We are investigating the role of cyclooxygenases (also known as prostaglandin H synthases or PGHSs) in the pulmonary response to environmental agents. At baseline, lung prostaglandin E2 levels are lower in PGHS-1 null mice compared to either wild type or PGHS-2 null mice, but there are no significant differences in basal lung function or in lung histopathology between the genotypes. Following allergen (ovalbumin) sensitization/exposure, lung inflammatory indices are significantly greater in PGHS-1 null and PGHS-2 null mice compared to wild type mice. Airways of allergic PGHS-1 null mice have increased numbers of eosinophils and increased numbers of CD3+/CD4+ lymphocytes (TH cells). Alveolar macrophages from allergic PGHS-1 null airways show biochemical and morphologic evidence of activation. Bronchoalveolar lavage fluid (BALF) from allergic PGHS-1 null mice contains significantly higher levels of the TH2 cytokines IL-4, IL-5 and IL-13, increased levels of LTB4 and the cysteinyl leukotrienes, and increased levels of the chemokines TARC and eotaxin. These changes in the PGHS-1 null mice are associated with increased BALF IgE levels and increased MUC5AC production/mucin secretion. Moreover, expression of the adhesion molecules VCAM-1 and ICAM-1 are increased in the lungs of allergic PGHS-1 null mice. Allergic PGHS-1 null mice have reduced lung compliance, increased allergen-induced 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 null and PGHS-2 null 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 null mice, but not PGHS-1 null 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. We have recently developed transgenic mice with lung-specific overexpression of human PGHS-1 (murine CC10 promoter driven). These mice will be used to determine the effect of increased PGHS-derived eicosanoids on lung function at baseline and after various stimuli.
Showing the most recent 10 out of 59 publications
