Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive scarring of the lungs and resulting in deterioration in lung function. Transforming growth factor-beta (TGF-β) is one of the most established drivers of fibrotic processes. TGF-β promotes transformation of tissue fibroblasts to myofibroblasts, a key finding in the pathogenesis of pulmonary fibrosis. We report here that TGF-β robustly upregulates the expression of the calcium-activated chloride channel Anoctamin-1 (ANO1) in human lung fibroblasts (HLF) at mRNA and protein levels. ANO1 is readily detected in fibrotic areas of IPF lungs in the same area with smooth muscle alpha-actin (SMA)-positive myofibroblasts. TGF-β-induced myofibroblast differentiation (determined by the expression of SMA, collagen-1 and fibronectin) is significantly inhibited by a specific ANO1 inhibitor, T16A-A01, or by siRNA-mediated ANO1 knockdown. T16A-A01 and ANO1 siRNA attenuate pro-fibrotic TGF-β signaling, including activation of RhoA pathway and AKT, without affecting initial Smad2 phosphorylation. Mechanistically, TGF-β treatment of HLF results in a significant increase in intracellular chloride levels, which is prevented by T16A-A01 or by ANO1 knockdown. The downstream mechanism involves the chloride-sensing "with-no-lysine (K)" kinase (WNK1). WNK1 siRNA significantly attenuates TGF-β-induced myofibroblast differentiation and signaling (RhoA pathway and AKT), whereas the WNK1 kinase inhibitor WNK463 is largely ineffective. Together, these data demonstrate that (i) ANO1 is a TGF-β-inducible chloride channel that contributes to increased intracellular chloride concentration in response to TGF-β; and (ii) ANO1 mediates TGF-β-induced myofibroblast differentiation and fibrotic signaling in a manner dependent on WNK1 protein, but independent of WNK1 kinase activity.
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http://dx.doi.org/10.1101/2023.06.07.544093 | DOI Listing |
Biomaterials
December 2024
Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology, Hypertension), RWTH Aachen University Medical Faculty, Aachen, Germany; Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address:
Chronic kidney disease (CKD) affects more than 10% of the global population. As kidney function negatively correlates with the presence of interstitial fibrosis, the development of new anti-fibrotic therapies holds promise to stabilize functional decline in CKD patients. The goal of the study was to generate a scalable bioprinted 3-dimensional kidney tubulo-interstitial disease model of kidney fibrosis.
View Article and Find Full Text PDFPLoS One
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Takeda Development Center Americas, Inc., San Diego, California, United States of America.
Cancer-associated fibroblasts (CAFs) play pivotal roles in solid tumor initiation, growth, and immune evasion. However, the optimal biomimetic modeling conditions remain elusive. In this study, we investigated the effects of 2D and 3D culturing conditions on human primary CAFs integrated into a modular tumor microenvironment (TME).
View Article and Find Full Text PDFIndian J Radiol Imaging
January 2025
Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Pulmonary sclerosing pneumocytoma is a rare benign neoplasm typically seen in middle-aged women. The exact preoperative diagnosis is quite challenging considering its nonspecific clinical and radiologic features along with complex histology. Moreover, obtaining an exact histopathological diagnosis can be difficult especially with the small biopsy specimens.
View Article and Find Full Text PDFSci Transl Med
December 2024
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
Excessive deposition of fibrillar collagen in the interstitial extracellular matrix (ECM) of human lung tissue causes fibrosis, which can ultimately lead to organ failure. Despite our understanding of the molecular mechanisms underlying the disease, no cure for pulmonary fibrosis has yet been found. We screened a drug library and found that dextromethorphan (DXM), a cough expectorant, reduced the amount of excess fibrillar collagen deposited in the ECM in cultured primary human lung fibroblasts, a bleomycin mouse model, and a cultured human precision-cut lung slice model of lung fibrosis.
View Article and Find Full Text PDFJ Clin Endocrinol Metab
December 2024
Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, and Center for Basic Medical Research and Innovation in Visual System Diseases of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
Context: CD34+ orbital fibroblasts (OFs) play a pathogenic role in thyroid eye disease (TED). Several micro (mi)RNAs have been shown to promote TED progression.
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