Neurokinin-1 and neurokinin-2 antagonism inhibits long-term acid fog-induced airway hyperresponsiveness.
BACKGROUND
We recently reported that airway hyperresponsiveness (AHR) induced by a 6-h exposure to sulfuric acid (H(2)SO(4)) was inhibited by either the neurokinin (NK)-1 receptor antagonist, FK888, or the NK-2 receptor antagonist, SR48968, when administered immediately before the exposure. The aims of this study were to determine whether these antagonists have any therapeutic efficiency against AHR after long-term H(2)SO(4) inhalation and to elucidate the mechanisms in ovalbumin sensitized guinea pigs.


METHODS
Specific airway resistance (sRaw), AHR, and BAL fluid were analyzed after an 8-week exposure to H(2)SO(4) aerosol (82 mg/m(3), pH 1.7, 40 mOsm) or hypotonic saline solution (pH 5.9, 40 mOsm) as a control. The H(2)SO(4) group then received a 2-week treatment with FK888, SR48968, or vehicle.


RESULTS
The AHR and the eosinophil count in BAL fluid were significantly increased in the H(2)SO(4) group compared to control animals, while sRaw was significantly elevated in both groups after the 8-week exposure. Treatment with both FK888 and SR48968 significantly reduced the AHR and tended to inhibit eosinophilia in BAL fluid, but sRaw did not change. The degree of AHR improvement with SR48968 was much larger than with FK888.


CONCLUSIONS
Our results show that both NK-1 and NK-2 receptor antagonists inhibited long-term H(2)SO(4)-induced AHR in sensitized guinea pigs, and the effect was much greater with an NK-2 antagonist. We suggest that NK-1 or NK-2 antagonism might partially inhibit the H(2)SO(4)-induced influx of eosinophils into the lung.
Teramoto
Shin
S
Third Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan. teramoto@sapmed.ac.jp
Tanaka
Hiroshi
H
Kaneko
Satoshi
S
Abe
Shosaku
S
D000403:Airway Resistance / Q000187:drug effects / Q000276:immunology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology*; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004151:Dipeptides / Q000494:pharmacology*; D004802:Eosinophilia / Q000139:chemically induced / Q000276:immunology; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology*; D007958:Leukocyte Count; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D013464:Sulfuric Acids / Q000633:toxicity*; D014887:Weather
D001549:Benzamides; D004151:Dipeptides; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D013464:Sulfuric Acids; C078949:FK 888; C073839:SR 48968; C033158:sulfuric acid