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Am. J. Respir. Crit. Care Med., Volume 156, Number 2, August 1997, 367-374

Role for Neurokinin-2 Receptor in Interleukin-5-induced Airway Hyperresponsiveness but not Eosinophilia in Guinea Pigs

ALETTA D. KRANEVELD, FRANS P. NIJKAMP, and ANTOON J. M. VAN OOSTERHOUT

Department of Pharmacology and Pathophysiology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

In the guinea pig, interleukin-5 (IL-5) has been shown to induce airway hyperresponsiveness as well as eosinophilia, which are important symptoms in asthma. IL-5 seems to be a critical cytokine since it selectively affects eosinophil functions. The mechanism of action by which IL-5 leads to airway hyperresponsiveness may be important for our understanding of the pathogenesis of asthma. Neurogenic inflammation, which is mediated by nonadrenergic noncholinergic nerves (NANC), may play a role in the IL-5-induced effects in guinea pig airways. In this study, the role of neuropeptides in the IL-5- induced airway hyperresponsiveness and eosinophilia in the guinea pig was examined using selective neurokinin receptor antagonists. Intra-airway application of IL-5 (1 µg, twice) induces a selective eosinophil migration (control: 12 [8 -22] × 105 cells and IL-5: 90 [67-187] × 105 cells, p < 0.05) and activation (control: 6.3 ± 0.9 ng eosinophil peroxidase [EPO]/ml bronchoalveolar lavage [BAL] fluid and IL-5: 29.3 ± 4.9 ng EPO/ml BAL fluid, p < 0.05) and a pronounced airway hyperresponsiveness in vivo. The maximal responses to histamine are increased by 160 ± 16% (p < 0.05) after IL-5. Treatment of guinea pigs with either the nonselective neurokinin (NK)-receptor antagonist, FK224, or the selective NK2-receptor antagonist, SR48968, results in a complete inhibition of the in vivo hyperresponsiveness found after application of IL-5. Vice versa, intra-airway administration of substance P (10 µg, twice) results in an airway hyperresponsiveness (increased maximal response after substance P: 166 ± 15% [p < 0.05]) without inducing migration or activation of eosinophils. All examined NK- receptor antagonists do not influence the IL-5-induced eosinophil accumulation. In addition, no effect of the NK-receptor antagonists is observed on the IL-5-induced eosinophil activation, as determined by BAL fluid EPO levels. The release of NK2-receptor active tachykinins plays an important role in the development of IL-5-induced airway hyperresponsiveness. This feature appears to be a step following eosinophil infiltration and activation since there are no effects on eosinophil function by pretreatment of the used NK-receptor antagonists.




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