Estudi del fenotip miofibroblast i la seva implicació en l'expressió de ciclooxigenasa-2 i en la secreció de prostaglandina E2 en la fibrosi pulmonar idiopàtica
[cat] Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with bad prognosis and mean survival from 2 to 5 years from the diagnosis. The most accepted hypothesis of its cause is that a repeated epithelial lung damage would cause epithelial cells apoptosis and the release of pro-fibro...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2014 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/65403 |
| Acceso en línea: | https://hdl.handle.net/2445/65403 http://hdl.handle.net/10803/290856 |
| Access Level: | acceso abierto |
| Palabra clave: | Fibrosi pulmonar Cèl·lules epitelials Prostaglandines Pulmonary fibrosis Epithelial cells Prostaglandins |
| Sumario: | [cat] Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with bad prognosis and mean survival from 2 to 5 years from the diagnosis. The most accepted hypothesis of its cause is that a repeated epithelial lung damage would cause epithelial cells apoptosis and the release of pro-fibrotic factors, like TGF-b1 and the diminishing of anti-fibrotic factors, like prostaglandin E2 (PGE2). In this profibrotic environment fibroblast foci are formed by fibroblasts, myofibroblasts and extracellular matrix deposits. PGE2 is synthesized via cyclooxygenase enzimes, COX-1 and COX-2. COX-2 is inducible by several pro-inflammatory stimuli, for example IL-1b. We obtained an enriched myofibroblast culture treating primary fibroblasts obtained from control and IPF lung tissue with TGF-b1 during 3 days. This treatment induced an upregulation of aSMA expression, a myofibroblast associated protein, and collagen synthesis. It also induced epithelial to mesenchymal transition (EMT) in A549 epithelial lung cell line. Myofibroblasts obtained from FPI cultures showed increased migratory capacity in comparison with control ones. Proliferation associated with this phenotype was very low. We also measured the closure of an in vitro wound by these cell types and we observed that fibroblasts are actually the most important phenotype associated to wound healing, and not myofibroblasts. Moreover, we analized aSMA and COX-2 expression and PGE2 secretion in those cells. IPF cultures showed increased aSMA levels but decreased COX-2 induced expression by IL-1b. Myofibroblast enriched cultures also showed these features, also associated to a suppressed PGE2 secretion. Both in cell cultures and in tissue inmunohisochemistry no coincidence was observed between aSMA and COX-2 positive cells, associating myofibroblasts to an altered COX-2 and PGE2 metabolism. A549-derived myofibroblasts shared the ssame alterations. We analyzed IL-1 specific receptor IL-1RI in order to stablish if it was an stimuli-dependent alteration, and we observed that both IPF and myofibroblasts showed diminished IL-1R expression. IL-1b failed to upregulate its own receptor expression specifically in myofibroblasts. In the profibrotic environment, miofibroblast transition is chronically induced by TGF-b. Moreover this phenotype is associated to a downregulated IL-1RI expression and therefore IL-1b is uncapable of inducing COX-2 expression and PGE2 secretion, worsening migratory and proliferative features of these cells and contributing to fibrotic progression. |
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