Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation

Our plain-English summary of Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation, by H. Yang, Z. Rivera, S. Jube, et al (Proceedings of the National Academy of Sciences of the United States of America, 2010).

The study

• Authors: H. Yang, Z. Rivera, S. Jube, M. Nasu, P. Bertino, C. Goparaju, G. Franzoso, M.T. Lotze, T. Krausz, H.I. Pass, M.E. Bianchi, M. Carbone
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2010;107(28):12611-6
• Cited by: 216 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos carcinogenesis has been linked to the release of cytokines and mutagenic reactive oxygen species (ROS) from inflammatory cells. Asbestos is cytotoxic to human mesothelial cells (HM), which appears counterintuitive for a carcinogen. We show that asbestos-induced HM cell death is a regulated form of necrosis that links to carcinogenesis. Asbestos-exposed HM activate poly(ADP-ribose) polymerase, secrete H(2)O(2), deplete ATP, and translocate high-mobility group box 1 protein (HMGB1) from the nucleus to the cytoplasm, and into the extracellular space. The release of HMGB1 induces macrophages to secrete TNF-alpha, which protects HM from asbestos-induced cell death and triggers a chronic inflammatory response; both favor HM transformation. In both mice and hamsters injected with asbestos, HMGB1 was specifically detected in the nuclei, cytoplasm, and extracellular space of mesothelial and inflammatory cells around asbestos deposits. TNF-alpha was coexpressed in the same areas. HMGB1 levels in asbestos-exposed individuals were significantly higher than in nonexposed controls (P < 0.0001). Our findings identify the release of HMGB1 as a critical initial step in the pathogenesis of asbestos-related disease, and provide mechanistic links between asbestos-induced cell death, chronic inflammation, and carcinogenesis. Chemopreventive approaches aimed at inhibiting the chronic inflammatory response, and especially blocking HMGB1, may decrease the risk of malignant mesothelioma among asbestos-exposed cohorts.

In plain English

This laboratory study examined how crocidolite asbestos kills human mesothelial cells. In cell cultures, asbestos did not trigger the markers of apoptosis, a form of cell death that does not cause inflammation. Instead, asbestos raised activity of the enzyme PARP about 2.4-fold and depleted the cells' energy supply (ATP). It also caused the protein HMGB1 to be released into the surrounding fluid. A PARP-blocking drug protected the cells. Fluid from asbestos-exposed cells made macrophages (immune cells) secrete the inflammatory signal TNF-α, and an HMGB1 blocker reduced this. Six hamsters and 10 mice were injected in the abdomen with crocidolite. All developed chronic inflammation around asbestos deposits, with HMGB1 and TNF-α staining in those areas. In blood serum, 20 people with documented asbestos exposure averaged 80.2 ng/mL of HMGB1. This compared with 16.9 ng/mL in 20 unexposed nonsmokers (P less than 0.0001). It was also higher than the 26.1 ng/mL in 20 heavy smokers who had lung inflammation and bronchoscopic evidence of dysplasia but no asbestos exposure (P less than 0.001). The authors concluded that crocidolite kills these cells mainly through programmed necrosis involving HMGB1 release.

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: Laboratory study combining cell-culture experiments on human mesothelial cells, an animal experiment in hamsters and mice, and a comparison of serum HMGB1 levels in humans
• Who was studied: Primary human mesothelial cells from three donors and THP-1-derived macrophages. Six female Syrian hamsters and 10 BALB/c mice injected with crocidolite, with equal numbers of PBS-injected controls. Serum from 20 individuals with a documented history of asbestos exposure, 20 heavy smokers with lung inflammation and bronchoscopic evidence of dysplasia but no asbestos exposure, and 20 nonsmoking, non-asbestos-exposed healthy controls, plus an additional 15 asbestos-exposed individuals.
• Exposure: Crocidolite asbestos from the UICC: 0 to 10 μg/cm2 in cell culture (usually 5 μg/cm2). In animals, 0.4 mg crocidolite injected intraperitoneally every 2 weeks for 10 weeks (total 4 mg). The human participants had a documented history of asbestos exposure; fiber type is not stated in this text.
• Main results:
  • In human mesothelial cells, asbestos did not induce caspase-3 activation or PARP cleavage, the hallmarks of apoptosis.
  • PARP activity in mesothelial cells exposed to 5.0 μg/cm2 crocidolite for 24 h increased about 2.4-fold.
  • Pretreating mesothelial cells with the PARP inhibitor 3-ABA protected them from asbestos-induced cell death.
  • Mesothelial cells exposed to asbestos showed significant ATP depletion.
  • After 24 h of asbestos exposure, HMGB1 was released from mesothelial cells into the culture medium along with cell death.
  • Culture medium from asbestos-exposed mesothelial cells induced TNF-α secretion by macrophages. This secretion was significantly reduced by the HMGB1 antagonist Box A (P less than 0.05).
  • In all six hamsters and 10 mice injected with crocidolite, chronic inflammation and mesothelial hyperplasia were found in the peritoneum and tunica vaginalis around asbestos deposits.
  • In the injected animals, HMGB1 and TNF-α staining was specifically detected in the areas of chronic inflammation around asbestos deposits.
  • Mean (plus or minus standard error) serum HMGB1 was 80.2 plus or minus 12.4 ng/mL in the 20 asbestos-exposed individuals and 16.9 plus or minus 3.6 ng/mL in the 20 nonexposed controls (P less than 0.0001).
  • Serum HMGB1 in the asbestos-exposed individuals was about three times higher than in the 20 heavy smokers with lung inflammation and bronchoscopic evidence of dysplasia but no asbestos exposure. The smokers had 26.1 plus or minus 4.1 ng/mL (P less than 0.001).
  • The serum finding was reproduced in an additional 15 asbestos-exposed individuals compared with nonsmoking healthy controls.
• The authors' conclusion: The authors concluded that crocidolite asbestos kills human mesothelial cells primarily through programmed necrosis, involving PARP activation, H2O2 secretion, ATP depletion and HMGB1 release.

Topics

Medical terms in this study, explained in our Lexicon: Necrosis, Mesothelial Cells, Inflammation, Carcinogenesis, Cytokine, Reactive Oxygen Species (ROS), High Mobility Group Box 1 (HMGB1), Macrophage.

Related studies

• Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling — F. Qi, G. Okimoto, et al. (2013)
• Synthetic Secoisolariciresinol Diglucoside (LGM2605) Prevents Asbestos-Induced Inflammation and Genotoxic Cell Damage in Human Mesothelial Cells — R.A. Pietrofesa, S. Chatterjee, et al. (2022)
• HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma — J.S. Suarez, F. Novelli, et al. (2023)
• Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma — S. Jube, Z.S. Rivera, et al. (2012)
• Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters — B. Kroczynska, R. Cutrone, et al. (2006)
• HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma — L. Pellegrini, J. Xue, et al. (2017)

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