Arsenic exposure and lung fibrotic changes-evidence from a longitudinal cohort study and experimental models

Front Immunol. 2023 Aug 22:14:1225348. doi: 10.3389/fimmu.2023.1225348. eCollection 2023.

Abstract

Introduction: Arsenic (As) exposure is associated with lung toxicity and we aim to investigate the effects of arsenic exposure on lung fibrotic changes.

Methods: Participants (n= 976) enrolled via a general health survey underwent chest low-dose computed tomography (LDCT), spirometry forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and urinary arsenic examination during 2016 and 2018. Lung fibrotic changes from LDCT were defined. AsLtoL, low arsenic levels in both 2016 and 2018; AsLtoH, low arsenic in 2016 but high levels in 2018; AsHtoL, high arsenic in 2016 but low levels in 2018; AsHtoH, high arsenic levels in both 2016 and 2018. Mice exposed to 0. 0.2mg/L, 2 mg/L, 50 mg/L of sodium arsenite (NaAsO2) through drinking water for 12 weeks and 24 weeks were applied for histological analysis. Cultured lung epithelial cells were exposed to NaAsO2 and the mesenchymal changes were examined.

Results: AsHtoH increased the risk (OR= 1.65, 95% CI 1.10, 2.49) of Lung fibrotic positive to positive (reference: Lung fibrotic negative to negative) compared with AsLtoL. Moreover, the predicted mean of FVC and FEV1 in AsHtoH (-0.09 units, 95% CI: -0.27, -0.09; -0.09 units, 95% CI: -0.17, -0.01) and AsLtoH (-0.13 units, 95% CI: -0.30, -0.10; -0.13 units, 95% CI: -0.22, -0.04) was significantly lower than ASLtoL. Significant lung fibrotic changes including the increase of the alveolar septum thickness and collagen fiber deposition were observed upon 2 mg/L NaAsO2 treatment for 12 weeks, and the damage was dose- and time-dependent. In vitro, sodium arsenite treatment promotes the epithelial-mesenchymal transition (EMT)-like changes of the normal human bronchial epithelial cells, including upregulation of several fibrotic and mesenchymal markers (fibronectin, MMP-2, and Snail) and cell migration. Inhibition of reactive oxygen species (ROS) and MMP-2 impaired the arsenic-induced EMT changes. Administration of a flavonoid, apigenin, inhibited EMT in vitro and pulmonary damages in vivo with the reduction of mesenchymal markers.

Discussion: we demonstrated that continued exposure to arsenic causes lung fibrosis in humans and mice. Targeting lung epithelial cells EMT is effective on the development of therapeutic strategy. Apigenin is effective in the inhibition of arsenic-induced pulmonary fibrosis and EMT.

Keywords: LDCT images; apigenin; arsenic; epithelial-mesenchymal transition; lung fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apigenin
  • Arsenic* / toxicity
  • Cohort Studies
  • Humans
  • Longitudinal Studies
  • Lung
  • Matrix Metalloproteinase 2
  • Mice
  • Models, Theoretical
  • Pulmonary Fibrosis* / chemically induced

Substances

  • sodium arsenite
  • Arsenic
  • Matrix Metalloproteinase 2
  • Apigenin

Grants and funding

This study was supported by Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, KMHK-S-110-10, KMHK-H-110-009, KMHK-S110-004, KMHK-111-26, and KMHK-H-111-05; MOST 110-2314-B-037-021 and NHRIKMU-111-I004-3. The Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan and by Kaohsiung Medical University Research Center Grant (KMUTC111-A01 and KMUTC111IFSP01).