• Login
• Admin

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

Preview

PDF (Thesis - as examined) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader Download (6MB) | Preview

Abstract

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
URI:	https://eprints.nottingham.ac.uk/id/eprint/35925

Actions (Archive Staff Only)

Edit View