Acid aspiration-induced airways hyperresponsiveness in mice.
The role of gastroesophageal reflux and micro-aspiration as a trigger of airways hyperresponsiveness (AHR) in patients with asthma is controversial. The role of acid reflux and aspiration as a direct cause of AHR in normal subjects is also unclear. We speculated that aspiration of a weak acid with a pH (1.8) equivalent to the upper range of typical gastric contents would lead to AHR in naive mice. We further speculated that modest reductions in aspirate acidity to a level expected during gastric acid suppression therapy (pH 4.0) would impede aspiration-induced AHR. BALB/c female mice were briefly anesthetized with isoflurane and allowed to aspirate 75 microl of saline with HCl (pH 1.8, 4.0, or 7.4) or underwent sham aspiration. Mice were re-anesthetized 2 or 24 h later, underwent tracheostomy, and were coupled to a mechanical ventilator. Forced oscillations were used to periodically measure respiratory impedance (Zrs) following aerosol delivery of saline and increasing doses of methacholine to measure for AHR. Values for elastance (H), airways resistance (R(N)), and tissue damping (G) were derived from Zrs. Aspirate pH of 1.8 led to a significant overall increase in peak R(N), G, and H compared with pH 4.0 and 7.4 at 2 and 24 h. Differences between pH 7.4 and 4.0 were not significant. In mice aspirating pH 1.8 compared with controls, airway lavage fluid contained more neutrophils, higher protein, and demonstrated higher permeability. We conclude that acid aspiration triggers an acute AHR, driven principally by breakdown of epithelial barrier integrity within the airways.
Allen
Gilman B
GB
Department of Medicine, Vermont Lung Center, University of Vermont, Burlington, Vermont, USA. Gil.Allen@uvm.edu
Leclair
Timothy R
TR
von Reyn
Jessica
J
Larrabee
Yuna C
YC
Cloutier
Mary E
ME
Irvin
Charles G
CG
Bates
Jason H T
JH
D000280:Administration, Inhalation; D000336:Aerosols; D000704:Analysis of Variance; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000276:immunology*; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000276:immunology; D006851:Hydrochloric Acid / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D016210:Methacholine Chloride / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D015656:Respiratory Mechanics / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors
D000336:Aerosols; D016210:Methacholine Chloride; D006851:Hydrochloric Acid