Determining the Role of Prostanoids in the Pathogenesis of Pulmonary Fibrosis Public Deposited

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  • March 20, 2019
Creator
  • Lovgren, Alysia Kern
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Idiopathic pulmonary fibrosis is a relentless, fatal disease characterized by alveolar epithelial cell injury, proliferation of mesenchymal cell populations, and extracellular matrix deposition. Unknown microinjuries to the lung initiate an aberrant repair process in susceptible individuals which ultimately alters lung architecture and leads to progressive loss of pulmonary function. Lipid mediators called prostanoids have been implicated in both inflammatory and fibrotic signaling pathways. It has been postulated that the COX-2 metabolite prostaglandin E2 (PGE2) is responsible for protection against pulmonary fibrosis. To study this lipid mediator, we first generated a mouse line deficient in the putative cytosolic PGE2 synthase, cPGES/p23. These mice died at birth due to respiratory failure, and our data shows that cPGES/p23 is a co-chaperone that is important for both DNA-bindingdependent and -independent mechanisms of the glucocorticoid receptor. However, characterization of primary embryonic fibroblasts derived from the cPGES/p23-deficient mice, as well as embryonic tissues, demonstrated that cPGES/p23 is not required for the direct production of PGE2 from COX-derived PGH2. We, therefore, went on to demonstrate that upregulation of PGE2 after bleomycin administration was dependent on the microsomal PGE2 synthase, mPGES1. However, neither loss of PGE2 synthesis nor signaling through the Gs-coupled EP2 and EP4 receptors had an effect on the development of fibrotic lung disease. Interestingly, we show that COX-2-dependent production of prostacyclin plays an important role in the development of disease, limiting both the development of fibrosis and the consequential alterations in lung mechanics. Our studies reveal an important role for the COX-2-prostacyclin synthetic pathway in protection from bleomycin-induced pulmonary fibrosis.
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  • In Copyright
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  • Koller, Beverly H.
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