Repeated pulmonary exposures to zinc ions enhance inflammatory responses to subsequent metal exposures

Abstract

Aim of Study: Metal contaminants contribute to adverse human health effects via acute and chronic exposures. Acute metal exposures followed by prolonged secondary metal exposures may elicit exaggerated inflammatory responses in certain individuals. The aim of this study is to determine whether repeated pulmonary exposures to zinc chloride (ZnCl₂) alter subsequent responses to zinc or cerium exposures. Materials and Methods: Rats were intratracheally (IT) instilled with physiologic saline (n = 24) or 0.05 mg/kg ZnCl₂ (n = 16) twice weekly for 4 weeks. Four days after last dosing, the saline group was divided into three subgroups, each IT-instilled with either saline, ZnCl₂ or CeCl₃ (both at 0.1 mg/kg). The ZnCl₂ pre-instilled rats were divided into two subgroups, each instilled with 0.1 mg/kg ZnCl₂ or CeCl₃. Biomarkers of lung injury/inflammation were assessed in bronchoalveolar lavage (BAL) fluid collected 24 hours later. Oxidative stress was evaluated as total and reduced glutathione in BAL. Results: Increases in inflammatory cells, LDH, albumin, leptin, MCP-1, IP-10, fractalkine, TNFα and RANTES were observed in rats instilled with multiple PBS and then with 0.1 mg/kg ZnCl₂ and CeCl₃. However, rats pre-exposed repeatedly to 0.05 mg/kg ZnCl₂ and then challenged with 0.1 mg/kg ZnCl₂ or CeCl₃ showed even more eosinophils, lymphocytes, and increased concentrations of hemoglobin and MIP-1α. Significant reduction in GSH/GSSG ratios in BAL in response to all ZnCl₂ or CeCl₃ exposures indicated oxidative stress. Conclusion: Previous exposure to zinc ions increases responsiveness to subsequent exposures to zinc and cerium ions. These findings suggest enhanced sensitization possibly due to a reduction in antioxidant defenses.

Keywords:

• Metals
• metal ions
• sensitization
• oxidative stress
• reactive oxygen species
• zinc
• cerium

Acknowledgments

We thank Melissa Curran for editorial assistance.

Declaration of interest

The authors report no conflict of interest.

Additional information

Funding

This study was supported by The Hoffman Program on Chemicals and Health, Harvard T.H. Chan School of Public Health, and National Institutes of Health Grants (ES00002 and HL007118). S.R. and P.Q. received support from the Science Without Borders Program of Brazil administered by CAPES, the Brazilian Coordinating Office for the Advancement of Higher Education. C.W. received support from the Harvard Yerby Fellowship Program.