Acid aspiration-induced airways hyperresponsiveness in mice

Abstract

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.

Physiological Mechanisms of Airway Hyperresponsiveness in Obese Asthma

“…In fact, this mechanism has been shown to explain almost completely the AHR seen in BALB/c mice during acute allergic inflammation (33). Furthermore, AHR can become extreme if wall thickening is combined with an increased capacity of the ASM to shorten, either as a result of increased delivery of the agonist to the ASM (34,35) or if the ASM has an intrinsically increased capacity to shorten (36).…”

“…This, in fact, may be a very poor assumption. Mice treated with agents known to compromise epithelial barrier function have been shown to become hyperresponsive to methacholine aerosol in a way that can only be explained by a substantially greater fraction of the administered dose reaching the ASM (35,39). In addition, although allergically inflamed mice appear to respond to methacholine aerosol without any increase in ASM shortening, when the same animals are given intravenous injections of methacholine, they respond with greatly exaggerated ASM shortening (40).…”

Mechanical Properties of the Lung

“…The magnitude of the FVC is normally closely related to height and gender (and, to a certain extent, ethnicity), so the value of FVC measured in a particular subject can be compared to its expected value. FVC is typically abnormally low in restrictive lung diseases such as pulmonary fibrosis (Allen et al, 2009).…”

“…The other effort-independent aspect of the lung concerns the maximum _ V that can be achieved during a forced expiration (Allen et al, 2009). Normal individuals above the age of about 5 years can voluntarily generate sufficient expiratory muscle pressure to reach their maximal flows over about the lower 80% of the vital capacity range.…”

AEOL10150: A Novel Therapeutic For Rescue Treatment Following Toxic Gas Lung Injury

“…Additionally, epithelial cells are capable of storing, producing, and releasing large quantities of the antioxidant glutathione in response to oxidative stress. [13] The aim of the current study was to assess the efficacy of a novel catalytic antioxidant in ameliorating airway damage when administered after an acute exposure to inhaled Cl 2 gas. For this purpose, we utilized a catalytic metalloporphyrin that is a member of a novel class of low-molecular-weight antioxidants.…”