Role of insulin in antigen-induced airway eosinophilia and neuronal M2 muscarinic receptor dysfunction.
In the lungs, neuronal M2 muscarinic receptors limit ACh release from parasympathetic nerves. In antigen-challenged animals, eosinophil proteins block these receptors, resulting in increased ACh release and vagally mediated hyperresponsiveness. In contrast, diabetic rats are hyporesponsive and have increased M2 receptor function. Because there is a low incidence of asthma among diabetic patients, we investigated whether diabetes protects neuronal M2 receptor function in antigen-challenged rats. Antigen challenge of sensitized rats decreased M2 receptor function, increased vagally mediated hyperreactivity by 75%, and caused a 10-fold increase in eosinophil accumulation around airway nerves. In antigen-challenged diabetic rats, neuronal M2 receptor function was preserved and there was no eosinophil accumulation around airway nerves. Insulin treatment of diabetic rats completely restored loss of M2 receptor function, vagally mediated hyperresponsiveness, and eosinophilia after antigen challenge. These data demonstrate that insulin is required for development of airway inflammation, loss of neuronal M2 muscarinic receptor function, and subsequent hyperresponsiveness in antigen-challenged rats and may explain decreased incidence of asthma among diabetic humans.
Belmonte
K E
KE
Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins Asthma and Allergy Center, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
Fryer
A D
AD
Costello
R W
RW
D000818:Animals; D000941:Antigens / Q000276:immunology; D001786:Blood Glucose / Q000378:metabolism / Q000502:physiology; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology; D006493:Heparin / Q000494:pharmacology; D007328:Insulin / Q000502:physiology*; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011657:Pulmonary Eosinophilia / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D014630:Vagus Nerve / Q000502:physiology
D000941:Antigens; D001786:Blood Glucose; D007328:Insulin; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D006493:Heparin