CCN1 secretion and cleavage regulate the lung epithelial cell functions after cigarette smoke
CCN1 secretion and cleavage regulate the lung epithelial cell functions after cigarette smoke
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CCN1分泌和裂解调节吸烟后肺上皮细胞功能
DOI：
10.1152/ajplung.00102.2014
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发表时间：
2014-08-15
影响因子：
4.9
通讯作者：
Jin, Yang
中科院分区：
文献类型：
--
作者：
Moon, Hyung-Geun;Kim, Sang-Heon;Jin, Yang
尽管进行了广泛的研究，但吸烟（CS）相关肺气肿的发病机制仍不完全清楚，从而阻碍了新的治疗，诊断和生物标志物的发展。在这里，我们报告了一种新的范式，可能涉及的发展上皮死亡和组织损失的CS相关肺气肿。在长时间暴露于CS后，在体外和体内均检测到CCN 1裂解。全长CCN 1（flCCN 1）以外泌体穿梭的方式分泌，并且分泌的纤溶酶在细胞外基质中将flCCN 1转化为裂解的CCN 1（cCCN 1）。有趣的是，外泌体穿梭的flCCN 1促进响应香烟烟雾提取物（CSE）的白细胞介素（IL）-8和血管内皮生长因子（VEGF）的释放。因此，flCCN 1可能通过IL-8介导的中性粒细胞募集促进CS诱导的炎症，并且还通过VEGF分泌维持肺内稳态。有趣的是，cCCN 1废除了这些功能。此外，cCCN 1促进CSE后蛋白酶和基质金属蛋白酶（MMP）-1的产生。这些作用主要是由切割后的CCN 1的COOH末端片段介导的。VEGF的降低和MMPs的升高均有利于肺气肿的发生发展。因此，cCCN 1可能有助于CS后的上皮细胞损伤。此外，CSE和cCCN 1均刺激肺上皮细胞中整合素α 7的表达。整合素α 7似乎是cCCN 1的结合受体，随后通过促进MMP 1介导其细胞功能。与我们对cCCN 1体外功能作用的观察一致，在CS暴露6个月后肺气肿变化小鼠的支气管肺泡灌洗液中发现cCCN 1水平升高。综上所述，我们假设cCCN 1促进了长时间CS暴露后的上皮细胞死亡和组织损失。
Despite extensive research, the pathogenesis of cigarette smoking (CS)-associated emphysema remains incompletely understood, thereby impeding development of novel therapeutics, diagnostics, and biomarkers. Here, we report a novel paradigm potentially involved in the development of epithelial death and tissue loss in CS-associated emphysema. After prolonged exposure of CS, CCN1 cleavage was detected both in vitro and in vivo. Full-length CCN1 (flCCN1) was secreted in an exosome-shuttled manner, and secreted plasmin converted flCCN1 to cleaved CCN1 (cCCN1) in extracellular matrix. Interestingly, exosome-shuttled flCCN1 facilitated the interleukin (IL)-8 and vascular endothelial growth factor (VEGF) release in response to cigarette smoke extract (CSE). Therefore, flCCN1 potentially promoted CS-induced inflammation via IL-8-mediated neutrophil recruitment and also maintained the lung homeostasis via VEGF secretion. Interestingly, cCCN1 abolished these functions. Furthermore, cCCN1 promoted protease and matrix metalloproteinase (MMP)-1 production after CSE. These effects were mainly mediated by the COOH-terminal fragments of CCN1 after cleavage. Both the decrease of VEGF and the elevation of MMPs favor the development of emphysema. cCCN1, therefore, likely contributes to the epithelial cell damage after CS. Additionally, CSE and cCCN1 both stimulated integrin-alpha(7) expressions in lung epithelial cells. The integrin-alpha(7) appeared to be the binding receptors of cCCN1 and, subsequently, mediated its cellular function by promoting MMP1. Consistent with our observation on the functional roles of cCCN1 in vitro, elevated cCCN1 level was found in the bronchoalveolar lavage fluid from mice with emphysematous changes after 6 mo CS exposure. Taken together, we hypothesize that cCCN1 promoted the epithelial cell death and tissue loss after prolonged CS exposure.