title: Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation.
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.
authors.affiliation: Cancer Research Center of Hawaii, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA. hyang@crch.hawaii.edu
authors.forename: Haining
authors.initials: H
authors.lastname: Yang
authors.forename: Zeyana
authors.initials: Z
authors.lastname: Rivera
authors.forename: Sandro
authors.initials: S
authors.lastname: Jube
authors.forename: Masaki
authors.initials: M
authors.lastname: Nasu
authors.forename: Pietro
authors.initials: P
authors.lastname: Bertino
authors.forename: Chandra
authors.initials: C
authors.lastname: Goparaju
authors.forename: Guido
authors.initials: G
authors.lastname: Franzoso
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Thomas
authors.initials: T
authors.lastname: Krausz
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001194:Asbestos / Q000378:metabolism / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism / Q000494:pharmacology; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D002477:Cells / Q000378:metabolism; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D024002:HMGB Proteins / Q000378:metabolism / Q000494:pharmacology; D024243:HMGB1 Protein / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008647:Mesocricetus; D008654:Mesothelioma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000378:metabolism; D010997:Pleural Neoplasms / Q000378:metabolism; D011064:Poly Adenosine Diphosphate Ribose / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002273:Carcinogens; D016207:Cytokines; D024002:HMGB Proteins; D024243:HMGB1 Protein; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D001194:Asbestos; D000246:Adenosine Diphosphate Ribose; D011064:Poly Adenosine Diphosphate Ribose; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases