학술논문
Stretch regulates alveologenesis and homeostasis via mesenchymal Gαq/11-mediated TGFβ2 activation.
Document Type
Academic Journal
Author
Goodwin AT; Centre for Respiratory Research, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, NG7 2RD, UK.; Respiratory Medicine, Nottingham NIHR Biomedical Research Centre, Nottingham, NG7 2RD, UK.; Respiratory Medicine, Biodiscovery Institute, University Park, University of Nottingham, Nottingham, NG7 2RD, UK.; John AE; Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.; Joseph C; Centre for Respiratory Research, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, NG7 2RD, UK.; Respiratory Medicine, Nottingham NIHR Biomedical Research Centre, Nottingham, NG7 2RD, UK.; Respiratory Medicine, Biodiscovery Institute, University Park, University of Nottingham, Nottingham, NG7 2RD, UK.; Habgood A; Centre for Respiratory Research, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, NG7 2RD, UK.; Respiratory Medicine, Nottingham NIHR Biomedical Research Centre, Nottingham, NG7 2RD, UK.; Respiratory Medicine, Biodiscovery Institute, University Park, University of Nottingham, Nottingham, NG7 2RD, UK.; Tatler AL; Centre for Respiratory Research, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, NG7 2RD, UK.; Respiratory Medicine, Nottingham NIHR Biomedical Research Centre, Nottingham, NG7 2RD, UK.; Respiratory Medicine, Biodiscovery Institute, University Park, University of Nottingham, Nottingham, NG7 2RD, UK.; Susztak K; Department of Medicine, Division of Nephrology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.; Palmer M; Department of Pathology, Division of Nephrology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-4238, USA.; Offermanns S; Department of Pharmacology, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Henderson NC; Centre for Inflammation Research, University of Edinburgh, EH16 4TJ, UK.; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.; Jenkins RG; Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.
Source
Publisher: Company Of Biologists Limited Country of Publication: England NLM ID: 8701744 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1477-9129 (Electronic) Linking ISSN: 09501991 NLM ISO Abbreviation: Development Subsets: MEDLINE
Subject
Language
English
Abstract
Alveolar development and repair require tight spatiotemporal regulation of numerous signalling pathways that are influenced by chemical and mechanical stimuli. Mesenchymal cells play key roles in numerous developmental processes. Transforming growth factor-β (TGFβ) is essential for alveologenesis and lung repair, and the G protein α subunits Gαq and Gα11 (Gαq/11) transmit mechanical and chemical signals to activate TGFβ in epithelial cells. To understand the role of mesenchymal Gαq/11 in lung development, we generated constitutive (Pdgfrb-Cre+/-;Gnaqfl/fl;Gna11-/-) and inducible (Pdgfrb-Cre/ERT2+/-;Gnaqfl/fl;Gna11-/-) mesenchymal Gαq/11 deleted mice. Mice with constitutive Gαq/11 gene deletion exhibited abnormal alveolar development, with suppressed myofibroblast differentiation, altered mesenchymal cell synthetic function, and reduced lung TGFβ2 deposition, as well as kidney abnormalities. Tamoxifen-induced mesenchymal Gαq/11 gene deletion in adult mice resulted in emphysema associated with reduced TGFβ2 and elastin deposition. Cyclical mechanical stretch-induced TGFβ activation required Gαq/11 signalling and serine protease activity, but was independent of integrins, suggesting an isoform-specific role for TGFβ2 in this model. These data highlight a previously undescribed mechanism of cyclical stretch-induced Gαq/11-dependent TGFβ2 signalling in mesenchymal cells, which is imperative for normal alveologenesis and maintenance of lung homeostasis.
Competing Interests: Competing interests R.G.J. reports grants or contracts from AstraZeneca, Biogen, Galecto, GSK, Nordic Bioscience, Redx and Pliant; consulting fees from Bristol Myers Squibb, Chiesi, Daewoong, GSK, Veracyte, Resolution Therapeutics and Pliant; honoraria from Boehringer Ingelheim, Chiesi, Roche, patientMpower and AstraZeneca; payment for expert testimony from Pinsent Masons LLP; advisory or data monitoring roles with Boehringer Ingelheim, Galapagos and Vicore Pharma; a leadership role in NuMedii; President of Action for Pulmonary Fibrosis.
(© 2023. Published by The Company of Biologists Ltd.)
Competing Interests: Competing interests R.G.J. reports grants or contracts from AstraZeneca, Biogen, Galecto, GSK, Nordic Bioscience, Redx and Pliant; consulting fees from Bristol Myers Squibb, Chiesi, Daewoong, GSK, Veracyte, Resolution Therapeutics and Pliant; honoraria from Boehringer Ingelheim, Chiesi, Roche, patientMpower and AstraZeneca; payment for expert testimony from Pinsent Masons LLP; advisory or data monitoring roles with Boehringer Ingelheim, Galapagos and Vicore Pharma; a leadership role in NuMedii; President of Action for Pulmonary Fibrosis.
(© 2023. Published by The Company of Biologists Ltd.)