Role of Mitogen activated-kinase (MAPK)-phosphatase (MKP)-5 in pulmonary fibrosis

Background: MAP kinase phosphatase 5 (MKP5) is a negative regulator of P38 and JNK and a vitamin D responsive gene. Recent data demonstrate that MKP5 knockout mice exhibit improved muscle repair with minimal fibrosis in an animal model of muscular dystrophy. Objective: To determine the role of MKP5 in lung fibrosis Methods and Results: MKP5 knockdown through siRNA or MKP5 inhibition through a pharmacologic inhibitor of the catalytic domain reduced responsiveness of normal human lung fibroblasts (NHLF) to pro- fibrotic stimuli (10 ng/ml TGFB1) leading to significant reductions in:cell survival,(increased activated caspase-3, 2-fold increase, p Conclusion: Intact MKP5 is required for induction of changes in lung fibroblasts in-vitro and during bleomycin-induced lung fibrosis in-vivo. MKP5 inhibition represent a promising therapeutic target for experimental and lung fibrosis.