and 2. We anticipate that our research will provide insight into the pathogenesis of inflammatory lung reactions that are influenced by eicosanoid production.