Role of tachykinin NK₁ and NK₂ receptors in allergen‐induced early and late asthmatic reactions, airway hyperresponsiveness, and airway inflammation in conscious, unrestrained guinea pigs

Abstract

Using a guinea pig model of allergic asthma, we investigated the effects of the inhaled, highly selective nonpeptide tachykinin NK1 and NK2 receptor antagonists SR 140333 and SR 48968, respectively, on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions, and infiltration of inflammatory cells in the airways. Both SR 140333 (100 nM, 3 min) and SR 48968 (100 nM, 3 min) had no effect on the severity of the EAR, while the NK2 receptor antagonist SR 48968, but not the NK1 receptor antagonist SR 140333, caused significant inhibition of the LAR. SR 140333 significantly reduced the allergen-induced AHR to histamine, both after the EAR and the LAR. By contrast, SR 48968 did not affect the AHR after the EAR, but significantly attenuated the AHR after the LAR. Bronchoalveolar lavage studies performed after the LAR indicated that SR 140333 caused significant inhibition of allergen-induced infiltration of eosinophils, neutrophils and lymphocytes, while SR 48968 attenuated the infiltration of neutrophils and lymphocytes, but not of eosinophils. Both NK receptor antagonists tended to reduce the accumulation of ciliated epithelial cells in the airways. These results indicate that NK1 and NK2 receptors are importantly, but differentially, involved in the development of allergen-induced airways obstruction, AHR and infiltration of inflammatory cells in the airways. Therefore, both NK1 and NK2 receptor antagonists, or dual NK1 and NK2 antagonists, could be useful in the treatment of allergic asthma.

Regulation of the immune response and inflammation by histamine and histamine receptors

“…The 56-kd H1R is expressed by a broad range of cell types, including neurons, airway and vascular smooth muscle cells, hepatocytes, chondrocytes, endothelial cells, DCs, monocytes, neutrophils, and T and B cells. [26][27][28][29] H1R gene expression can be upregulated by IL-3, IL-4, and histamine. 30 H1R activation results in airway and vascular smooth muscle cell contraction, increased vascular endothelial cell permeability, synthesis of prostacyclin and plateletactivating factor, and release of von Willebrand factor and nitric oxide.…”

Histamine receptor H1 signaling on dendritic cells plays a key role in the IFN-γ/IL-17 balance in T cell–mediated skin inflammation

“…H1R is a Gaq/11 receptor that contains 7 membrane-spanning domains and an extracellular NH2 terminal glycosylated domain. Activation of cellular process after histamine binding to H1R occurs via phospholipase C-mediated calcium mobilization, 6 protein kinase C activation, and nuclear factor-kB-mediated signaling pathways. 7 Histamine, originally considered as a mediator of acute inflammatory and immediate hypersensitivity responses, has also been demonstrated to affect chronic inflammation and regulate several events in the immune response.…”

Histamine in Allergic Inflammation and Immune Modulation

“…The human G q/11 -coupled HR1 is encoded by a single exon gene located on the distal short arm of chromosome 3p25b and contains 487 aminoacids. HR1 is expressed in numerous cells, including airway and vascular smooth muscle cells, hepatocytes, chondrocytes, nerve cells, endothelial cells, DCs, monocytes, neutrophils and T and B cells [18,19,20]. Histamine binds to transmembrane domains 3 and 5.…”