title: Oral administration of aflatoxin G₁ induces chronic alveolar inflammation associated with lung tumorigenesis.
abstract: Our previous studies showed oral gavage of aflatoxin G₁ (AFG₁) induced lung adenocarcinoma in NIH mice. We recently found that a single intratracheal administration of AFG₁ caused chronic inflammatory changes in rat alveolar septum. Here, we examine whether oral gavage of AFG₁ induces chronic lung inflammation and how it contributes to carcinogenesis. We evaluated chronic lung inflammatory responses in Balb/c mice after oral gavage of AFG₁ for 1, 3 and 6 months. Inflammatory responses were heightened in the lung alveolar septum, 3 and 6 months after AFG₁ treatment, evidenced by increased macrophages and lymphocytes infiltration, up-regulation of NF-κB and p-STAT3, and cytokines production. High expression levels of superoxide dismutase (SOD-2) and hemoxygenase-1 (HO-1), two established markers of oxidative stress, were detected in alveolar epithelium of AFG₁-treated mice. Promoted alveolar type II cell (AT-II) proliferation in alveolar epithelium and angiogenesis, as well as increased COX-2 expression were also observed in lung tissues of AFG₁-treated mice. Furthermore, we prolonged survival of the mice in the above model for another 6 months to examine the contribution of AFG₁-induced chronic inflammation to lung tumorigenesis. Twelve months later, we observed that AFG₁ induced alveolar epithelial hyperplasia and adenocarcinoma in Balb/c mice. Up-regulation of NF-κB, p-STAT3, and COX-2 was also induced in lung adenocarcinoma, thus establishing a link between AFG₁-induced chronic inflammation and lung tumorigenesis. This is the first study to show that oral administration of AFG₁ could induce chronic lung inflammation, which may provide a pro-tumor microenvironment to contribute to lung tumorigenesis.
authors.affiliation: Lab of Pathology, Hebei Medical University, Shijiazhuang, China; Department of Dermatology, The Third Hospital, Hebei Medical University, Shijiazhuang, China.
authors.forename: Chunping
authors.initials: C
authors.lastname: Liu
authors.affiliation: Lab of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Shen
authors.affiliation: Lab of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yi
authors.affiliation: Lab of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Peilu
authors.initials: P
authors.lastname: Shao
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA, USA.
authors.forename: Athena M
authors.initials: AM
authors.lastname: Soulika
authors.affiliation: Lab of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Xinxing
authors.initials: X
authors.lastname: Meng
authors.affiliation: Lab of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Xing
authors.affiliation: Lab of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Yan
authors.affiliation: Lab of Pathology, Hebei Medical University, Shijiazhuang, China; Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, China. Electronic address: xianghongzhang2008@163.com.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000348:Aflatoxins / Q000633:toxicity*; D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced*; D002908:Chronic Disease; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced*; D008171:Lung Diseases / Q000139:chemically induced*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D000348:Aflatoxins; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C494087:Stat3 protein, mouse; C027955:aflatoxin G1; C496542:Hmox1 protein, mouse
keywords: Aflatoxin G(1); Alveolar type II cell; COX-2; Chronic inflammation; Lung tumorigenesis; Oxidative stress