Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 39, Issue 6, Pages 730-738Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2008-0045OC
Keywords
asthma; eosinophils; cytokines; parasympathetic nerves; lungs
Funding
- National Institutes of Health Grants [HL-55543, ES-014601, HL-54659, HL-071795, RR-023424]
- M.E. Steinberg Fellowship
- [AHA 0810148Z]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL055543, R01HL054659, R01HL071795] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES014601] Funding Source: NIH RePORTER
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Ozone exposure in the lab and environment causes airway hyperreactivity lasting at least 3 days in humans and animals. in guinea pigs I day after ozone exposure, airway hyperreactivity is mediated by eosinophils that block neuronal M-2 muscarinic receptor function, thus increasing acetylcholine release from airway parasympathetic nerves. However, mechanisms of ozone-induced airway hyperreactivity change over time, so that depleting eosinophils 3 days after ozone makes airway hyperreactivity worse rather than better. Ozone exposure increases IL-1 beta in bone marrow, which may contribute to acute and chronic airway hyperreactivity. To test whether IL-1 beta mediates ozone-induced airway hyperreactivity I and 3 days after ozone exposure, guinea pigs were pretreated with an IL-1 receptor antagonist (anakinra, 30 mg/kg, intraperitoneally) 30 minutes before exposure to filtered air or to ozone (2 ppm, 4 h). One or three days after exposure, airway reactivity was measured in anesthetized guinea pigs. The IL-1 receptor antagonist prevented ozone-induced airway hyperreactivity 3 days, but not I day, after ozone exposure. Ozone-induced airway hyperreactivity was vagally mediated, since bronchoconstriction induced by intravenous acetylcholine was not changed by ozone. The IL-1 receptor antagonist selectively prevented ozone-induced reduction of eosinophils around nerves and prevented ozone-induced deposition of extracellular eosinophil major basic protein in airways. These data demonstrate that IL-1 mediates ozone-induced airway hyperreactivity at 3 days, but not I day, after ozone exposure. Furthermore, preventing hyperreactivity was accompanied by decreased eosinophil major basic protein deposition within the lung, suggesting that IL-1 affects eosinophil activation 3 days after ozone exposure.
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