Effects of a selective ET(A)-receptor antagonist, atrasentan (ABT-627), in murine models of allergic asthma: demonstration of mouse strain specificity.
Asthma is a chronic respiratory disease that is characterized by airway inflammation, bronchoconstriction and the influx of pro-inflammatory cells, mostly eosinophils in the lung tissue and bronchoalveolar space. Amongst the many physiopathological roles attributed to endothelins (ETs), one is to modulate pulmonary functions. It is established that Balb/c mice develop allergen-induced Th(2)-cytokine gene expression, airway inflammation and hyper-responsiveness whereas C57Bl/6 mice are much less reactive. In the present study, we investigated the roles of ETs in these two murine models of allergic asthma (AA). Mice were sensitized and challenged with either saline (S) and/or ovalbumin (O) over 6 weeks (groups S/S and O/O) and treated chronically with ABT-627 or its vehicle. Twenty-four hours after the last sensitization, challenged mice developed a marked airway inflammatory response characterized by the accumulation of total inflammatory cells (a 21-fold increase) in the bronchoalveolar space, similar in both mouse strains. The increase in eosinophils was marked in both groups, representing 98% of total cell count in O/O versus <1% in S/S. Macrophages were also increased 3-fold in both strains. ABT-627 did reduce the accumulation of macrophages in both stains (36 to 53%) whereas it blocked by 76% the influx of eosinophils in Balb/c but not in C57Bl/6 mice. These results show that ET(A)-receptor antagonism is more effective against O/O-induced AA in Balb/c mice, even though both strains were associated with the same increase in key pro-inflammatory cells in the bronchoalveolar space. It is unclear whether this is due to a lack or a disproportionate expression of ET(A) receptors in these two murine strains, or in post-receptor transduction modulation, or different regulation of ET receptors in various pulmonary cells, after sensitization and challenge.
Gosselin
Mélanie
M
Laval Hospital Research Center, Quebec Heart and Lung Institute, 2725 Chemin Ste-Foy, Ste-Foy, QC G1V 4G5, Canada.
Goulet
Stéphanie
S
Wu-Wong
Jinshyun R
JR
Wessale
Jerry L
JL
Opgenorth
Terry J
TJ
Boulet
Louis-Philippe
LP
Battistini
Bruno
B
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D000077868:Atrasentan; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D065128:Endothelin Receptor Antagonists; D004804:Eosinophils / Q000276:immunology; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D013045:Species Specificity
D000970:Antineoplastic Agents; D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D000077868:Atrasentan