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Grant Abstract: Mechanistic roles of Cytochrome P4501A enzymes in hyperoxic lung injury

Grant Number: 5R01HL129794-03
PI Name: Moorthy
Project Title: Mechanistic roles of Cytochrome P4501A enzymes in hyperoxic lung injury

Abstract: We are writing this application in response to PA-17-307 (Administrative supplement for research on dietary supplements). In this application, we plan to address the effect of omega 3-fatty acids, i.e., eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) on hyperoxic lung injury in mice in vivo, in relation to ARDS in humans. The research proposed under this plan aligns with the following strategic plans 1-1 and 3-1 of the Office of Dietary Supplements (ODS). Hyperoxia is frequently used in the treatment of pulmonary insufficiency in premature infants and adults with acute respiratory distress syndrome (ARDS). However, hyperoxia exacerbates lung injury in ARDS patients. We recently obtained preliminary data that show that mice pretreated with a combination of omega 3 fatty acids, i.e. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), followed by exposure to hyperoxia for 70 h were less susceptible to lung injury and inflammation than those that were treated with vehicle corn oil (CO). However, the mechanisms by which omega 3 fatty acids will prevent against lung injury are not known. The central hypothesis of this supplemental application is that oral pretreatment of mice with omega 3 fatty acids, i.e. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) either alone or in combination, followed by hyperoxia will lead to attenuation of lung injury compared to mice treated with the vehicle corn oil, and that these fatty acids will rescue the phenotype of Cyp1a1null-, 1a2- null-, or Cyp1a1_1a2_double null mice, which are more susceptible than WT mice to hyperoxic lung injury. We will also test the hypothesis that Fat-1-transgenic (Fat-1-Tg) mice, which will convert endogenous omega-6 fatty acids into omega-3 fatty acids in vivo, and decrease the ratios of omega-6/omega-3, will be less susceptible than WT mice to oxygen-mediated lung injury. In order to test the central hypotheses, we propose the following Specific Aims: 1. To test the hypothesis that oral pretreatment of mice with omega 3 fatty acids, i.e. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) either alone or in combination, at levels that are used by humans as dietary supplements, followed by hyperoxia will lead to attenuation of lung injury compared to mice treated with the vehicle corn oil, and that these fatty acids will rescue the phenotype of Cyp1a1-null-, 1a2-null-, or Cyp1a1_1a2_double null mice, which are more susceptible than WT mice to hyperoxic lung injury. 2. To test the hypothesis that Fat-1-transgenic (Fat-1-Tg) mice, which will convert endogenous omega-6 fatty acids into omega-3 fatty acids in vivo, and decrease the ratios of omega-6/omega-3, will be less susceptible than WT mice to oxygen-mediated lung injury, and that pre-treatment of these animals with soluble epoxide hydrolase inhibitors will lead to attenuation of hyperoxic lung injury in WT mice and further protection in Fat-1 mice. Successful accomplishment of the aims could lead to the development of omega 3 fatty acid supplementation as a dietary supplement in humans for the prevention of ARDS.

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