title: Niflumic acid and AG-1478 reduce cigarette smoke-induced mucin synthesis: the role of hCLCA1.
abstract: BACKGROUND
  Cigarette smoke induces bronchial mucus secretion. However, the mechanism of this induction is still unidentified. In this study, we investigated the role of the putative calcium-activated chloride channel 1 (CLCA1) and its blocker, niflumic acid, in cigarette smoke-induced mucin synthesis both in vivo and in vitro.
  
  
  RESULTS
  Sprague-Dawley rats were exposed to cigarette smoke for 4 weeks. The CLCA1, epidermal growth factor receptor (EGFR), and MUC5AC expressions were increased in the trachea and lung tissues. Goblet-cell hyperplasia with marked mucin staining was detected in the tracheal and bronchial epithelium. In the human bronchial epithelial cell line NCI-H292, cigarette smoke solution also induced mucin production as well as the RNA and protein expressions of CLCA1, EGFR, and MUC5AC. Both in vivo and in vitro, the induction of MUC5AC and mucin synthesis were inhibited by niflumic acid, and/or a selective EGFR tyrosine kinase inhibitor, AG-1478. Niflumic acid also blocked the epidermal growth factor-induced MUC5AC and mucin staining in the NCI-H292 cell line.
  
  
  CONCLUSIONS
  Both EGFR and niflumic acid-sensitive chloride channels (probably CLCA1) are dependently affecting the mucin production as a part of a single complex signaling pathway. CLCA1 may be a key signaling member that can be targeted with pharmacologic interventions to treat mucus hypersecretion.
authors.affiliation: Department of Pulmonary Medicine, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Hegab
authors.forename: Tohru
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nomura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishii
authors.forename: Yuko
authors.initials: Y
authors.lastname: Morishima
authors.forename: Takashi
authors.initials: T
authors.lastname: Iizuka
authors.forename: Takumi
authors.initials: T
authors.lastname: Kiwamoto
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Matsuno
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Homma
authors.forename: Kiyohisa
authors.initials: K
authors.lastname: Sekizawa
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001984:Bronchial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018277:Carcinoma, Mucoepidermoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018118:Chloride Channels / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D055271:Mucin 5AC; D009077:Mucins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D009544:Niflumic Acid / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011799:Quinazolines; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018118:Chloride Channels; C504023:Clca5 protein, rat; C524678:MUC5AC protein, human; C524680:Muc5ac protein, rat; D055271:Mucin 5AC; D009077:Mucins; D011799:Quinazolines; D012333:RNA, Messenger; D020032:Tyrphostins; C101044:RTKI cpd; D009544:Niflumic Acid; D066246:ErbB Receptors; D017027:Protein Tyrosine Phosphatases