Zhou Lu, Le Yanqing, Tian Jieyu, Yang Xia, Jin Rong, Gai Xiaoyan, Sun Yongchang
Department of Respiratory Medicine, Peking University Third Hospital, Beijing, China,
Department of Respiratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Int J Chron Obstruct Pulmon Dis. 2018 Dec 20;14:81-91. doi: 10.2147/COPD.S190023. eCollection 2019.
Cigarette smoke (CS) induces alveolar destruction through overproduction of proteinases including matrix metalloproteinase (MMP)-9 by alveolar macrophages (AMs). Receptor activator of nuclear factor-κB ligand (RANKL) functions in immune regulation and cytokine secretion; whether it is involved in CS-induced MMP-9 expression is unknown. The purpose of our study was to investigate the expression and functional role of RANKL pathway in MMP-9 production pertaining to the pathogenesis of COPD.
We first localized RANKL and its receptor RANK in the lungs of mice exposed to long-term CS exposure. Next, we studied RANKL and RANK expression under CS extract (CSE) stimulation in vitro. Lastly, we studied the in vitro biological function of RANKL in CS-induced production of MMP-9.
Both RANKL and RANK were highly expressed in AMs in CS-exposed mice, but not in the control mice. In vitro, CSE increased the expressions of RANKL and RANK in macrophages. AMs responded to CSE and RANKL stimulation by overexpressing MMP-9, and CSE-induced MMP-9 expression was partly blocked by using monoclonal anti-RANKL antibody.
RANKL/RANK pathway mediates CS-induced MMP-9 expression in AMs, suggesting a novel mechanism for CS-associated emphysema.
香烟烟雾（CS）通过肺泡巨噬细胞（AMs）过度产生包括基质金属蛋白酶（MMP）-9在内的蛋白酶，导致肺泡破坏。核因子κB受体活化因子配体（RANKL）在免疫调节和细胞因子分泌中发挥作用；其是否参与CS诱导的MMP-9表达尚不清楚。本研究的目的是探讨RANKL通路在与慢性阻塞性肺疾病（COPD）发病机制相关的MMP-9产生中的表达及功能作用。
我们首先在长期暴露于CS的小鼠肺中定位RANKL及其受体RANK。接下来，我们研究了体外CS提取物（CSE）刺激下RANKL和RANK的表达。最后，我们研究了RANKL在CS诱导的MMP-9产生中的体外生物学功能。
RANKL和RANK在暴露于CS的小鼠AMs中高表达，但在对照小鼠中不表达。在体外，CSE增加了巨噬细胞中RANKL和RANK的表达。AMs对CSE和RANKL刺激的反应是过表达MMP-9，并且使用单克隆抗RANKL抗体可部分阻断CSE诱导的MMP-9表达。
RANKL/RANK通路介导CS诱导的AMs中MMP-9的表达，提示CS相关肺气肿的一种新机制。
