title: Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis.
abstract: Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic fibrotic diseases involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive fibrosis are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase (Rho/ROCK), actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 (MKL1), that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung fibrosis and in human subjects with idiopathic pulmonary fibrosis (IPF), we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung fibrosis. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.
authors: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0006, USA. yzhou@uab.edu
authors: Yong
authors: Y
authors: Zhou
authors: Xiangwei
authors: X
authors: Huang
authors: Louise
authors: L
authors: Hecker
authors: Deepali
authors: D
authors: Kurundkar
authors: Ashish
authors: A
authors: Kurundkar
authors: Hui
authors: H
authors: Liu
authors: Tong-Huan
authors: TH
authors: Jin
authors: Leena
authors: L
authors: Desai
authors: Karen
authors: K
authors: Bernard
authors: Victor J
authors: VJ
authors: Thannickal
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D008841:Actin Cytoskeleton / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C431575:MRTFA protein, human; D015514:Oncogene Proteins, Fusion; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; C049347:fasudil