Involvement of Tachykinin NK₁Receptor in the Development of Allergen-induced Airway Hyperreactivity and Airway Inflammation in Conscious, Unrestrained Guinea Pigs

Abstract

It has been suggested that tachykinin NK1 receptor-mediated neurogenic inflammation, characterized by microvascular leakage, mucus secretion, and infiltration and activation of inflammatory cells in the airways, may be involved in allergic asthma. Therefore, in a guinea pig model of allergic asthma, we investigated the involvement of the NK1 receptor in allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions and airway inflammation, using the selective nonpeptide NK1 receptor antagonist SR140333. On two different occasions, separated by 1 wk interval, OA-sensitized guinea pigs inhaled either saline (3 min) or SR140333 (100 nM, 3 min) at 30 min before as well as at 5.5 h after OA provocation (between the EAR and LAR) in a random crossover design. A control group, receiving saline inhalations before and at 5.5 h after the two OA provocations, was included as well. SR140333 had no significant effect on either the EAR or the LAR compared with saline control inhalations. However, the NK1 receptor antagonist significantly reduced the OA-induced AHR to histamine, both after the EAR at 5 h after OA challenge (1.77 +/- 0.13-fold increase in histamine reactivity versus 2.50 +/- 0.25-fold increase in the control animals, p < 0.01) and after the LAR at 23 h after OA challenge (1.15 +/- 0.12-fold increase versus 1.98 +/- 0. 34-fold increase, respectively, p < 0.05). Moreover, bronchoalveolar lavage studies performed at 25 h after the second OA provocation indicated that SR140333 significantly inhibited the allergen-induced infiltration of eosinophils, neutrophils, and lymphocytes in the airways (p < 0.05 for all observations), whereas a tendency to reduced accumulation of ciliated epithelial cells in the airway lumen was observed (p = 0.10). These results indicate that the NK1 receptor is involved in the development of allergen-induced AHR to histamine, and that NK1 receptor-mediated infiltration of inflammatory cells in the airways may contribute to this AHR.

Activation of Neurokinin-1 Receptors during Ozone Inhalation Contributes to Epithelial Injury and Repair

“…Another potential protective effect of SR140333 may be related to its ability to block substance P-induced vasodilation and microvascular permeability (38). Acute ozone inhalation in humans has been shown to result in the elevation in BAL fluid of several macromolecules normally restricted to the vascular compartment that may contribute to cellular injury and necrosis, including complement 3a (39).…”

The role of the tachykinin NK1 receptor in airway changes in a mouse model of allergic asthma

“…[9][10][11] Our results contrast with another study in guinea pigs in which signaling through the tachykinin NK 1 receptor augmented the allergen-induced infiltration of eosinophils, neutrophils, and lymphocytes in the airways. 3 Differences according to species specificity and/or methodology may explain these conflicting results. In another mouse model of lung inflammation, a NK 1 receptor antagonist reduced significantly the total number of inflammatory cells retrieved by BAL, 16 but this model represented inflammation compartmentalized in lung parenchyma.…”

“…On day 0, all mice where actively immunized with ovalbumin (grade III; Sigma Chemical Co, Poole, UK) by intraperitoneal injection of 10 lg ovalbumin, adsorbed to 1 mg Al(OH) 3 . From days 14 to 21, the mice were exposed daily to PBS or ovalbumin aerosols (1%) for 30 minutes as previously described.…”

“…NK 3 receptors have not been detected in the airways yet, despite emerging functional evidence for a role in inflammation and responsiveness.…”

“…1 In guinea pigs, the tachykinin NK 1 receptor is involved in both the antigen-induced airway hyperresponsiveness to histamine and the infiltration of inflammatory cells. 3 Substance P also exerts several proinflammatory actions on macrophages [4][5][6][7] ; even an autocrine function of this peptide has been suggested. 8 Because alveolar macrophages can be considered the first line of defense against inhaled particular matter and microorganisms, this effect may also contribute to the pathology of asthma.…”