Effects of dexamethasone on antigen-induced airway eosinophilia and M(2) receptor dysfunction.
In antigen-challenged guinea pigs, airway hyperreactivity is due to recruitment of eosinophils to the airway nerves and dysfunction of M(2) muscarinic receptors. M(2) receptor dysfunction is caused by eosinophil major basic protein, which is an allosteric antagonist at the receptor. Because glucocorticoids inhibit airway hyperreactivity in humans and in animal models of asthma, we tested whether dexamethasone treatment (6 microg. kg(-)(1). d(-)(1) for 3 d, intraperitoneal) before antigen challenge prevents M(2) receptor dysfunction and airway hyperreactivity. Guinea pigs were sensitized to ovalbumin via intraperitoneal injections, and were challenged with ovalbumin via inhalation. Twenty-four hours later, hyperreactivity and M(2) receptor function were tested. Antigen-challenged animals were hyperreactive to vagal stimulation, and demonstrated loss of M(2) receptor function. Dexamethasone pretreatment prevented hyperreactivity and M(2) receptor dysfunction in antigen-challenged guinea pigs. Antigen challenge resulted in recruitment of eosinophils to the airways and to the airway nerves. Dexamethasone prevented recruitment of eosinophils to the airway nerves but did not affect total eosinophil influx into the airways. These results demonstrate that dexamethasone prevents antigen-induced hyperreactivity by protecting neuronal M(2) muscarinic receptors from antagonism by eosinophil major basic protein, and this protective mechanism appears to be by specifically inhibiting eosinophil recruitment to the airway nerves.
Evans
C M
CM
Department of Environmental Health Sciences, Johns Hopkins School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Jacoby
D B
DB
Fryer
A D
AD
D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology* / Q000627:therapeutic use*; D000941:Antigens / Q000009:adverse effects; D001447:Balantidiasis / Q000276:immunology; D001706:Biopsy; D016535:Bronchial Hyperreactivity / Q000209:etiology*; D003907:Dexamethasone / Q000276:immunology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D005938:Glucocorticoids / Q000276:immunology* / Q000627:therapeutic use*; D006168:Guinea Pigs; D007114:Immunization; D010047:Ovalbumin / Q000009:adverse effects; D011657:Pulmonary Eosinophilia / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D000941:Antigens; D005938:Glucocorticoids; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D003907:Dexamethasone; D010047:Ovalbumin