期刊
FRONTIERS IN PHARMACOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.788714
关键词
pulmonary fibrosis; latent transforming growth factor-beta binding protein-2; fibroblast-to-myofibroblast differentiation; extracellular matrix; NF-kappa B signaling
资金
- National Natural Science Foundation of China [82070062, 81870057]
- Natural Science Foundation of Hubei Province [2020CFA018]
- Science, Technology and Innovation Seed Fund of Zhongnan Hospital of Wuhan University [znpy2019052]
The elevated expression of LTBP2 plays a critical role in pulmonary fibrosis (PF) and contributes to fibroblast-to-myofibroblast differentiation. Silencing LTBP2 protects against PF and suppresses the differentiation of fibroblasts into myofibroblasts. Meanwhile, overexpression of LTBP2 induces this differentiation process even in the absence of TGF beta 1, indicating a potential therapeutic target for PF.
Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. The aberrantly activated lung myofibroblasts, predominantly emerging through fibroblast-to-myofibroblast differentiation, are considered to be the key cells in PF, resulting in excessive accumulation of extracellular matrix (ECM). Latent transforming growth factor-beta (TGF beta) binding protein-2 (LTBP2) has been suggested as playing a critical role in modulating the structural integrity of the ECM. However, its function in PF remains unclear. Here, we demonstrated that lungs originating from different types of patients with PF, including idiopathic PF and rheumatoid arthritis-associated interstitial lung disease, and from mice following bleomycin (BLM)-induced PF were characterized by increased LTBP2 expression in activated lung fibroblasts/myofibroblasts. Moreover, serum LTBP2 was also elevated in patients with COVID-19-related PF. LTBP2 silencing by lentiviral shRNA transfection protected against BLM-induced PF and suppressed fibroblast-to-myofibroblast differentiation in vivo and in vitro. More importantly, LTBP2 overexpression was able to induce differentiation of lung fibroblasts to myofibroblasts in vitro, even in the absence of TGF beta 1. By further mechanistic analysis, we demonstrated that LTBP2 silencing prevented fibroblast-to-myofibroblast differentiation and subsequent PF by suppressing the phosphorylation and nuclear translocation of NF-kappa B signaling. LTBP2 overexpression-induced fibroblast-to-myofibroblast differentiation depended on the activation of NF-kappa B signaling in vitro. Therefore, our data indicate that intervention to silence LTBP2 may represent a promising therapy for PF.
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