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Activation of Cold-Sensitive Channels TRPM8 and TRPA1 Inhibits the Proliferative Airway Smooth Muscle Cell Phenotype

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Abstract

Purpose

Airway smooth muscle cell (ASMC) phenotypic modulation is one of the key factors contributing to asthma. Temperature changes may induce asthma, and these changes are known to be related to the temperature-sensitive transient receptor potential channels (TS-TRPs). The present study was designed to investigate the cellular functions of cold-sensitive channels, TRPM8 and TRPA1, in the phenotypic modulation of ASMCs.

Methods

A rat asthma model was constructed and the expression of TS-TRPs in ASM was tested. Using the agonists and antagonists for both TRPM8 and TRPA1, the effects of cold-sensitive channels on the phenotypic modulation of ASMCs were evaluated by measurement of contractile protein expression and cell proliferation and migration. Signaling pathways and matrix metalloproteinase-2 (MMP-2) activity were assayed with Western blotting and gelatin zymography.

Results

TRPM8 and TRPA1 were decreased in the ASM of the rat asthma model. Icilin and menthol, agonists for TRPM8 and TRPA1, inhibited ASMC proliferation and migration induced by fetal bovine serum (FBS) or platelet-derived growth factor (PDGF). Moreover, icilin reversed the FBS-induced inhibition of the expression of contractile phenotype markers, smooth muscle α-actin, and SM22α. Icilin also antagonized the activation of p38 and MMP-2 and the repression of p21 caused by FBS.

Conclusions

Our findings show, for the first time, that the activation of TRPM8 and TRPA1 inhibits ASMC proliferative phenotype. These data suggest that TRPM8 and TRPA1 agonists may be promising new therapies for asthma.

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Acknowledgments

We would like to thank Dr. Weifang Rong for his excellent advice. We would also like to thank Dr. Hanyi Zhuang of Shanghai Jiao Tong University School of Medicine, Yufei Liu of Stanford University, for the grammatical revision of this manuscript. This work was supported by Grants from the National Natural Science Foundation of China (30800380, 81170505, and 81470841). Additionally, this work was sponsored by Shanghai Pujiang Program by Science and Technology Commission of Shanghai Municipality (16PJ1405400).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China

    Lin Zhang

  2. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China

    Qiuyu Wang & Ming He

  3. Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai, China

    Ming He

  4. Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China

    Xiaofei An

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  1. Lin Zhang
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  2. Xiaofei An
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Correspondence to Ming He.

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Zhang, L., An, X., Wang, Q. et al. Activation of Cold-Sensitive Channels TRPM8 and TRPA1 Inhibits the Proliferative Airway Smooth Muscle Cell Phenotype. Lung 194, 595–603 (2016). https://doi.org/10.1007/s00408-016-9901-4

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  • DOI: https://doi.org/10.1007/s00408-016-9901-4

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