We are investigating the role of cyclooxygenases in basal lung function and in the pulmonary response to environmental agents. At baseline, lung prostaglandin E2 levels are lower in COX-1 null mice compared to either wild type or COX-2 null mice, but there are no significant differences in basal lung function or in lung histopathology between the genotypes. Following allergen (ovalbumin) sensitizationexposure, lung inflammatory indices are significantly greater in COX-1 null and COX-2 null mice compared to wild type mice. Airways of allergic COX-1 null mice have increased numbers of eosinophils and increased numbers of CD3CD4 lymphocytes (Th cells). Alveolar macrophages from allergic COX-1 null airways show biochemical and morphologic evidence of activation. Bronchoalveolar lavage fluid (BALF) from allergic COX-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 COX-1 null mice are associated with increased BALF IgE levels and increased MUC5AC productionmucin secretion. Moreover, expression of the adhesion molecules VCAM-1 and ICAM-1 are increased in the lungs of both allergic COX-1 and allergic COX-2 null mice. Allergic COX-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 COX genes on the pulmonary responses to other environmentally relevant agents including inhaled endotoxin (bacterial lipopolysaccharide, LPS), vanadium pentoxide, and influenza virus. Following LPS exposure, all mice exhibit increased bronchoconstriction and methacholine hyperresponsiveness;however, these changes are much more pronounced in both the COX-1 null and COX-2 null mice relative to wild type controls. Interestingly, there are no significant differences in BALF cells or lung histopathology between the genotypes following LPS exposure. Thus, the balance of COX-1 and COX-2 is important in regulating the physiologic but not the inflammatory responses to inhaled LPS. Following vanadium pentoxide (V2O5) exposure, COX-2 null mice, but not COX-1 null mice, have increased acute lung inflammation and develop more lung fibrosis (increased lung hydroxyproline and enhanced trichrome staining). We have also utilized a pulmonary influenza infectivity model to evaluate host resistance and to determine if there are defects in innate or adaptive immune responses to viral infection in COX-1 null and COX-2 null mice. Infection induced less severe illness in COX-2 null mice in comparison to wild type and COX-1 null mice as evidenced by body weight and body temperature changes. Mortality was significantly reduced in COX-2 null mice. COX-1 null mice had enhanced inflammation and earlier appearance of pro-inflammatory cytokines in the BAL fluid, whereas the inflammatory and cytokine responses were blunted in COX-2 null mice. However, lung viral titres were markedly elevated in COX-2 null mice relative to wild type and COX-1 null mice. Levels of prostaglandin E2 were reduced in COX-1 null airways whereas cysteinyl leukotrienes were elevated in COX-2 null airways following infection. Thus, deficiency of COX-1 and COX-2 leads to contrasting effects in the host response to influenza infection, and these differences are associated with altered production of prostaglandins and leukotrienes following infection. The response of COX-deficient mice varies depending on the environmental stimulus. More recently, we developed transgenic mice with lung-specific overexpression of human COX-1 (murine CC10 promoter driven). Whereas no differences in basal respiratory or lung mechanical parameters were observed, COX-1 transgenic mice had increased bronchoalveolar lavage fluid prostaglandin E2 content compared to wild type littermates and exhibited decreased airway responsiveness to inhaled methacholine. In an ovalbumin-induced allergic airway inflammation model, comparable upregulation of COX-2 protein was observed in the lungs of allergic wild-type and COX 1 transgenic mice. Furthermore, no genotype differences were observed in allergic mice in total cell number, eosinophil content and inflammatory cytokine content of bronchoalveolar lavage fluid, or in airway responsiveness to inhaled methacholine. To eliminate the presumed confounding effects of COX-2 upregulation, COX-1 transgenic mice were bred into a COX-2 null background. In these mice, presence of the COX-1 transgene did not alter allergen-induced inflammation but significantly attenuated allergen-induced airway hyperresponsiveness, coincident with reduced airway leukotriene levels. Collectively, these data indicate that COX-1 overexpression attenuates airway responsiveness under basal conditions but does not influence allergic airway inflammation. We are currently developing transgenic mice with overexpression of COX-2 in type II cells (SPA promoter driven) to examine the role of COX-2 in the distal airway. We are also developing mice with selective knockout of COX-2 in the lung (Clara cells, type II alveolar cells) to determine if systemic or local biosynthesis of prostaglandins is important in regulating the lung response to environmental agents. Finally, we are studying the role of COX-1 and COX-2 in differentiation of lung T-cells in vitro and in vivo.
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