Cyproheptadine-induced attenuation of type-I immediate-hypersensitivity reactions of airway smooth muscle from immune-sensitized cats

Philip A. Padrid From the Asthma, Allergy, and Immunology Disease Research Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine (Padnd, Mitchell, Ndukwu, Cozzi, Left), and the Committees on Comparative Medicine and Pathology (Padrid), Cell Physiology and Clinical Pharmacology (Leff), Division of the Biological Sciences, The University of Chicago, Chicago, IL 60637, and the Eli Lilly Corp, Indianapolis, IN 46206 (Spaethe).

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Richard W. Mitchell From the Asthma, Allergy, and Immunology Disease Research Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine (Padnd, Mitchell, Ndukwu, Cozzi, Left), and the Committees on Comparative Medicine and Pathology (Padrid), Cell Physiology and Clinical Pharmacology (Leff), Division of the Biological Sciences, The University of Chicago, Chicago, IL 60637, and the Eli Lilly Corp, Indianapolis, IN 46206 (Spaethe).

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I. M. Ndukwu From the Asthma, Allergy, and Immunology Disease Research Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine (Padnd, Mitchell, Ndukwu, Cozzi, Left), and the Committees on Comparative Medicine and Pathology (Padrid), Cell Physiology and Clinical Pharmacology (Leff), Division of the Biological Sciences, The University of Chicago, Chicago, IL 60637, and the Eli Lilly Corp, Indianapolis, IN 46206 (Spaethe).

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Stephen Spaethe From the Asthma, Allergy, and Immunology Disease Research Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine (Padnd, Mitchell, Ndukwu, Cozzi, Left), and the Committees on Comparative Medicine and Pathology (Padrid), Cell Physiology and Clinical Pharmacology (Leff), Division of the Biological Sciences, The University of Chicago, Chicago, IL 60637, and the Eli Lilly Corp, Indianapolis, IN 46206 (Spaethe).

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Peter Shiou From the Asthma, Allergy, and Immunology Disease Research Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine (Padnd, Mitchell, Ndukwu, Cozzi, Left), and the Committees on Comparative Medicine and Pathology (Padrid), Cell Physiology and Clinical Pharmacology (Leff), Division of the Biological Sciences, The University of Chicago, Chicago, IL 60637, and the Eli Lilly Corp, Indianapolis, IN 46206 (Spaethe).

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Phillip Cozzi From the Asthma, Allergy, and Immunology Disease Research Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine (Padnd, Mitchell, Ndukwu, Cozzi, Left), and the Committees on Comparative Medicine and Pathology (Padrid), Cell Physiology and Clinical Pharmacology (Leff), Division of the Biological Sciences, The University of Chicago, Chicago, IL 60637, and the Eli Lilly Corp, Indianapolis, IN 46206 (Spaethe).

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Alan R. Leff From the Asthma, Allergy, and Immunology Disease Research Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine (Padnd, Mitchell, Ndukwu, Cozzi, Left), and the Committees on Comparative Medicine and Pathology (Padrid), Cell Physiology and Clinical Pharmacology (Leff), Division of the Biological Sciences, The University of Chicago, Chicago, IL 60637, and the Eli Lilly Corp, Indianapolis, IN 46206 (Spaethe).

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SUMMARY

We assessed the effect of serotonergic inhibition by cyproheptadine on the responsiveness of tracheal smooth muscle (tsm) strips and epithelium-intact third-generation bronchial rings from immune-sensitized (Ascaris suum) cats after exposure to antigen. Cats were sensitized by im administration of antigen and adjuvant twice over a 4-week period. Sensitization was confirmed in vivo by skin testing with antigen and by physiologic airway responses after exposure to nebulized antigen. Tissues were tethered isometrically to force transducers and were actively equilibrated by exposures to KCl-substituted perfusate. Maximal response after exposure to antigen (expressed as percentage of maximal contraction of each tissue to 63 mM KCl (%KCl) was 169 ± 18% KCl for sensitized tsm and 43 ± 18% KCl for sensitized tsm pretreated with cyproheptadine (P < 0.001). Similarly, maximal response to antigen was 81 ± 27% KCl for sensitized bronchial rings, compared with 16 ± 14% KCl for sensitized bronchial rings pretreated with cyproheptadine (P = 0.05 vs control). Blockade of leukotriene synthesis by 10−6 to 10−4 M A-64077, a selective 5-lipoxygenase inhibitor, had no significant effect on peak response for either tsm (193 ± 13% KCl vs 169 ± 18% KCl for sensitized untreated tsm) or bronchial rings (79 ± 20% KCl vs 81 ± 27% KCl for sensitized untreated bronchial rings). Release of serotonin from airway tissues was confirmed by the presence of serotonin in the perfusate of 8 sensitized tsm preparations after, but not before, antigen challenge. Our data indicate that airways from immune-sensitized cats have typical immediate-type hypersensitivity responses when exposed to antigen and that these responses are inhibited by serotonin-receptor blockade, but not by blockade of 5-lipoxygenase. These data implicate serotonin as an important mediator in the immediate-type hypersensitivity reaction in the immune-sensitized airways of cats and suggest a potential role for serotonin antagonists in the clinical treatment of asthma in this species.

SUMMARY

We assessed the effect of serotonergic inhibition by cyproheptadine on the responsiveness of tracheal smooth muscle (tsm) strips and epithelium-intact third-generation bronchial rings from immune-sensitized (Ascaris suum) cats after exposure to antigen. Cats were sensitized by im administration of antigen and adjuvant twice over a 4-week period. Sensitization was confirmed in vivo by skin testing with antigen and by physiologic airway responses after exposure to nebulized antigen. Tissues were tethered isometrically to force transducers and were actively equilibrated by exposures to KCl-substituted perfusate. Maximal response after exposure to antigen (expressed as percentage of maximal contraction of each tissue to 63 mM KCl (%KCl) was 169 ± 18% KCl for sensitized tsm and 43 ± 18% KCl for sensitized tsm pretreated with cyproheptadine (P < 0.001). Similarly, maximal response to antigen was 81 ± 27% KCl for sensitized bronchial rings, compared with 16 ± 14% KCl for sensitized bronchial rings pretreated with cyproheptadine (P = 0.05 vs control). Blockade of leukotriene synthesis by 10−6 to 10−4 M A-64077, a selective 5-lipoxygenase inhibitor, had no significant effect on peak response for either tsm (193 ± 13% KCl vs 169 ± 18% KCl for sensitized untreated tsm) or bronchial rings (79 ± 20% KCl vs 81 ± 27% KCl for sensitized untreated bronchial rings). Release of serotonin from airway tissues was confirmed by the presence of serotonin in the perfusate of 8 sensitized tsm preparations after, but not before, antigen challenge. Our data indicate that airways from immune-sensitized cats have typical immediate-type hypersensitivity responses when exposed to antigen and that these responses are inhibited by serotonin-receptor blockade, but not by blockade of 5-lipoxygenase. These data implicate serotonin as an important mediator in the immediate-type hypersensitivity reaction in the immune-sensitized airways of cats and suggest a potential role for serotonin antagonists in the clinical treatment of asthma in this species.

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