cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis
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 Pros...
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| Format: | Thesis (University of Nottingham only) |
| Language: | English |
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2016
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| Online Access: | https://eprints.nottingham.ac.uk/35925/ |
| _version_ | 1848795192146001920 |
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| author | Wright, Rebecca |
| author_facet | Wright, Rebecca |
| author_sort | Wright, Rebecca |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:28:10Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-35925 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T19:28:10Z |
| publishDate | 2016 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-359252025-02-28T11:50:33Z https://eprints.nottingham.ac.uk/35925/ cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis Wright, Rebecca 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. 2016-12-16 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en arr https://eprints.nottingham.ac.uk/35925/1/Thesis%20-%20FINAL%20CORRECTIONS%2020_05_2016%20%28changes%20highlighted%29.pdf Wright, Rebecca (2016) cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis. PhD thesis, University of Nottingham. Pulmonary fibrosis Myofibroblasts PGE2 cAMP levels |
| spellingShingle | Pulmonary fibrosis Myofibroblasts PGE2 cAMP levels Wright, Rebecca cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis |
| title | cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis |
| title_full | cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis |
| title_fullStr | cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis |
| title_full_unstemmed | cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis |
| title_short | cAMP mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis |
| title_sort | camp mediated regulation of fibroblast to myofibroblast differentiation in idiopathic pulmonary fibrosis |
| topic | Pulmonary fibrosis Myofibroblasts PGE2 cAMP levels |
| url | https://eprints.nottingham.ac.uk/35925/ |