Respiratory Research | |
Tropomyosin 2.1 collaborates with fibronectin to promote TGF-β1-induced contraction of human lung fibroblasts | |
Dianne Sylvester1  Geraldine M. O’Neill2  Sandra Rutting3  Cassandra P. Nader4  Aylin Cidem4  Patrick He5  Maria C. Rezcallah5  Peta Bradbury5  Alaina J. Ammit5  | |
[1] Children’s Cancer Research Unit, Kids Research Institute, Children’s Hospital at Westmead, Sydney, NSW, Australia;Children’s Hospital at Westmead Clinical School, Sydney, Australia;Children’s Cancer Research Unit, Kids Research Institute, Children’s Hospital at Westmead, Sydney, NSW, Australia;Children’s Hospital at Westmead Clinical School, Sydney, Australia;School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia;Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia;Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia;Woolcock Emphysema Centre, Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia;Woolcock Emphysema Centre, Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia;School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia; | |
关键词: Lung fibrosis; Tropomyosins; Fibronectin; Collagen contraction; Fibroblasts; | |
DOI : 10.1186/s12931-021-01730-y | |
来源: Springer | |
【 摘 要 】
Many lung diseases are characterized by fibrosis, leading to impaired tissue patency and reduced lung function. Development of fibrotic tissue depends on two-way interaction between the cells and the extra-cellular matrix (ECM). Concentration-dependent increased stiffening of the ECM is sensed by the cells, which in turn increases intracellular contraction and pulling on the matrix causing matrix reorganization and further stiffening. It is generally accepted that the inflammatory cytokine growth factor β1 (TGF-β1) is a major driver of lung fibrosis through the stimulation of ECM production. However, TGF-β1 also regulates the expression of members of the tropomyosin (Tm) family of actin associating proteins that mediate ECM reorganization through intracellular-generated forces. Thus, TGF-β1 may mediate the bi-directional signaling between cells and the ECM that promotes tissue fibrosis. Using combinations of cytokine stimulation, mRNA, protein profiling and cellular contractility assays with human lung fibroblasts, we show that concomitant induction of key Tm isoforms and ECM by TGF-β1, significantly accelerates fibrotic phenotypes. Knocking down Tpm2.1 reduces fibroblast-mediated collagen gel contraction. Collectively, the data suggest combined ECM secretion and actin cytoskeleton contractility primes the tissue for enhanced fibrosis. Our study suggests that Tms are at the nexus of inflammation and tissue stiffening. Small molecules targeting specific Tm isoforms have recently been designed; thus targeting Tpm2.1 may represent a novel therapeutic target in lung fibrosis.
【 授权许可】
CC BY
【 预 览 】
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