Stretch-induced Activation of Transforming Growth Factor-β1 in Pulmonary Fibrosis

American Journal of Respiratory and Critical Care Medicine
Aaron R FroeseMartin Kolb

Abstract

Recent findings suggesting transforming growth factor (TGF)-β1 activation by mechanical stimuli in vitro raised the question of whether this phenomenon was relevant in vivo in the context of pulmonary fibrosis. To explore the effect of mechanical stress on TGF-β1 activation and its signaling pathway in rat and human fibrotic lung tissue using a novel ex vivo model. Rat lung fibrosis was induced using transient gene expression of active TGF-β1. Lungs were harvested at Day 14 or 21 and submitted to various stimuli in a tissue bath equipped with a force transducer and servo-controlled arm. Fibrotic lung strips responded to tensile force by releasing active TGF-β1 from latent stores with subsequent increase in tissue phospho-Smad2/3. In contrast, measurable active TGF-β1 and phospho-Smad2/3 were not induced by mechanical stress in nonfibrotic lungs. Protease inhibition did not affect the release of active TGF-β1. A TGF-β1 receptor inhibitor, Rho-associated protein kinase inhibitor, and αv integrin inhibitor all attenuated mechanical stretch-induced phospho-Smad2/3 in fibrotic lung strips. Furthermore, the induction of phospho-Smad2/3 was enhanced in whole fibrotic rat lungs undergoing ventilation pressure challenge compared with co...Continue Reading

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