VEGF/Src signaling mediated pleural barrier damage and increased permeability contributes to subpleural pulmonary fibrosis
VEGF/Src signaling mediated pleural barrier damage and increased permeability contributes to subpleural pulmonary fibrosis
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VEGF/Src信号介导的胸膜屏障损伤和通透性增加导致胸膜下肺纤维化
DOI：
10.1152/ajplung.00436.2020
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发表时间：
2021-06-01
影响因子：
4.9
通讯作者：
Ma, Wan-Li
中科院分区：
文献类型：
--
作者：
Lu, Yu-Zhi;Liang, Li-Mei;Ma, Wan-Li
特发性肺纤维化（IPF）的纤维化分布为胸膜下，以基底为主。肺泡上皮细胞被认为是IPF初始阶段的关键细胞。然而，肺泡上皮细胞活化和损伤的观点很难解释为什么纤维化分布在胸膜下区域。本研究以人胸膜间皮细胞（PMC）系和原代大鼠PMC作为体外模型。采用腹腔注射博来霉素制作肺纤维化模型。培养的单层 PMC 的完整性由跨上皮电阻 (TEER) 确定。通过测量异硫氰酸荧光素 (FITC) 结合的右旋糖酐的细胞旁转运来估计胸膜通透性。通过Masson染色和免疫荧光染色分析IPF患者肺组织的变化。我们发现博莱霉素诱导 PMCs 损伤并增加 PMCs 通透性； PMCs 通透性增加加剧了博来霉素诱导的胸膜下炎症和肺纤维化。此外，博莱霉素被发现可以激活 VEGF/Src 信号传导，从而增加 PMC 的通透性。在体内，抑制 VEGF/Src 信号传导可预防博莱霉素诱导的胸膜下肺纤维化。最后，在 IPF 患者的胸膜下区域证实了 VEGF/Src 信号的激活。综上所述，我们的研究结果表明 VEGF/Src 信号传导介导胸膜屏障损伤和通透性增加，从而导致胸膜下肺纤维化。
The distribution of fibrosis in idiopathic pulmonary fibrosis (IPF) is subpleural with basal predominance. Alveolar epithelial cell was considered as the key cell in the initial phase of IPF. However, the idea of activation and damage of alveolar epithelial cells is very difficult to explain why fibrosis distributes in the subpleural area. In this study, human pleural mesothelial cell (PMC) line and primary rat PMC was used as in vitro model. Intraperitoneal injection of bleomycin was used for making a pulmonary fibrosis model. The integrity of cultured monolayer PMCs was determined by transepithelial electric resistance (TEER). Pleural permeability was estimated by measuring paracellular transport of fluorescein isothiocyanate (FITC)-conjugated dextran. Changes in lung tissue of patients with IPF were analyzed by Masson's and immunofluorescence staining. We found bleomycin induced PMCs damage and increased PMCs permeability; increased PMCs permeability aggravated bleomycin-induced subpleural inflammation and pulmonary fibrosis. Moreover, bleomycin was found to activate VEGF/Src signaling which increased PMCs permeability. In vivo, inhibition of VEGF/Src signaling prevented bleomycin-induced subpleural pulmonary fibrosis. At last, activation of VEGF/Src signaling was confirmed in subpleural area in patients with IPF. Taken together, our findings indicate that VEGF/Src signaling mediated pleural barrier damage and increased permeability which contributes to subpleural pulmonary fibrosis.