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      TGF-β Signaling in Lung Health and Disease


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          Transforming growth factor (TGF)-β is an evolutionarily conserved pleiotropic factor that regulates a myriad of biological processes including development, tissue regeneration, immune responses, and tumorigenesis. TGF-β is necessary for lung organogenesis and homeostasis as evidenced by genetically engineered mouse models. TGF-β is crucial for epithelial-mesenchymal interactions during lung branching morphogenesis and alveolarization. Expression and activation of the three TGF-β ligand isoforms in the lungs are temporally and spatially regulated by multiple mechanisms. The lungs are structurally exposed to extrinsic stimuli and pathogens, and are susceptible to inflammation, allergic reactions, and carcinogenesis. Upregulation of TGF-β ligands is observed in major pulmonary diseases, including pulmonary fibrosis, emphysema, bronchial asthma, and lung cancer. TGF-β regulates multiple cellular processes such as growth suppression of epithelial cells, alveolar epithelial cell differentiation, fibroblast activation, and extracellular matrix organization. These effects are closely associated with tissue remodeling in pulmonary fibrosis and emphysema. TGF-β is also central to T cell homeostasis and is deeply involved in asthmatic airway inflammation. TGF-β is the most potent inducer of epithelial-mesenchymal transition in non-small cell lung cancer cells and is pivotal to the development of tumor-promoting microenvironment in the lung cancer tissue. This review summarizes and integrates the current knowledge of TGF-β signaling relevant to lung health and disease.

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          Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.

          Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional growth factor that has profound regulatory effects on many developmental and physiological processes. Disruption of the TGF-beta 1 gene by homologous recombination in murine embryonic stem cells enables mice to be generated that carry the disrupted allele. Animals homozygous for the mutated TGF-beta 1 allele show no gross developmental abnormalities, but about 20 days after birth they succumb to a wasting syndrome accompanied by a multifocal, mixed inflammatory cell response and tissue necrosis, leading to organ failure and death. TGF-beta 1-deficient mice may be valuable models for human immune and inflammatory disorders, including autoimmune diseases, transplant rejection and graft versus host reactions.
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            Asthma-one of the most common chronic, non-communicable diseases in children and adults-is characterised by variable respiratory symptoms and variable airflow limitation. Asthma is a consequence of complex gene-environment interactions, with heterogeneity in clinical presentation and the type and intensity of airway inflammation and remodelling. The goal of asthma treatment is to achieve good asthma control-ie, to minimise symptom burden and risk of exacerbations. Anti-inflammatory and bronchodilator treatments are the mainstay of asthma therapy and are used in a stepwise approach. Pharmacological treatment is based on a cycle of assessment and re-evaluation of symptom control, risk factors, comorbidities, side-effects, and patient satisfaction by means of shared decisions. Asthma is classed as severe when requiring high-intensity treatment to keep it under control, or if it remains uncontrolled despite treatment. New biological therapies for treatment of severe asthma, together with developments in biomarkers, present opportunities for phenotype-specific interventions and realisation of more personalised treatment. In this Seminar, we provide a clinically focused overview of asthma, including epidemiology, pathophysiology, clinical diagnosis, asthma phenotypes, severe asthma, acute exacerbations, and clinical management of disease in adults and children older than 5 years. Emerging therapies, controversies, and uncertainties in asthma management are also discussed.
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              DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.

              About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-beta (TGF-beta)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.

                Author and article information

                Int J Mol Sci
                Int J Mol Sci
                International Journal of Molecular Sciences
                20 August 2018
                August 2018
                : 19
                : 8
                [1 ]Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; mhorie-tky@ 123456umin.ac.jp (M.H.); takahide-tky@ 123456umin.ac.jp (T.N.)
                [2 ]Division for Health Service Promotion, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
                [3 ]Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
                Author notes
                [* ]Correspondence: asaitou-tky@ 123456umin.ac.jp ; Tel.: +81-338-155-411; Fax: +81-338-155-954
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).


                Molecular biology
                tgf-β,bronchial asthma,emphysema,pulmonary fibrosis,lung cancer
                Molecular biology
                tgf-β, bronchial asthma, emphysema, pulmonary fibrosis, lung cancer


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