Obliterative bronchiolitis (OB), considered to be a manifestation of chronic allograft dysfunction in lung transplant recipients, is an irreversible fibroproliferative process that represents the major barrier to long term survival. Hence, research directed at identifying the factors involved in the development of OB in lung transplant recipients is paramount to finding effective treatment for this otherwise untreatable disease. We have found that Transforming Growth Factor-p (TGFp) via its signal transducer, SmadS, is necessary for the development of OB as well as the myofibroblast transdifferentiation that accompanies OB. Hence, we have focused on the mechanisms regulating TGFp/Smad signaling in OB and have made a number of key observations. First, oxidation of the extracellular cysteine-cystine (Cys/CySS) redox couple induces upregulation and activation of TGFp and SrnadS. Second, SmadS expression and DNA binding in lung fibroblasts, and consequently, myofibroblast transformation, is augmented by aberrant transitional matrix, components, e.g., fibronectin and type I collagen, which are invariably found in the setting of OB. And third, activation of the nuclear transcription factor, peroxisome proliferator-activated receptor-y (PPARy), inhibits TGFpl -induced myofibroblast transdifferentiation by disrupting SmadS-dependent gene transcription. These findings led us to the hypothesis that activation of TGFp1/Smad3 signaling in airway fibroblasts is a critical driver of myofibroblast transdifferentiation in OB that is intensified by the presence of chronic extracellular oxidant stress, aberrant transitional matrices, and defective PPARy signaling. This hypothesis will be tested in fibroblast cultures and in experimental models of OB in three specific aims designed to: 1) examine the mechanisms by which chronic extracellular oxidative stress activates TGFp1/Smad3-dependent signaling events in vitro and in vivo through the Cys/CySS redox couple 2) examine how transitional matrices promote activation of TGFpl /SmadS signaling and myofibroblast transdifferentiation through integrin-dependent signals 3) determine the mechanisms by which PPARy affects the SmadS signaling pathway and the induction of myofibroblast transdifferentiation and matrix expression in experimental OB. These complex issues will be addressed with the assistance of expert advisors and collaborators with the broader objective of unveiling novel targets for therapy.
| Iyer, Smita S; Ramirez, Allan M; Ritzenthaler, Jeffrey D et al. (2009) Oxidation of extracellular cysteine/cystine redox state in bleomycin-induced lung fibrosis. Am J Physiol Lung Cell Mol Physiol 296:L37-45 |
