We are investigating the role of cyclooxygenases or prostaglandin H synthases (PGHS) in the pulmonary response to environmental agents. At baseline, lung PGE2 is lower in PGHS-1-/- mice compared to either wild type or PGHS-2-/- mice, but there are no significant differences in basal lung function or in lung histopathology between the three genotypes. Following allergen (ovalbumin) sensitization/exposure, lung inflammatory indices are significantly greater in PGHS-1-/- and PGHS-2-/- mice compared to wild type mice. Airways of allergic PGHS-1-/- mice have increased numbers of eosinophils and increased numbers of CD4+ (TH) lymphocytes. Alveolar macrophages from PGHS-1-/- airways show biochemical and morphologic evidence of activation. Bronchoalveolar lavage fluid (BALF) from PGHS-1-/- mice contains significantly higher levels of the proinflammatory cytokines IL-4, IL-5 and IL-13, and also increased levels of LTB4 and the cysteinyl leukotrienes LTC4, LTD4 and LTE4. These changes in the PGHS-1-/- mice are associated with increased BALF IgE levels and increased MUC5AC production/mucin secretion. Allergic PGHS-1-/- mice have reduced lung compliance, increased bronchoconstriction and display hyperresponsiveness to inhaled methacholine. We have also examined the effects of disruption of Pghs genes on the pulmonary responses to inhaled endotoxin (bacterial lipopolysaccharide, LPS). All mice exhibit increased bronchoconstriction and methacholine hyperresponsiveness following LPS exposure; however, these changes are much more pronounced in both the PGHS-1-/- and PGHS-2-/- mice relative to wild type mice. Interestingly, there are no significant differences in BALF cells or lung histopathology between the genotypes following LPS exposure. Thus, the balance of PGHS-1 and PGHS-2 is important in regulating the physiologic but not the inflammatory responses to inhaled LPS. Following vanadium pentoxide (V2O5) exposure, PGHS-2-/- mice, but not PGHS-1-/- mice, have increased acute lung inflammation and develop more lung fibrosis (increased lung hydroxyproline and enhanced trichrome staining). Thus, the response of PGHS-deficient mice vary depending on the environmental stimulus. Future studies will seek to: (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.
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