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Published ahead of print on April 30, 2003, doi:10.1164/rccm.200201-021OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 568-574, (2003)
© 2003 American Thoracic Society

Original Article

Chlorine-induced Injury to the Airways in Mice

James G. Martin, Holly R. Campbell, Hiroaki Iijima, Denyse Gautrin, Jean-Luc Malo, David H. Eidelman, Qutayba Hamid and Karim Maghni

Meakins-Christie Laboratories, Department of Medicine, McGill University; and Respiratory Division, Hôpital Sacre Coeur, University of Montreal, Montreal, Quebec, Canada

Correspondence and requests for reprints should be addressed to James G. Martin, M.D., Meakins-Christie Laboratories, 3626 St Urbain, Montreal, PQ, H2X 2P2 Canada. E-mail: james.martin{at}mcgill.ca

Exposure to chlorine gas (Cl2) causes occupational asthma that we hypothesized occurs through the induction of airway inflammation and airway hyperresponsiveness by oxidative damage. Respiratory mechanics and airway responsiveness to methacholine were assessed in A/J mice 24 hours after a 5-minute exposure to 100, 200, 400, or 800 ppm Cl2 and 2 and 7 days after inhalation of 400 ppm Cl2. Airway responsiveness was higher 24 hours after 400 and 800 ppm Cl2. Responsiveness after inhalation of 400 ppm Cl2 returned to normal by 2 days but was again elevated at 7 days. Airway epithelial loss, patchy alveolar damage, proteinaceous exudates, and inflammatory cells within alveolar walls were observed in animals exposed to 800 ppm Cl2. Macrophages, granulocytes, epithelial cells, and nitrate/nitrite levels increased in lung lavage fluid. Increased inducible nitric oxide synthase expression and oxidation of lung proteins were observed. Epithelial cells and alveolar macrophages from mice exposed to 800 ppm Cl2 stained for 3-nitrotyrosine residues. Inhibition of inducible nitric oxide synthase with 1400W (1 mg/kg) abrogated the Cl2-induced changes in responsiveness. We conclude that chlorine exposure causes functional and pathological changes in the airways associated with oxidative stress. Inducible nitric oxide synthase is involved in the induction of changes in responsiveness to methacholine.

Key Words: chlorine • inducible nitric oxide synthase • nitric oxide • oxidative injury




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