Latent Transforming Growth Factor-β Binding Protein-2 Regulates Lung Fibroblast-to-Myofibroblast Differentiation in Pulmonary Fibrosis via NF-κB Signaling.
Latent Transforming Growth Factor-β Binding Protein-2 Regulates Lung Fibroblast-to-Myofibroblast Differentiation in Pulmonary Fibrosis via NF-κB Signaling.
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潜在转化生长因子-β 结合蛋白-2 通过 NF-κ B 信号传导调节肺纤维化中肺成纤维细胞向肌成纤维细胞的分化
DOI：
10.3389/fphar.2021.788714
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发表时间：
2021
影响因子：
5.6
通讯作者：
Cheng Z
中科院分区：
文献类型：
--
作者：
Zou M;Zou J;Hu X;Zheng W;Zhang M;Cheng Z
尽管过去进行了广泛的研究，但肺纤维化（PF）的机制仍然知之甚少。异常激活的肺肌成纤维细胞，主要通过成纤维细胞向肌成纤维细胞的分化出现，被认为是PF的关键细胞，导致细胞外基质（ECM）的过度积累。潜在转化生长因子-β (TGFβ)结合蛋白-2 （LTBP2）被认为在调节ECM的结构完整性中起着关键作用。然而，其在PF中的作用尚不清楚。在这里，我们证明了来自不同类型PF患者的肺，包括特发性PF和类风湿关节炎相关的间质性肺疾病，以及来自博来霉素（BLM）诱导PF的小鼠的肺，其特征是激活的肺成纤维细胞/肌成纤维细胞中LTBP2表达增加。此外，LTBP2在covid -19相关PF患者的血清中也有所升高，通过慢病毒shRNA转染沉默LTBP2可在体内和体外保护blm诱导的PF，并抑制成纤维细胞向肌成纤维细胞的分化。更重要的是，即使在缺乏tgf - β1的情况下，LTBP2过表达也能在体外诱导肺成纤维细胞向肌成纤维细胞分化。通过进一步的机制分析，我们证明LTBP2沉默通过抑制NF-κB信号的磷酸化和核易位来阻止成纤维细胞向肌成纤维细胞分化和随后的PF。LTBP2过表达诱导成纤维细胞向肌成纤维细胞分化依赖于NF-κB信号的激活。因此，我们的数据表明，干预沉默LTBP2可能是一种有希望的PF治疗方法。
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-β (TGFβ) 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 TGFβ1. 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-κB signaling. LTBP2 overexpression-induced fibroblast-to-myofibroblast differentiation depended on the activation of NF-κB signaling in vitro. Therefore, our data indicate that intervention to silence LTBP2 may represent a promising therapy for PF.
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