Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea;
Am J Physiol Lung Cell Mol Physiol. 2014 Aug 15;307(4):L326-37. doi: 10.1152/ajplung.00102.2014. Epub 2014 Jun 27.
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-α7 expressions in lung epithelial cells. The integrin-α7 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.
尽管进行了广泛的研究，但香烟烟雾（CS）相关肺气肿的发病机制仍不完全清楚，从而阻碍了新型疗法、诊断和生物标志物的开发。在这里，我们报告了一个可能涉及 CS 相关肺气肿中上皮细胞死亡和组织损失发展的新范例。在 CS 的长期暴露后，在体外和体内都检测到了 CCN1 的切割。全长 CCN1（flCCN1）以外泌体转运的方式分泌，分泌的纤溶酶将 flCCN1 转化为切割的 CCN1（cCCN1）在细胞外基质中。有趣的是，外泌体转运的 flCCN1 促进了对香烟烟雾提取物（CSE）的白细胞介素（IL）-8 和血管内皮生长因子（VEGF）的释放。因此，flCCN1 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，cCCN1 消除了这些功能。此外，cCCN1 在 CSE 后促进蛋白酶和基质金属蛋白酶（MMP）-1 的产生。这些作用主要是通过 CCN1 切割后的 COOH 末端片段介导的。VEGF 的减少和 MMPs 的升高都有利于肺气肿的发展。因此，cCCN1 可能有助于 CS 后的上皮细胞损伤。此外，CSE 和 cCCN1 都刺激肺上皮细胞中整合素-α7 的表达。整合素-α7 似乎是 cCCN1 的结合受体，通过促进 MMP1 来介导其细胞功能。与我们在体外观察到的 cCCN1 的功能作用一致，在经过 6 个月 CS 暴露后发生肺气肿变化的小鼠的支气管肺泡灌洗液中发现了升高的 cCCN1 水平。总之，我们假设 cCCN1 促进了 CS 长期暴露后上皮细胞的死亡和组织损失。
