Effects of a selective ETA-receptor antagonist, atrasentan (ABT-627), in murine models of allergic asthma: demonstration of mouse strain specificity

Abstract

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.

Endothelin A receptor antagonist modulates lymphocyte and eosinophil infiltration, hyperreactivity and mucus in murine asthma

“…The antagonist of ET A receptor markedly reduced the lung eosinophilia, corroborating previous reports [21][22][23].…”

Relationship between endothelin-1 and interleukin-1β in inflamed periodontal tissues

“…In the present study, we demonstrated that ET-1-stimulated upregulation of both IL-1β protein production and secretion by HPdLF and KB cells were inhibited by ET A and ET B receptor antagonists, which block the ET-1 signal to the cells. To date, there have been several reports on the inhibition of inflammatory development by ET receptor antagonists in various diseases (15,16,18,28,30). Thus, the inhibition of ET-1 signaling to cells presents a potential therapeutic approach for controlling the IL-1β-dependent inflammatory response, and treatment with an ET A or ET B receptor antagonist may contribute to regulating the inflammation of gingival tissue.…”

Nonpeptide Ligands That Target Peptide-Activated GPCRs In Inflammation

“…They are 21-residue peptides with 2 intramolecular disulphide bridges. Prominently known for with human psoriasis lesions [67][68][69] [70]) of series designed on a 3,3-diphenyl-2-(pyrimidin-2-yloxy)-propionic acid scaffold [61]. This series has antiinflammatory properties in models of ET-1 induced inflammation and cardiomyopathy and pancreatitis [71,72].…”