Differential Effects of Dexamethasone on the Proximal and Distal Lung Response to Antigen Challenge in Allergic Cynomolgus Monkeys

Abstract

The proximal and distal portions of the lungs may respond differently to antigen challenge and bronchodilator treatment. This difference may contribute to differences in actual and perceived efficacy of therapies. In this study we used the forced oscillation technique (FOT) to measure impedance in the pulmonary system and discern the effects of antigen challenge on proximal (large airway) and distal (small airway and lung parenchyma) portions of the lung. In addition we treated the animals with two i.m. injections of either a saline control or dexamethasone (0.5 mg/kg) 18 and 1 hour(s) before the antigen challenge. The FOT technique was used to measure indices of proximal airway status, Newtonian airway resistance (R(N)), and distal airway status, including tissue damping (G) and tissue elastance (H). Challenging the animals with Ascaris Suum antigen caused a significant increase in both the proximal and distal lung measures. Pretreatment with dexamethasone significantly reduced the peak increase in R(N) but not G or H. In addition, the area under the curve (AUC) of the FOT response over 60 minutes was significantly reduced for the R(N) but again, G and H were not significantly reduced. These data indicate that, using the FOT, we can dissociate the response of proximal and distal airways to an antigen challenge. Moreover, steroid pre-treatment can reduce the bronchoconstrictor response to inhaled antigen but this effect is primarily via effects on the proximal airways with little effect on the distal airways and parenchymal component of pulmonary impedance. These data may help to provide a mechanism for evaluation of novel therapies for small airway dysfunction.

IL-9 Governs Allergen-induced Mast Cell Numbers in the Lung and Chronic Remodeling of the Airways

“…Similar findings describing a correlation between subepithelial fibrosis and progression of AHR have also been reported in mice after chronic HDM exposure (52). Notably, and in agreement with our observations, a recent study in allergic cynomolgus monkeys suggests that treatments aimed at improving smaller airways dysfunction might be more effective in asthma (53).…”

Principles of Safety Pharmacology

“…Respiratory rate and other measures of respiratory function (e.g., tidal volume or hemoglobin oxygen saturation) should be evaluated. Initial assessment can be performed in NHPs using head-out or whole-body plethysmography (Iizuka et al 2010;Lawler et al 2006;Nalca et al 2010), and follow-up evaluation, such as measurement of pulmonary resistance, can be done in anesthetized animals (Chapman et al 2005;Skeans et al 2005;Curran et al 2008). 7.3, ICH 7A 2000).…”