Dissociation of inflammatory and epithelial responses in a murine model of chronic asthma.
To study pathogenetic mechanisms in chronic asthma, we employed a novel experimental model that replicates characteristic features of the human disease. Chronic inflammation and epithelial changes, specifically localized to the airways, were induced by repeated exposure of systemically sensitized BALB/c mice to low mass concentrations of aerosolized ovalbumin for 6 weeks. The contribution of Th2 cytokine-driven inflammation to the development of airway lesions and hyperreactivity was assessed in cytokine-deficient mice. In interleukin-5-deficient animals, intraepithelial eosinophils and chronic inflammatory cells in the lamina propria of the airways were markedly decreased; however, these animals developed epithelial hypertrophy and subepithelial fibrosis comparable with that observed in sensitized wild type mice. Airway hyperreactivity to inhaled methacholine did not develop in interleukin-5-deficient mice. In contrast, interleukin-4-deficient mice exhibited no decrease in airway inflammation, but had significantly greater epithelial hypertrophy and subepithelial fibrosis, as well as exaggerated hyperreactivity to methacholine. We conclude that interleukin-5, but not interleukin-4, plays a central role in the development of chronic inflammation of the airways and the induction of airway hyperreactivity. Furthermore, chronic epithelial and fibrotic changes occur independently of interleukin-5 and are not required for the development of airway hyperreactivity. The dissociation between airway wall remodeling and airway hyperreactivity has important implications for therapeutic approaches to chronic asthma.
Foster
P S
PS
Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra. Paul.Foster@anu.edu.au
Ming
Y
Y
Matthei
K I
KI
Young
I G
IG
Temelkovski
J
J
Kumar
R K
RK
D000818:Animals; D001249:Asthma / Q000209:etiology*; D002465:Cell Movement; D002908:Chronic Disease; D004195:Disease Models, Animal; D004848:Epithelium / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006984:Hypertrophy; D007249:Inflammation / Q000209:etiology*; D015847:Interleukin-4 / Q000502:physiology; D015848:Interleukin-5 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000502:physiology
D015848:Interleukin-5; D015847:Interleukin-4