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

• Published in: American journal of respiratory and critical care medicine Vol. 156; no. 2; pp. 367 - 374
• Main Authors: KRANEVELD, ALETTA D., NIJKAMP, FRANS P., VAN OOSTERHOUT, ANTOON J. M.
• Format: Journal Article
• Language: English
• Published: New York, NY American Lung Association 01.08.1997
• Subjects: Airway Resistance - drug effects; Animals; Biological and medical sciences; Bronchial Hyperreactivity - chemically induced; Bronchial Hyperreactivity - physiopathology; Bronchoalveolar Lavage Fluid - cytology; Chronic obstructive pulmonary disease, asthma; Dipeptides - pharmacology; Eosinophilia - chemically induced; Eosinophilia - physiopathology; Eosinophils - cytology; Eosinophils - drug effects; Eosinophils - physiology; Guinea Pigs; Indoles - pharmacology; Interleukin-5 - pharmacology; Leukocyte Count - drug effects; Male; Medical sciences; Peptides, Cyclic - pharmacology; Pneumology; Receptors, Neurokinin-2 - antagonists & inhibitors; Receptors, Neurokinin-2 - drug effects; Receptors, Neurokinin-2 - physiology; Specific Pathogen-Free Organisms; Substance P - pharmacology; Immunopathology; Allergy; Neurokinin 2; Hyperreactivity; Respiratory disease; Pathogenesis; Cytokine; Hemopathy; Eosinophilia; Asthma; Pig; Respiratory tract; Vertebrata; Mammalia; Interleukin 5; Animal; Artiodactyla; Obstructive pulmonary disease; Ungulata
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/ajrccm.156.2.9608101

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 microgram, twice) induces a selective eosinophil migration (control: 12 [8-22] x 10(5) cells and IL-5: 90 [67-187] x 10(5) 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 micrograms, 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.