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Title: The role of cyclooxygenase-2 and prostaglandin E2 in pulmonary fibrosis
Author: Hodges, Rebecca Jane
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2004
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Although the pathogenesis of pulmonary fibrosis is incompletely understood, an accepted underlying molecular mechanism is the dysregulation of soluble mediators which regulate fibroblast function in the lung. One such mediator is prostaglandin E2 (PGE2), which is a potent inhibitor of fibroblast proliferation, collagen production, chemotaxis and myofibroblast differentiation. Levels of PGE2 have been shown to be decreased in bronchoalveolar lavage fluid (BALF) and lung fibroblasts from patients with pulmonary fibrosis. In lung fibroblasts this has been shown to be due to limited expression of the rate limiting enzyme in its biosynthesis, cyclooxygenase-2 (COX-2). However, there is currently no direct proof that limited expression of COX-2 and PGE2 contribute to the pathogenesis of pulmonary fibrosis. This thesis has used pharmacological and genetic inhibition of COX-2 to address the hypothesis that limited expression of COX-2 and PGE2 potentiates bleomycin-induced pulmonary fibrosis. Through the use of the highly selective COX-2 inhibitor NS398, this thesis demonstrates that bleomycin-induced PGE2 production in the lung is COX-2 mediated for at least 14 days following injury. However, administration of NS398 had no effect on the development of bleomycin-induced lung fibrosis in wild type (WT) mice. Unexpectedly, COX-2-/- mice showed a compensatory upregulation in PGE2 biosynthesis following bleomycin injury compared with both WT and COX-2-/- animals, which is evident in macrophage/monocytes but not fibroblasts derived from these mice. Lung homogenates showed increased expression of COX-1 in COX-2-/- mice compared with WT controls suggesting the compensatory synthesis is via increased expression of COX-1. COX-2-/- mice show an enhanced and persistent inflammatory response to bleomycin, however the fibrotic response to injury was unaltered compared with WT animals. In contrast, COX-2+/- mice showed reduced expression of COX-2 and subsequently limited induction of PGE2 following bleomycin injury. This resulted in an enhanced fibrotic response at day 28 with increased total lung collagen content compared with both WT and COX-2-/- mice (WT, 2.6 0.22; COX-2+/-, 3.77 0.12; COX-2-/-, 2.51 0.26 mg collagen/lung, p 0.001).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available