Pulmonary fibrosis (PF) is a chronic progressive lung disease without effective medical treatment options leading to respiratory failure and death within 3-5years of diagnosis. The pathological process of PF is driven by aberrant wound-healing involving fibroblasts and myofibroblasts differentiated by secreted profibrotic transforming growth factor beta (TGF-beta1). Classical transient receptor potential 6 (TRPC6), a Na(+)- and Ca(2+)-permeable cation channel, is able to promote myofibroblast conversion of primary rat cardiac and human dermal fibroblasts and TRPC6-deficiency impaired wound healing after injury. To study a potential role of TRPC6 in the development of PF we analyzed lung function, gene and protein expression in wild-type (WT) and TRPC6-deficient (TRPC6-/-) lungs utilizing a bleomycin-induced PF-model. Fibrotic WT-mice showed a significant higher death rate while bleomycin-treated TRPC6-deficient mice were partly protected from fibrosis as a consequence of a lower production of collagen and an almost normal function of the respiratory system (reduced resistance and elastance compared to fibrotic WT-mice). On a molecular level TGF-beta1 induced TRPC6 up-regulation, increased Ca(2+) influx and nuclear NFAT localization in WT primary murine lung fibroblasts (PMLFs) resulting in higher stress fiber formation and accelerated contraction rates as compared to treated TRPC6-deficient fibroblasts. Therefore, we conclude that TRPC6 is an important determinant for TGF-beta1-induced myofibroblast differentiation during fibrosis and specific channel inhibitors might be beneficial in a future treatment of PF.
- Hofmann, K.
- Fiedler, S.
- Vierkotten, S.
- Weber, J.
- Klee, S.
- Jia, J.
- Zwickenpflug, W.
- Flockerzi, V.
- Storch, U.
- Yildirim, A. O.
- Gudermann, T.
- Konigshoff, M.
- Dietrich, A.
Keywords
- *Cell contraction
- *Myofibroblast differentiation
- *Primary murine lung fibroblasts
- *Pulmonary fibrosis
- *TGF-beta1
- *Trpc6
