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The role of cyclooxygenase-2 (COX-2) in the pathogenesis of pulmonary fibrosis, and the potential for its regulation by gene transfer

Jenkins, Richard Gisli; (2002) The role of cyclooxygenase-2 (COX-2) in the pathogenesis of pulmonary fibrosis, and the potential for its regulation by gene transfer. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown aetiology and pathogenesis, with an appalling prognosis and no effective treatment. Fibroblasts derived from people with pulmonary fibrosis exhibit a diminished capacity to upregulate cyclooxygenase-2 (COX-2) and reduced prostaglandin E2 (PGE2) synthesis. PGE2 modulates the inflammatory response and inhibits fibroblast proliferation and collagen synthesis. This thesis aims to address the hypothesis that pulmonary fibrosis is exacerbated by defective upregulation of COX-2, and that functional levels of COX-2 may be restored, in the lung, using a non-viral gene delivery system, the LID vector, composed of lipofectin (L), an integrin-targeted peptide (I) and DNA (D). In order to test the hypothesis, I have used COX-2 gene "knockout" mice, the highly selective COX-2 inhibitor NS398 and I developed the LID vector for use in the lung. I demonstrate, indirectly by using NS398, that COX-2 is upregulated following bleomycin induced lung injury, and that in animals without COX-2 there is a persistent and exaggerated neutrophilic inflammatory response following bleomycin. I show that successful COX-2 gene transfer stimulates PGE2 production and inhibits fibroblast proliferation in vitro. I describe the in vivo development of this delivery system, demonstrating high levels of pulmonary gene expression from both the luciferase and lac Z marker genes. Although gene expression was transient, it lasted for at least one week and I was able to re-administer the LID vector with minimal toxicity. Furthermore, when optimised for maximal gene expression, COX-2 over-expression in the lungs of mice generated high levels of bronchoalveolar lavage PGE2. In summary this thesis describes the role of COX-2 in the evolution of bleomycin induced lung fibrosis and demonstrates that a non-viral gene delivery system can be used to augment COX-2 in the lung. Ultimately it offers the hope of a novel therapy for people with this devastating condition.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of cyclooxygenase-2 (COX-2) in the pathogenesis of pulmonary fibrosis, and the potential for its regulation by gene transfer
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Pulmonary fibrosis
URI: https://discovery.ucl.ac.uk/id/eprint/10105402
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