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Vascular-Parenchymal Cross-Talk Promotes Lung Fibrosis through BMPR2 Signaling.
- Source :
-
American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2023 Jun 01; Vol. 207 (11), pp. 1498-1514. - Publication Year :
- 2023
-
Abstract
- Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive lung scarring. IPF-related pulmonary vascular remodeling and pulmonary hypertension (PH) result in a particularly poor prognosis. Objectives: To study the pathogenesis of vascular remodeling in fibrotic lungs and its contribution to progression of fibrosis. Methods: We used an experimental model of lung fibrosis associated with PH by transient overexpression of active TGF-β1 (transforming growth factor-β1). Samples from patients with fibrotic lung diseases were analyzed in depth using immunostaining, gene expression, and gene mutations. Measurements and Main Results: We found a reduction in endothelial cells (ECs) and activation of vascular smooth muscle cells (VSMCs) in fibrotic lungs. Coculturing fibroblasts with VSMCs or ECs from fibrotic lungs induced fibrotic phenotypes in fibroblasts. IPF fibroblasts induced EC death and activation of VSMCs in coculture systems. Decreased concentrations of BMPR2 (bone morphogenic protein receptor 2) and its signaling were observed in ECs and VSMCs from fibrotic lungs in both rats and humans. On fibroblasts treated with media from VSMCs, BMPR2 suppression in VSMCs led to fibrogenic effects. Tacrolimus activated BMPR2 signaling and attenuated fibrosis and PH in rodent lungs. Whole-exome sequencing revealed rare mutations in PH-related genes, including BMPR2 , in patients with IPF undergoing transplantation. A unique missense BMPR2 mutation (p.Q721R) was discovered to have dysfunctional effects on BMPR2 signaling. Conclusions: Endothelial dysfunction and vascular remodeling in PH secondary to pulmonary fibrosis enhance fibrogenesis through impaired BMPR2 signaling. Tacrolimus may have value as a treatment of advanced IPF and concomitant PH. Genetic abnormalities may determine the development of PH in advanced IPF.
- Subjects :
- Humans
Rats
Animals
Vascular Remodeling
Endothelial Cells metabolism
Tacrolimus
Lung pathology
Transforming Growth Factor beta1 metabolism
Fibroblasts metabolism
Bone Morphogenetic Protein Receptors, Type II genetics
Idiopathic Pulmonary Fibrosis pathology
Hypertension, Pulmonary genetics
Hypertension, Pulmonary metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4970
- Volume :
- 207
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- American journal of respiratory and critical care medicine
- Publication Type :
- Academic Journal
- Accession number :
- 36917778
- Full Text :
- https://doi.org/10.1164/rccm.202109-2174OC