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      Matrix abnormalities in pulmonary fibrosis

      , , ,

      European Respiratory Review

      European Respiratory Society (ERS)

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          Abstract

          Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive disease, marked by excessive scarring, which leads to increased tissue stiffness, loss in lung function and ultimately death. IPF is characterised by progressive fibroblast and myofibroblast proliferation, and extensive deposition of extracellular matrix (ECM). Myofibroblasts play a key role in ECM deposition. Transforming growth factor (TGF)-β1 is a major growth factor involved in myofibroblast differentiation, and the creation of a profibrotic microenvironment. There is a strong link between increased ECM stiffness and profibrotic changes in cell phenotype and differentiation. The activation of TGF-β1 in response to mechanical stress from a stiff ECM explains some of the influence of the tissue microenvironment on cell phenotype and function. Understanding the close relationship between cells and their surrounding microenvironment will ultimately facilitate better management strategies for IPF.

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          Most cited references 33

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          Transforming growth factor beta in tissue fibrosis.

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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.
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              Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.

              We have identified a new role for the matrix enzyme lysyl oxidase-like-2 (LOXL2) in the creation and maintenance of the pathologic microenvironment of cancer and fibrotic disease. Our analysis of biopsies from human tumors and fibrotic lung and liver tissues revealed an increase in LOXL2 in disease-associated stroma and limited expression in healthy tissues. Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models. Inhibition of LOXL2 resulted in a marked reduction in activated fibroblasts, desmoplasia and endothelial cells, decreased production of growth factors and cytokines and decreased transforming growth factor-beta (TGF-beta) pathway signaling. AB0023 outperformed the small-molecule lysyl oxidase inhibitor beta-aminoproprionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncologic and fibrotic diseases.
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                Author and article information

                Journal
                European Respiratory Review
                Eur Respir Rev
                European Respiratory Society (ERS)
                0905-9180
                1600-0617
                June 27 2018
                June 30 2018
                June 27 2018
                June 30 2018
                : 27
                : 148
                : 180033
                Article
                10.1183/16000617.0033-2018
                © 2018

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