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Ozone-induced loss of neuronal M2 muscarinic receptor function is prevented by cyclophosphamide
L M Gambone1, C L Elbon, A D Fryer
1Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205.
Abstract:
We tested the hypothesis that inflammatory cells mediate the loss of neuronal M2 muscarinic receptors in the lung after ozone exposure. Pathogen-free guinea pigs treated with cyclophosphamide (30 mg.kg-1.day-1 i.p. for 7 days) before exposure to ozone were compared with untreated ozone-exposed animals. This dose of cyclophosphamide significantly reduced leukocytes in peripheral blood and bronchoalveolar lavage fluid. Twenty-four hours after ozone, muscarinic receptor function was tested in anesthetized animals. In air-exposed guinea pigs, vagally induced bronchoconstriction was attenuated by the muscarinic agonist pilocarpine (0.1-100 micrograms/kg i.v.) and potentiated by the selective M2 antagonist gallamine (0.1-10 mg/kg i.v.), indicating that the neuronal M2 muscarinic receptors were functioning. These responses were significantly reduced after ozone, indicating loss of neuronal M2 muscarinic receptor function. However, in those animals treated with cyclophosphamide, M2 muscarinic receptor function was not altered by ozone. These data suggest that ozone-induced loss of neuronal muscarinic receptor function is mediated via inflammatory cells and that the link between ozone-induced hyperresponsiveness and inflammation may be the neuronal M2 muscarinic receptor.
Insights
Ozone exposure reduces neuronal M2 muscarinic receptor function in the lungs. Inflammatory cells mediate this loss, suggesting a link between ozone-induced inflammation and airway hyperresponsiveness.
Area of Science:
- Pulmonary toxicology
- Neuroimmunology
- Respiratory pharmacology
Background:
- Ozone exposure is known to cause airway hyperresponsiveness.
- Neuronal M2 muscarinic receptors play a critical role in regulating airway function.
- The role of inflammatory cells in ozone-induced M2 receptor dysfunction was unclear.
Purpose of the Study:
- To investigate whether inflammatory cells mediate the loss of neuronal M2 muscarinic receptors in the lung following ozone exposure.
- To determine the functional consequences of ozone exposure on M2 muscarinic receptor activity.
Main Methods:
- Guinea pigs were exposed to ozone or filtered air.
- Some animals received cyclophosphamide to deplete leukocytes before ozone exposure.
- Vagally induced bronchoconstriction was measured using muscarinic agonists and antagonists to assess M2 receptor function.
Main Results:
- Ozone exposure significantly reduced neuronal M2 muscarinic receptor function.
- Cyclophosphamide treatment prevented the ozone-induced loss of M2 receptor function.
- Inflammatory cell depletion abrogated the effects of ozone on M2 receptor function.
Conclusions:
- Ozone-induced loss of neuronal M2 muscarinic receptor function is mediated by inflammatory cells.
- Neuronal M2 muscarinic receptors may represent a key link between ozone-induced inflammation and airway hyperresponsiveness.