LUNG EOSINOPHILS INCREASE VAGUS NERVE MEDIATED AIRWAY REFLEX BRONCHOCONSTRICTION IN MICE.

BACKGROUND: Eosinophils mediate airway hyperresponsiveness by increasing vagally-mediated reflex bronchoconstriction. Here we tested whether circulating or airway eosinophils change nerve function.

METHODS: Airway resistance in response to aerosolized 5-hydroxytryptamine (5-HT, 10-300 mM) was measured in wild type mice or transgenic mice that over express IL5 in T cells (+IL5T ), over express IL5 in airway epithelium (+IL5AE ), or over express IL5 but devoid of eosinophils (+IL5AE /-Eos). Inflammatory cells in bronchoalveolar lavage (BAL), blood and bone marrow were quantified.

RESULTS: Blood eosinophils were increased in +IL5T and +IL5AE mice compare with wild type mice. +IL5T mice had increased eosinophils in bone marrow while +IL5AE mice had increased eosinophils in BAL. Eosinophils surrounding large airways were significantly increased only in +IL5AE mice. With intact vagal innervation, aerosolized 5-HT significantly increased airway resistance in +IL5AE mice. 5-HT induced bronchoconstriction was blocked by vagotomy or atropine, demonstrating that it was mediated via a vagal reflex. Airway resistance was not increased in +IL5AE /-Eos mice, demonstrating that it required lung eosinophils, but not affected by increased bone marrow or blood eosinophils, or increased IL5 in the absence of eosinophils. Eosinophils did not change M3 function on airway smooth muscle since airway responses to methacholine in vagotomized mice were not different among strains.

CONCLUSIONS: Eosinophils surrounding large airways were sufficient, even in the absence of increased IL5 or external insult, to increase vagally-mediated reflex bronchoconstriction. Specifically blocking or reducing eosinophils surrounding large airway may effectively inhibit reflex hyperresponsiveness mediated by vagus nerves in eosinophilic asthma.