Eosinophil recruitment to the airway nerves.
Increased vagal reflexes contribute to bronchoconstriction in asthma. Antigen challenge of sensitized animals induces vagal hyperresponsiveness. This review will discuss the evidence that eosinophils increase release of acetylcholine from the parasympathetic nerves. After antigen challenge, eosinophils are actively recruited to the airway nerves, possibly through expression of chemotactic substances and adhesion molecules by the nerves. Tachykinins acting on neurokinin 1 receptors activate the eosinophils. Activated eosinophils release eosinophil major basic protein (MBP), which is an endogenous antagonist for M2 muscarinic receptors. The M2 muscarinic receptors on the parasympathetic nerves in the lungs normally inhibit release of acetylcholine. When M2 receptors are blocked by MBP, acetylcholine release is increased, resulting in hyperresponsiveness. Neutralization of MBP with polyanionic substances restores M2 receptor function and eliminates hyperresponsiveness. Antibodies to MBP prevent M2 receptor dysfunction and hyperresponsiveness, as do antibodies to the adhesion molecule very late antigen 4, which prevent eosinophil migration. A low dose of dexamethasone, which does not affect total eosinophil influx into the lungs and airways, prevents eosinophils from clustering around the nerves and prevents antigen-induced M2 dysfunction and hyperresponsiveness. Furthermore, animal studies show that viral infections, which are important precipitants of asthma attacks, and exposure to air pollutants such as ozone can also activate airway eosinophils, leading to a chain of events similar to that seen after antigen challenge. Finally, a similar clustering of eosinophils around airway nerves, as well as release of MBP onto the nerves, is seen in fatal asthma, suggesting that similar mechanisms may be involved in human airway hyperresponsiveness.
Jacoby
D B
DB
Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Johns Hopkins University, Baltimore, Md 21205, USA.
Costello
R M
RM
Fryer
A D
AD
D001249:Asthma / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D002465:Cell Movement; D004804:Eosinophils / Q000166:cytology*; D006801:Humans; D008168:Lung / Q000294:innervation*; D010275:Parasympathetic Nervous System / Q000502:physiology