IL-1 receptors mediate persistent, but not acute, airway hyperreactivity to ozone in guinea pigs.
Ozone exposure in the lab and environment causes airway hyperreactivity lasting at least 3 days in humans and animals. In guinea pigs 1 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-1beta in bone marrow, which may contribute to acute and chronic airway hyperreactivity. To test whether IL-1beta mediates ozone-induced airway hyperreactivity 1 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 1 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 1 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.
Verhein
Kirsten C
KC
Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, USA.
Jacoby
David B
DB
Fryer
Allison D
AD
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001919:Bradycardia / Q000150:complications; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid; D004558:Electric Stimulation; D047093:Eosinophil Major Basic Protein / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D007275:Injections, Intravenous; D053583:Interleukin-1beta / Q000378:metabolism; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010126:Ozone / Q000494:pharmacology*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014630:Vagus Nerve / Q000187:drug effects
D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D010126:Ozone; D047093:Eosinophil Major Basic Protein; D000109:Acetylcholine