Vascular–Parenchymal Cross-Talk Promotes Lung Fibrosis through BMPR2 Signaling
Toyoshi Yanagihara, Kazuya Tsubouchi, Quan Zhou, Michael Chong, Kohei Otsubo, Takuma Isshiki, Jonas C. Schupp, Seidai Sato, Ciaran Scallan, Chandak Upagupta, Spencer Revill, Anmar Ayoub, Sy Giin Chong, Anna Dvorkin‐Gheva, Naftali Kaminski, Jussi Tikkanen, Shaf Keshavjee, Guillaume Paré, Christophe Guignabert, Kjetil Ask, Martin Kolb
Abstract
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.