Strategies targeting fibrosis in pulmonary disease

Pulmonary fibrosis is potentially a curable disease, but this potential is dependent on correct identification of disease targets at the research stage. While invaluable work has been done in animal models to identify factors involved in the initiation of fibrogenesis, we must now shift our focus towards identifying factors involved in the chronic progression of fibrosis and how to modulate the progressive nature of the disease towards repair or regeneration of non-functioning pulmonary tissue.

The small heat-shock protein α B-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix (ECM) in the lungs. TGF-β1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. αB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of αB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that αB-crystallin is stron…

094 Transition épithélio-mésenchymateuse (TEM) lors de la fibrose pleurale induite par Transforming Growth Factor (TGF)-1

017 Fibrose pleurale progressive induite par le transfert du gène de Transforming Growth Factor (TGF)-β1 à la plèvre

Introduction De nombreux agents ou toxines (medicaments, radiation, amiante, maladies infectieuses) sont responsables de fibrose pleurale, pathologie invalidante entrainant un syndrome restrictif parfois severe. Les mecanismes conduisant a cette fibrose pleurale ont ete jusqu’ici peu explores. TGF-β est un facteur cle de l’initiation et de la progression de la fibrose dans de nombreux organes. Le transfert transitoire du gene de TGF-β1 actif (AdTGF-β1) aux poumons de rat, a l’aide d’adenovirus induit une fibrose pulmonaire severe et progressive ( J Clin Invest 1997; 100: 768-76). Nous avons developpe un modele de fibrose pleurale par transfert du gene de TGF-β1 au mesothelium pleural afin d…

Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3

Tissue repair is a well-orchestrated biological process involving numerous soluble mediators, and an imbalance between these factors may result in impaired repair and fibrosis. Transforming growth factor (TGF)-beta is a key profibrotic element in this process and it is thought that its three isoforms act in a similar way. Here, we report that TGF-beta3 administered to rat lungs using transient overexpression initiates profibrotic effects similar to those elicited by TGF-beta1, but causes less severe and progressive changes. The data suggest that TGF-beta3 does not lead to inhibition of matrix degradation in the same way as TGF-beta1, resulting in non-fibrotic tissue repair. Further, TGF-bet…

Transfer of the active form of transforming growth factor-beta 1 gene to newborn rat lung induces changes consistent with bronchopulmonary dysplasia.

Bronchopulmonary dysplasia is a chronic lung disease of premature human infancy that shows pathological features comprising varying sized areas of interstitial fibrosis in association with distorted large alveolar spaces. We have previously shown that transfer of active transforming growth factor (TGF)-beta 1 (AdTGF beta 1(223/225)) genes by adenovirus vector to embryonic lungs results in inhibition of branching morphogenesis and primitive peripheral lung development, whereas transfer to adult lungs results in progressive interstitial fibrosis. Herein we show that transfer of TGF-beta1 to newborn rat pups results in patchy areas of interstitial fibrosis developing throughout a period of 28 …