Molecular Medicine Reports 2014 December 19 [Epub ahead of print] [Link]
Li P, Liu T, Kamp DW, Lin Z, Wang Y, Li D, Yang L, He H, Liu G.
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 mitochondriaâ€‘regulated (intrinsic) AEC apoptosis and, if so, whether this induction occurs via the activation of mitogenâ€‘activated protein kinases (MAPK). Human A549 bronchoalveolar carcinomaâ€‘derived cells with alveolar epithelial type IIâ€‘like features were used. The present study showed that chrysotile asbestos induced a doseâ€‘ and timeâ€‘dependent decrease in A549 cell viability, which was accompanied by the activation of the MAPK câ€‘Jun Nâ€‘terminal kinases (JNK), but not the MAPKs extracellular signalâ€‘regulated kinase 1/2 and p38. Chrysotile asbestos was also shown to induce intrinsic AEC apoptosis, as evidenced by the upregulation of the proâ€‘apoptotic genes Bax and Bak, alongside the activation of caspaseâ€‘9, poly (ADPâ€‘ribose) polymerase (PARP), and the release of cytochrome c. Furthermore, the specific JNK inhibitor SP600125 blocked chrysotile asbestosâ€‘induced JNK activation and subsequent apoptosis, as assessed by both caspaseâ€‘9 cleavage and PARP activation. The results of the present study demonstrated that chrysotile asbestos induces intrinsic AEC apoptosis by a JNKâ€‘dependent mechanism, and suggests a potential novel target for the modulation of chrysotile asbestosâ€‘associated lung diseases.