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      Cellular and Molecular Mechanisms of Chronic Inflammation-Associated Organ Fibrosis

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          Organ fibrosis is a pathological condition associated with chronic inflammatory diseases. In fibrosis, excessive deposition of extracellular matrix (ECM) severely impairs tissue architecture and function, eventually resulting in organ failure. This process is mediated primarily by the induction of myofibroblasts, which produce large amounts of collagen I, the main component of the ECM. Accordingly, the origin, developmental pathways, and mechanisms of myofibroblast regulation are attracting increasing attention as potential therapeutic targets. The fibrotic cascade, from initial epithelial damage to eventual myofibroblast induction, is mediated by complex biological processes such as macrophage infiltration, a shift from Th1 to Th2 phenotype, and by inflammatory mediators such as transforming growth factor-β. Here, we review the current understanding of the cellular and molecular mechanisms underlying organ fibrosis.

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          Most cited references 50

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          Macrophages: master regulators of inflammation and fibrosis.

          Macrophages are found in close proximity with collagen-producing myofibroblasts and indisputably play a key role in fibrosis. They produce profibrotic mediators that directly activate fibroblasts, including transforming growth factor-beta1 and platelet-derived growth factor, and control extracellular matrix turnover by regulating the balance of various matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Macrophages also regulate fibrogenesis by secreting chemokines that recruit fibroblasts and other inflammatory cells. With their potential to act in both a pro- and antifibrotic capacity, as well as their ability to regulate the activation of resident and recruited myofibroblasts, macrophages and the factors they express are integrated into all stages of the fibrotic process. These various, and sometimes opposing, functions may be performed by distinct macrophage subpopulations, the identification of which is a growing focus of fibrosis research. Although collagen-secreting myofibroblasts once were thought of as the master "producers" of fibrosis, this review will illustrate how macrophages function as the master "regulators" of fibrosis. Copyright Thieme Medical Publishers.
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            BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.

            Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.
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              The myofibroblast in wound healing and fibrocontractive diseases.

               G Gabbiani (2003)
              The demonstration that fibroblastic cells acquire contractile features during the healing of an open wound, thus modulating into myofibroblasts, has open a new perspective in the understanding of mechanisms leading to wound closure and fibrocontractive diseases. Myofibroblasts synthesize extracellular matrix components such as collagen types I and III and during normal wound healing disappear by apoptosis when epithelialization occurs. The transition from fibroblasts to myofibroblasts is influenced by mechanical stress, TGF-beta and cellular fibronectin (ED-A splice variant). These factors also play important roles in the development of fibrocontractive changes, such as those observed in liver cirrhosis, renal fibrosis, and stroma reaction to epithelial tumours. Copyright 2003 John Wiley & Sons, Ltd.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immun.
                Frontiers in Immunology
                Frontiers Research Foundation
                10 April 2012
                : 3
                1simpleDepartment of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo Bunkyo-ku, Tokyo, Japan
                2simpleJapan Science and Technology Agency, Core Research for Evolutional Science and Technology Tokyo, Japan
                3simpleDepartment of Pharmacology, University of Melbourne Melbourne, VIC, Australia
                Author notes

                Edited by: Masaaki Murakami, Osaka University, Japan

                Reviewed by: Daisuke Kamimura, Osaka University, Japan; Hideki Ogura, Osaka University, Japan

                *Correspondence: Kouji Matsushima, Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. e-mail: koujim@

                This article was submitted to Frontiers in Molecular Innate Immunity, a specialty of Frontiers in Immunology.

                Copyright © 2012 Ueha, Shand and Matsushima.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 61, Pages: 6, Words: 5747
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                chemokine, fibroblast, fibrosis, collagen i, mesenchymal stem cell, myofibroblast, tgfb, pericyte


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