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This Article Full Text Full Text (PDF) All Versions of this Article: 289/4/L627    most recent 00377.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Yost, B. L. Articles by Fryer, A. D. Search for Related Content PubMed PubMed Citation Articles by Yost, B. L. Articles by Fryer, A. D.

The changing role of eosinophils in long-term hyperreactivity following a single ozone exposure

Departments of ¹Environmental Health Sciences and ²Medicine, Johns Hopkins University Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; ³School of Medicine, Oregon Health and Science University, Portland, Oregon; ⁴Departments of Immunology and Medicine, Mayo Clinic and Foundation, Rochester, Minnesota; and ⁵Departments of Dermatology and Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah

Submitted 8 October 2004 ; accepted in final form 25 May 2005

Ozone hyperreactivity over 24 h is mediated by blockade of inhibitory M₂ muscarinic autoreceptors by eosinophil major basic protein. Because eosinophil populations in the lungs fluctuate following ozone, the contribution of eosinophils to M₂ dysfunction and airway hyperreactivity was measured over several days. After one exposure to ozone, M₂ function, vagal reactivity, smooth muscle responsiveness, and inflammation were measured in anesthetized guinea pigs. Ozone-induced hyperreactivity to vagal stimulation persisted over 3 days. Although hyperreactivity one day after ozone is mediated by eosinophils, AbVLA-4 did not inhibit either eosinophil accumulation in the lungs or around the nerves or prevent hyperreactivity at this time point. Two days after ozone, eosinophils in BAL, around airway nerves and in lungs, were decreased, and neuronal M₂ receptor function was normal, although animals were still hyperreactive to vagal stimulation. Depleting eosinophils with AbIL-5 prevented hyperreactivity, thus eosinophils contribute to vagal hyperreactivity by mechanisms separate from M₂ receptor blockade. Three days after ozone, vagal hyperreactivity persisted, eosinophils were again elevated in BAL in lungs and around nerves, and M₂ receptors were again dysfunctional. At this point, airway smooth muscle was also hyperresponsive to methacholine. Eosinophil depletion with AbIL-5, AbVLA-4, or cyclophosphamide protected M₂ function 3 days after ozone and prevented smooth muscle hyperreactivity. However, vagal hyperreactivity was significantly potentiated by eosinophil depletion. The site of hyperreactivity, muscle or nerve, changes over 3 days after a single exposure to ozone. Additionally, the role of eosinophils is complex; they mediate hyperreactivity acutely while chronically may be involved in repair.

M₂ muscarinic receptors; vagus nerves