Methacholine-induced pulmonary gas trapping in a mouse model of allergic asthma: effect of inhaled budesonide and ciglitazone.
Previously, we found pulmonary gas trapping to be a rapid, simple and objective measure of methacholine-induced airway obstruction in naïve 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.
Stengel
Peter W
PW
Eli Lilly and Company, Lilly Research Laboratories, 2001 West Main Street, Greenfield, Indiana 46140, USA. stengel_peter_w@lilly.com
Zeckner
Douglas J
DJ
Guo
Wen-Kai Kevin
WK
Wolos
Jeffrey A
JA
Snyder
David W
DW
D000280:Administration, Inhalation; D000402:Airway Obstruction / Q000139:chemically induced / Q000188:drug therapy; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019819:Budesonide / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010047:Ovalbumin; D047495:PPAR gamma / Q000819:agonists; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*
D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D016210:Methacholine Chloride; D019819:Budesonide; D010047:Ovalbumin; C039671:ciglitazone