Li Peng, Liu Tie, Kamp David W, Lin Ziying, Wang Yahong, Li Donghong, Yang Lawei, He Huijuan, Liu Gang
Clinical Research Center, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
Department of Hematology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Mol Med Rep. 2015 May;11(5):3626-34. doi: 10.3892/mmr.2014.3119. Epub 2014 Dec 19.
Exposure to chrysotile asbestos exposure is associated with an increased risk of mortality in combination with pulmonary diseases including lung cancer, mesothelioma and asbestosis. Multiple mechanisms by which chrysotile asbestos fibers induce pulmonary disease have been identified, however the role of apoptosis in human lung alveolar epithelial cells (AEC) has not yet been fully explored. Accumulating evidence implicates AEC apoptosis as a crucial event in the development of both idiopathic pulmonary fibrosis and asbestosis. The aim of the present study was to determine whether chrysotile asbestos induces mitochondria‑regulated (intrinsic) AEC apoptosis and, if so, whether this induction occurs via the activation of mitogen‑activated protein kinases (MAPK). Human A549 bronchoalveolar carcinoma‑derived cells with alveolar epithelial type II‑like features were used. The present study showed that chrysotile asbestos induced a dose‑ and time‑dependent decrease in A549 cell viability, which was accompanied by the activation of the MAPK c‑Jun N‑terminal kinases (JNK), but not the MAPKs extracellular signal‑regulated kinase 1/2 and p38. Chrysotile asbestos was also shown to induce intrinsic AEC apoptosis, as evidenced by the upregulation of the pro‑apoptotic genes Bax and Bak, alongside the activation of caspase‑9, poly (ADP‑ribose) polymerase (PARP), and the release of cytochrome c. Furthermore, the specific JNK inhibitor SP600125 blocked chrysotile asbestos‑induced JNK activation and subsequent apoptosis, as assessed by both caspase‑9 cleavage and PARP activation. The results of the present study demonstrated that chrysotile asbestos induces intrinsic AEC apoptosis by a JNK‑dependent mechanism, and suggests a potential novel target for the modulation of chrysotile asbestos‑associated lung diseases.
接触温石棉与包括肺癌、间皮瘤和石棉肺在内的肺部疾病合并时死亡率增加有关。已经确定了温石棉纤维诱发肺部疾病的多种机制，然而，细胞凋亡在人肺泡上皮细胞（AEC）中的作用尚未得到充分研究。越来越多的证据表明，AEC凋亡是特发性肺纤维化和石棉肺发展过程中的关键事件。本研究的目的是确定温石棉是否诱导线粒体调节（内在）的AEC凋亡，如果是，这种诱导是否通过丝裂原活化蛋白激酶（MAPK）的激活而发生。使用具有II型肺泡上皮样特征的人A549支气管肺泡癌细胞系。本研究表明，温石棉诱导A549细胞活力呈剂量和时间依赖性下降，同时伴有MAPK c-Jun氨基末端激酶（JNK）的激活，但不伴有细胞外信号调节激酶1/2和p38 MAPK的激活。温石棉还被证明可诱导内在的AEC凋亡，促凋亡基因Bax和Bak的上调以及caspase-9、聚（ADP-核糖）聚合酶（PARP）的激活以及细胞色素c的释放证明了这一点。此外，特异性JNK抑制剂SP600125阻断了温石棉诱导的JNK激活和随后的凋亡，这通过caspase-9裂解和PARP激活进行评估。本研究结果表明，温石棉通过JNK依赖性机制诱导内在的AEC凋亡，并提示了一个调节温石棉相关肺部疾病的潜在新靶点。
