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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES025043-03
Application #
6672855
Study Section
(LPP)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Chu, Chun-Hsien; Chen, Shih-Heng; Wang, Qingshan et al. (2015) PGE2 Inhibits IL-10 Production via EP2-Mediated ?-Arrestin Signaling in Neuroinflammatory Condition. Mol Neurobiol 52:587-600
He, Zuowen; Zhang, Xu; Chen, Chen et al. (2015) Cardiomyocyte-specific expression of CYP2J2 prevents development of cardiac remodelling induced by angiotensin II. Cardiovasc Res 105:304-17
Li, Hong; Edin, Matthew L; Gruzdev, Artiom et al. (2013) Regulation of T helper cell subsets by cyclooxygenases and their metabolites. Prostaglandins Other Lipid Mediat 104-105:74-83
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Li, Rui; Xu, Xizhen; Chen, Chen et al. (2012) Cytochrome P450 2J2 is protective against global cerebral ischemia in transgenic mice. Prostaglandins Other Lipid Mediat 99:68-78
Li, Xuguang; Yang, Guangtian; Zhao, Gang et al. (2011) Rosuvastatin attenuates the elevation in blood pressure induced by overexpression of human C-reactive protein. Hypertens Res 34:869-75
Card, Jeffrey W; Carey, Michelle A; Voltz, James W et al. (2010) Modulation of allergic airway inflammation by the oral pathogen Porphyromonas gingivalis. Infect Immun 78:2488-96
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Card, Jeffrey W; Voltz, James W; Carey, Michelle A et al. (2007) Cyclooxygenase-2 deficiency exacerbates bleomycin-induced lung dysfunction but not fibrosis. Am J Respir Cell Mol Biol 37:300-8

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