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      Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis

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          Abstract

          Fibrosis after solid organ transplantation is considered an irreversible process and remains the major cause of graft dysfunction and death with limited therapies. This remodeling is characterized by aberrant accumulation of contractile myofibroblasts that deposit excessive extracellular matrix (ECM) and increase tissue stiffness. However, studies demonstrate that a stiff ECM, itself, promotes fibroblast-to-myofibroblast differentiation, stimulating further ECM production. This creates a positive feedback loop that perpetuates fibrosis. We hypothesized that simultaneously targeting myofibroblast contractility with relaxin and ECM stiffness with lysyl oxidase inhibitors could break the feedback loop, thereby, reversing established fibrosis.

          To test this, we used the orthotopic tracheal transplanted (OTT) mouse model, which develops robust fibrotic airway remodeling. Mice with established fibrosis were treated with saline, mono-, or combination therapies. While monotherapies had no effect, combining these agents decreased collagen deposition and promoted re-epithelialization of remodeled airways. Relaxin inhibited myofibroblast differentiation and contraction, in a matrix-stiffness-dependent manner through prostaglandin E 2 (PGE 2). Furthermore, the effect of combination therapy was lost in PGE 2 receptor knockout and PGE 2 inhibited OTT mice. This study reveals the important synergistic roles of cellular contractility and tissue stiffness in the maintenance of fibrotic tissue and suggests a new therapeutic principle for fibrosis.

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          Author and article information

          Journal
          100968638
          29770
          Am J Transplant
          Am. J. Transplant.
          American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
          1600-6135
          1600-6143
          5 November 2016
          05 December 2016
          May 2017
          01 May 2018
          : 17
          : 5
          : 1229-1241
          Affiliations
          [1 ] Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, California; USA
          [2 ] Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA
          [3 ] Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan, Ann Arbor, Ann Arbor, Michigan, USA
          Author notes
          [* ] Corresponding author: Mark R. Nicolls, MD, Division of Critical Care Medicine, Department of Medicine, Stanford University, VA Palo Alto Health Care System, Medical Service 111P, 3801 Miranda Ave. Palo Alto, CA 94304 mnicolls@ 123456stanford.edu
          Article
          PMC5409855 PMC5409855 5409855 nihpa827864
          10.1111/ajt.14103
          5409855
          27804215
          c7c1f617-f12c-473e-843b-db0bbffa0a09
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