Retraction.

Abstract

Early life exposure to environmentally relevant ozone (O 3 ) may have long term consequences for asthma susceptibility. Earlier studies showed that mice exposed to intermittent, repeated O 3 during early life (1 ppm x 3h/day, 3 days/week x 4 weeks) demonstrated airway hyperresponsiveness (AHR) to inhaled methacholine challenge compared with filtered air controls at adult age (4 wk), and after an additional 4 wk recovery period (age 8wk). To determine the mechanism, we exposed mice to filtered air or O 3 as described above beginning at birth. After two weeks recovery in air, we measured ex vivo tracheal smooth muscle mechanics in response to acetylcholine and electrical field stimulation. We found significant but relatively modest impairment of relaxation in ozone exposed mice. In vivo measurements of respiratory system mechanics using forced oscillometry in response to nebulized methacholine showed persistence of O 3 -exposure induced AHR that was substantially ablated in mice that had undergone: 1) pre-treatment with muscarinic receptor agonist pilocarpine, or 2) bilateral cervical vagotomy, just before undergoing forced oscillometry. Separate treatment groups that received intravenous acetylcholine in place of nebulized methacholine showed no O 3 effect on AHR. Bronchoalveolar lavage of mice after two or four weeks recovery following air or O 3 exposure showed elevations of serum albumin, a marker of airway epithelial permeability in excess of total protein. We conclude that O 3 exposure in early life induces AHR to nebulized methacholine that is largely dependent on vagal innervation and increased airway epithelial permeability, and to a lesser extent on impaired smooth muscle relaxation.