Signs and Symptoms of Chest Diseases: Cough |

Role of CDK5 in the Pathogenesis of Cough Reflex Hypersensitivty in Guinea Pigs FREE TO VIEW

Xianghuai Xu, MD; Yu Li, MD; Qiang Chen, MD; Hanjing Lv, MD; Zhongmin Qiu, MD
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Tongji Hospital, Tongji University School of Medicine, Shanghai, China

Copyright 2016, American College of Chest Physicians. All Rights Reserved.

Chest. 2016;149(4_S):A540. doi:10.1016/j.chest.2016.02.564
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SESSION TYPE: Original Investigation Poster

PRESENTED ON: Saturday, April 16, 2016 at 11:45 AM - 12:45 PM

PURPOSE: The purpose of the study is to investigate the influence of CDK5 inhibitor preconditioning on the cough reflex hypersensitivity in chronic cough animal model and to explore the role of CDK5 in the cough reflex hypersensitivity of chronic cough animals.

METHODS: Healthy guinea pigs were subjected to inhlation of citric acid at 0.4 M for 3 min twice daily for a total of 15 days to establish chronic cough. Animals were pre-conditioned with CDK5 inhibitor (Roscovitine), TRPV1 antagonist (Capsazepine) or substance P inhibitor (FK888), and the cough hypersensitivity was determined. ELISA was employed to detect the substance P and CGRP in the BALF, real time PCR and Western blot assay were used to detect the mRNA and protein expressions of CDK5 and TRPV1, respectively, in the trachea and bronchus, and confocal microscopy after fluorescence immunostaining was used to localize the nerve fibers and their distribution by detecting CDK5 and TRPV1 co-expression in the mucosa of the trachea and bronchus.

RESULTS: After pre-conditioning with 3.0 mM roscovitine, the number of cough reduced from 12.5±4.1 to 7.3±2.5 (P=0.028) and the mRNA and protein expressions of TRPV1 in the trachea and bronchus were also lower than in 0.3 mM roscovitine group and 1.0 mM roscovitine group. After pre-conditioning with 5.0 μM capsazepine, the number of cough reduced from 12.5±4.1 to 6.7±3.8 (P=0.025). The cough reflex hypersensitivyt in 5.0 μM capsazepine group was similar to that in 3.0 mM roscovitine group, but pre-conditioning with both capsazepine and roscovitine significantly reduced the number of cough (12.5±4.1 vs 5.1±1.9, P=0.009), and the mRNA and protein expressions of CDK5 and TRPV1 in the trachea and bronchus were also lower. Pre-conditioning with 3.0 mM roscovitine was more potent to inhibit the mRNA and protein expressions of TRPV1; pre-conditioning with 5.0 μM capsazepine showed a poor capability to inhibit the mRNA and protein expressions of CDK5. Pre-conditioning with FK888 alone or in combiantion with above inhibitors failed to further inhibit the cough reflex hypersensitivity.

CONCLUSIONS: Pre-conditioning with roscovitine (an inhibitor of CDK5) at a high concentration may reduce the cough reflex hypersensitivity, which may be related to the activation of afferent vagal C-fibers of the airway and their TRPV1 expression.

CLINICAL IMPLICATIONS: There is evidence showing that a single inhalation of roscovitine, an inhibitor of CDK5, may significantly inhibit the capsaicin inhalation induced cough in healthy guinea pigs.

DISCLOSURE: The following authors have nothing to disclose: Xianghuai Xu, YU Li, Qiang Chen, Hanjing Lv, Zhongmin Qiu

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