title: Activation of Cold-Sensitive Channels TRPM8 and TRPA1 Inhibits the Proliferative Airway Smooth Muscle Cell Phenotype.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: An
authors.affiliation: 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.
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 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. heming@shsmu.edu.cn.|Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai, China. heming@shsmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: He
mesh_terms: D000199:Actins / Q000378:metabolism; D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D001980:Bronchi / Q000166:cytology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003080:Cold Temperature; D004195:Disease Models, Animal; D005260:Female; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008610:Menthol / Q000494:pharmacology; D008840:Microfilament Proteins / Q000378:metabolism; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000074025:TRPA1 Cation Channel / Q000235:genetics / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D014132:Trachea / Q000166:cytology; D054462:p21-Activated Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D002120:Calcium Channel Agonists; D020778:Matrix Metalloproteinase 2; D008610:Menthol; D008840:Microfilament Proteins; D009124:Muscle Proteins; D010982:Platelet-Derived Growth Factor; D011744:Pyrimidinones; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C480976:Trpa1 protein, rat; C498947:Trpm8 protein, rat; C498862:Acta2 protein, rat; C051615:transgelin; C490483:icilin; C522363:Mmp2 protein, rat
keywords: Airway smooth muscle cell; Asthma; Icilin; Proliferative genotype; TRPA1; TRPM8