Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis
Yong Zhou, … , Karen Bernard, Victor J. Thannickal
Yong Zhou, … , Karen Bernard, Victor J. Thannickal
Published February 22, 2013
Citation Information: J Clin Invest. 2013;123(3):1096-1108. https://doi.org/10.1172/JCI66700.
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Research Article

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

Yong Zhou, Xiangwei Huang, Louise Hecker, Deepali Kurundkar, Ashish Kurundkar, Hui Liu, Tong-Huan Jin, Leena Desai, Karen Bernard, Victor J. Thannickal

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Figure 7

Inhibition of myofibroblastic phenotype and lung fibrosis by targeting (myo)fibroblast contractility and MKL1-mediated intrinsic mechanotransduction with ROCK inhibitors.

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Inhibition of myofibroblastic phenotype and lung fibrosis by targeting (...
In response to extracellular biomechanical (e.g., matrix stiffness) and biochemical (e.g., active TGF-β1) stimuli, lung fibroblasts undergo actin cytoskeleton remodeling and activation of the actomyosin contractile system, resulting in MKL1 translocation from cytoplasm to nucleus, where it activates fibrotic genes that specify myofibroblast differentiation. Inhibition of ROCK blocks actin cytoskeletal reorganization, fibroblast acquisition of contractile activity, and MKL1 nuclear translocation, preventing fibroblast-to-myofibroblast differentiation. On the other hand, ROCK inhibition disrupts actin cytoskeleton required for myofibroblast contractility in preexisting myofibroblasts. This deactivates constitutively activated MKL1 nuclear signal in myofibroblasts, resulting in downregulation of the antiapoptotic protein BCL-2 and activation of the intrinsic apoptotic pathway.