Li Chao-Jun, Ning Wen, Matthay Michael A, Feghali-Bostwick Carol A, Choi Augustine M K
Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1297-303. doi: 10.1152/ajplung.00194.2006.
Cigarette smoking, a major risk factor for chronic obstructive pulmonary disease, can cause airway inflammation, airway narrowing, and loss of elasticity, leading to chronic airflow limitation. In this report, we sought to define the signaling pathways activated by smoke and to identify molecules responsible for cigarette smoke-induced inflammation. We applied cigarette smoke water extract (CSE) to primary human lung fibroblasts and found that CSE significantly increased CXC chemokine IL-8 production. Meanwhile, 70-kDa heat shock protein (HSP70) was also induced by CSE in a dose- and time-dependent manner. CSE treatment stimulated HSP70 secretion by primary fibroblasts, which augmented IL-8 production. This was further confirmed by exogenously added recombinant HSP70. Using HSP70 small interfering RNA, we confirmed that CSE-induced chemokine production was dependent on heat shock protein expression. Further investigation showed that CSE could also stimulate early growth response-1 (EGR-1) in an ERK-dependent manner and that the expression of HSP70 was EGR-1 dependent. In view of these findings, we hypothesize that the MAPK-EGR-1-HSP70 pathway regulates the cigarette smoke-induced inflammatory process.
吸烟是慢性阻塞性肺疾病的主要危险因素，可导致气道炎症、气道狭窄和弹性丧失，进而引起慢性气流受限。在本报告中，我们试图确定烟雾激活的信号通路，并识别导致香烟烟雾诱导炎症的分子。我们将香烟烟雾水提取物（CSE）应用于原代人肺成纤维细胞，发现CSE显著增加CXC趋化因子白细胞介素-8（IL-8）的产生。同时，CSE还以剂量和时间依赖性方式诱导70 kDa热休克蛋白（HSP70）。CSE处理刺激原代成纤维细胞分泌HSP70，从而增加IL-8的产生。外源性添加重组HSP70进一步证实了这一点。使用HSP70小干扰RNA，我们证实CSE诱导的趋化因子产生依赖于热休克蛋白表达。进一步研究表明，CSE还可以以ERK依赖的方式刺激早期生长反应-1（EGR-1），且HSP70的表达依赖于EGR-1。鉴于这些发现，我们推测丝裂原活化蛋白激酶-EGR-1-HSP70通路调节香烟烟雾诱导的炎症过程。
