The c-Jun N-terminal kinase signaling pathway mediates chrysotile asbestos-induced alveolar epithelial cell apoptosis

Our plain-English summary of The c-Jun N-terminal kinase signaling pathway mediates chrysotile asbestos-induced alveolar epithelial cell apoptosis, by P. Li, T. Liu, D.W. Kamp, et al (Molecular Medicine Reports, 2015).

The study

• Authors: P. Li, T. Liu, D.W. Kamp, Z. Lin, Y. Wang, D. Li, L. Yang, H. He, G. Liu
• Journal: Molecular Medicine Reports
• Published: 2015;11(5):3626-34
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This was a laboratory study of human cells grown in dishes, not a study of people. The authors exposed A549 cells, which come from a human lung carcinoma and share some features of the cells lining the lung's air sacs, to chrysotile asbestos from Qinghai, China (average fiber length 7.8 µm, diameter 0.2 µm). After 24 hours, 93.87% of untreated cells were alive, compared with 86.5, 64.93, 49.1, 44.43 and 23.63% of cells given 50, 100, 150, 200 and 300 µg/cm2. DNA fragmentation, a sign of programmed cell death (apoptosis), peaked at about 100 to 150 µg/cm2. Exposed cells showed activation of a signaling protein called JNK, with no significant change in the related proteins p38 and ERK. The cell-death proteins Bax and Bak, and the release of cytochrome c, increased over time. A JNK-blocking drug, SP600125, reversed these changes and partially reduced the cell death. The authors concluded that this JNK-dependent pathway may be a novel target for modulating chrysotile-related lung diseases. They stated that the relevance of these findings in living organisms requires further study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vitro laboratory experiment on a human cell line
• Who was studied: A549 cells, derived from a human bronchoalveolar carcinoma, with some features of alveolar epithelial type II cells, obtained from the American Type Culture Collection. Results are from three independent experiments.
• Exposure: Chrysotile asbestos mined in Qinghai, China, with an average length of 7.8 µm and an average diameter of 0.2 µm. Doses of 50 to 300 µg/cm2 were used for viability testing. 150 µg/cm2 was used for most mechanism experiments, lasting up to 48 h. Some cells were pretreated with the JNK inhibitor SP600125 (50 µM for 5 h).
• Main results:
  • Cell viability after 24 h fell with dose: 93.87% in untreated control cells, versus 86.5, 64.93, 49.1, 44.43 and 23.63% in cells treated with 50, 100, 150, 200 and 300 µg/cm2 chrysotile
  • In chrysotile-treated A549 cells, DNA fragmentation (a marker of apoptosis) increased with dose and time, peaking at about 100 to 150 µg/cm2
  • Chrysotile caused significant time-dependent activation of JNK in A549 cells, but no significant change in activation of p38 or ERK
  • Chrysotile increased Bax and Bak protein levels over time in A549 cells
  • In A549 cells, pretreatment with the JNK inhibitor SP600125 reversed the chrysotile-induced increases in Bax/Bak and cytochrome c
  • In A549 cells, SP600125 blocked chrysotile-induced caspase-9 and PARP activation
  • In A549 cells, SP600125 only partially decreased chrysotile-induced apoptosis
• The authors' conclusion: The authors concluded that chrysotile-induced intrinsic alveolar epithelial cell apoptosis through a JNK-dependent mechanism may be a novel target for modulating chrysotile asbestos-related lung diseases
• Limitations the authors state:
  • The authors state that the precise mechanisms, and whether these laboratory (in vitro) findings apply in living organisms (in vivo), require further study

Topics

The National Library of Medicine indexes this study under subjects our site covers: Chrysotile.

Medical terms in this study, explained in our Lexicon: Chrysotile, Apoptosis, Asbestos Exposure, Lung Cancer, Mesothelioma, Idiopathic, Pulmonary Fibrosis, Carcinoma.

Related studies

• AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy — Z. Lin, T. Liu, et al. (2014)
• Asbestos-induced alveolar epithelial cell apoptosis. The role of endoplasmic reticulum stress response — D.W. Kamp, G. Liu, et al. (2013)
• P53 mediates amosite asbestos-induced alveolar epithelial cell mitochondria-regulated apoptosis — V. Panduri, S. Surapureddi, et al. (2006)
• Apoptosis induced by crocidolite asbestos in human lung epithelial cells involves inactivation of Akt and MAPK pathways — A. Baldys, P. Pande, et al. (2007)
• SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis — R.P. Jablonski, S.J. Kim, et al. (2017)
• The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis — S.J. Kim, P. Cheresh, et al. (2015)

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