cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis

Wright, Rebecca (2016) cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis. PhD thesis, University of Nottingham.

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Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with no effective treatment. Myofibroblasts contribute to the pathology of IPF by secreting large amounts of extracellular matrix proteins such as alpha smooth muscle actin (α-SMA) and Collagen I (Col 1). Myofibroblasts have reduced Prostaglandin E2 (PGE2), a key anti-fibrotic mediator, due to diminished cyclooxygenase-2 (COX-2) expression.

Primary fibroblasts isolated from lungs of IPF patients (F-IPF) expressed significantly less COX-2 in response to IL-1β and increased α-SMA and Col I compared with fibroblasts isolated from lungs of non-fibrotic patients (F-NL). COX-2 was gradually lost in F-NL treated with transforming growth factor-β (TGF-β1), a pro-fibrotic cytokine, whereas PGE2, and cAMP elevating agents increased IL-1β-induced COX-2 expression in F-IPF. Ras, a small G protein, has been shown to have a role in several fibrotic conditions. Farnesylthiosalicylic acid (FTS), a Ras inhibitor, increased IL-1β-induced COX-2 and prevented TGF-β1-induced reduction of COX-2. Previous studies suggest that COX-2 is epigenetically repressed. LBH589, a HDAC inhibitor, prevented TGF-β1-induced repressed COX-2 whereas BIX01294, a DNA lysine methyltransferase inhibitor, and RG108, a G9a histone methyltransferase inhibitor, both increased IL-1β-induced COX-2 in F-IPF.

In conclusion, the gradual loss of PGE2/COX-2 anti-fibrotic mechanism during myofibroblast differentiation may contribute to the pathophysiology of pulmonary fibrosis and agents that increase cAMP levels, inhibit Ras or inhibit epigenetic repression of COX-2, may compensate for the lack of endogenous PGE2.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Pang, Linhua
Knox, Alan
Jenkins, Gisli
Keywords: Pulmonary fibrosis, Myofibroblasts, PGE2, cAMP levels
Subjects: W Medicine and related subjects (NLM Classification) > WF Respiratory system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 35925
Depositing User: Wright, Rebecca
Date Deposited: 25 Jan 2017 11:55
Last Modified: 13 Oct 2017 20:45

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