Methacholine-induced pulmonary gas trapping in a mouse model of allergic asthma: effect of inhaled budesonide and ciglitazone.

Author(s): Stengel PW, Zeckner DJ, Guo WK, Wolos JA, Snyder DW

Affiliation(s): Eli Lilly and Company, Lilly Research Laboratories, 2001 West Main Street, Greenfield, Indiana 46140, USA. stengel_peter_w@lilly.com

Publication date & source: 2008-01-06, Eur J Pharmacol., 578(1):65-75. Epub 2007 Sep 11.

Publication type: Comparative Study

Previously, we found pulmonary gas trapping to be a rapid, simple and objective measure of methacholine-induced airway obstruction in naive mice. In this study we extended that finding by using methacholine-induced pulmonary gas trapping to differentiate airway responses of ovalbumin-sensitized, ovalbumin-exposed (Positive Control) and ovalbumin-sensitized, sodium chloride-exposed (Negative Control) mice. Additionally, pulmonary gas trapping and enhanced pause were compared following methacholine exposure in sensitized and nonsensitized mice. Finally, we examined by nose-only inhalation the ability of the glucocorticosteroid budesonide and the peroxisome proliferator-activated receptor-gamma agonist ciglitazone to modify methacholine-induced airway responses in ovalbumin-sensitized mice. Positive Controls exhibited a 7.8-fold increase in sensitivity and a 2.4-fold enhancement in the maximal airway obstruction to methacholine versus Negative Controls. Following methacholine, individual Positive and Negative Control mouse enhanced pause values overlapped in 9 of 9 studies, whereas individual Positive and Negative Control mouse excised lung gas volume values overlapped in only 1 of 9 studies, and log[excised lung gas volume] correlated (P=0.023) with in vivo log[enhanced pause] in nonsensitized mice. Finally, budesonide (100.0 or 1000.0 microg/kg) reduced methacholine-mediated airway responses and eosinophils and neutrophils, whereas ciglitazone (1000.0 microg/kg) had no effect on methacholine-induced pulmonary gas trapping, but reduced eosinophils. In conclusion, pulmonary gas trapping is a more reproducible measure of methacholine-mediated airway responses in ovalbumin-sensitized mice than enhanced pause. Also, excised lung gas volume changes can be used to monitor drug interventions like budesonide. Finally, this study highlights the importance of running a positive comparator when examining novel treatments like ciglitazone.