We are investigating the role of eicosanoids in regulating platelet- derived growth factor (PDGF) receptor activity and proliferation in lung fibroblasts. Early passage human lung fibroblasts constitutively express PDGF-R and -R , and proliferate in response to PDGF ligands. Physiologic concentrations of PGE2 attenuate binding of PDGF to its receptors and decrease PDGF-stimulated 3H-thymidine. These findings are particularly important given the known effects of PGE2 on mesenchymal cell proliferation and in light of recent findings that fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize PGE2. Current efforts are focused on delineating the complex signaling mechanisms whereby PGE2 modulates PDGF receptor activity in human lung fibroblasts. In related studies, we are investigating the role of prostaglandin H synthases (PGHS) in allergen-induced pulmonary inflammation and airway hyperresponsiveness using PGHS-1 (-/-) and PGHS-2 (-/-) mice. Bronchoalveolar lavage fluid (BAL) PGE2 is significantly lower in nonimmunized PGHS-1 (-/-) mice compared to wild type or PGHS-2 (-/-) mice, but there are no significant differences in basal lung function or histopathology. Following allergen challenge, lung inflammatory indices (BALF cells, proteins, IgE and lung histopathology) are significantly greater in PGHS-1 (-/-) compared with PGHS-2 (-/-) mice, and both are far greater than in wild type mice. Both allergic PGHS-1 (-/-) and PGHS-2 (-/-) mice exhibit decreased baseline lung compliance compared with allergic wild type mice, while only allergic PGHS-1 deficient mice show increased baseline lung resistance and responsiveness to methacholine. Allergen exposure causes a modest increase in lung PGHS-2 protein and a corresponding increase in BAL fluid PGE2 in wild type mice. Thus, PGHS- 1 is the predominant enzyme that biosynthesizes PGE2 in normal mouse lung, both PGHS-1 and PGHS-2 products limit allergic lung inflammation and promote lung function, and there is a dissociation between the presence of airway inflammation and the development of airway hyperresponsiveness in PGHS-2 deficient mice. Current studies will: (a) elucidate the mechanisms whereby PGHS-derived eicosanoids modulate the lung immune response to inhaled allergens; (b) investigate the PGHS- dependent mechanisms involved in the inflammatory response to endotoxin inhalation; and (c) utilize well characterized pulmonary infectivity models to evaluate host resistance to intracellular and extracellular pathogens and to determine if there is an innate defect in T cell function in the PGHS deficient mice. - platelet derived growth factor fibroproliferative lung disease eicosanoids prostaglandins fibroblasts cyclooxygenases - Human Subjects