Lung fibrosis is a feature of a number of diseases including idiopathic pulmonary fibrosis, autoimmune collagen vascular diseases, and acute respiratory distress syndrome (ARDS). A hallmark of pulmonary fibrosis is the presence of increased levels of lung collagen. Our research is aimed at understand the role of TGF-B signaling in inducing fibrosis in the lung, as activation of TGF-β induced gene expression in the lung increases lung collagen.
We found that bortezomib, a proteasome inhibitor that prevents the degradation of PPARγ (repressing coactivator), inhibits TGF-β-mediated transcription in human lung fibroblasts, and prevents the development of fibrosis in mouse models.We have generated new data suggesting that TGF-β induces the generation of reactive oxygen species (ROS) from the mitochondria of human lung fibroblasts. ROS contributes to the TGF- β-induced activation of p38 and Akt and degradation of PPARγ. Inhibiting the genes that generate mitochondrial ROS or use of antioxidants reduces transcription of profibrotic genes through TGF- β. We hypothesize that TGF- β induces mitochondrial ROS generation via the TGF-β Type I (ALK5) receptor. These mitochondrial ROS activate downstream proteins and induce the degradation of PPARγ to increase the expression of TGF-β dependent genes.
GR Scott Budinger, MD