title: Niflumic acid and MSI-2216 reduce TNF-alpha-induced mucin expression in human airway mucosa.
abstract: BACKGROUND
  Human chloride channel, calcium-activated 1 (hCLCA1) has been shown to induce mucin (MUC) gene expression and mucus production in bronchial epithelial cells. Objective To investigate whether blocking hCLCA1 decreases mucus production.
  
  
  METHODS
  Expression of hCLCA1 and mucus was stimulated with TNF-alpha in human upper airway mucosal explant tissue. MUC5AC mRNA and mucus protein expression was blocked by inhibiting hCLCA1 by using channel blockers (niflumic acid [NFA] and MSI-2216) without and with TNF-alpha stimulation. Expression of MUC5AC, hCLCA1, and COX-2 mRNA was quantified by using real-time PCR. Mucus protein was assessed by periodic acid Schiff staining. Laser capture microdissection was performed to quantify hCLCA1 and MUC5AC mRNA expression in epithelial cells derived from mucosal explant tissue.
  
  
  RESULTS
  TNF-alpha significantly increased MUC5AC and hCLCA1 mRNA as well as mucus and hCLCA1 protein expression in the mucosal explant tissue ( P < .05). Inhibition of hCLCA1 with NFA or MSI-2216 showed a significant dose-dependent reduction of mucus production for both blockers in the mucosal explant tissue ( P < .05). MUC5AC mRNA was also decreased by both blockers in the whole mucosal tissue and in laser-captured mucosa epithelial cells.
  
  
  CONCLUSIONS
  Unstimulated and TNF-alpha-induced mucin expression could be decreased by NFA and MSI-2216. Inhibiting hCLCA1 may be a potential new approach to reduce mucus overproduction.
authors.affiliation: Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada. hphauber@fz-borstel.de
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hauber
authors.forename: Patrick
authors.initials: P
authors.lastname: Daigneault
authors.forename: Saul
authors.initials: S
authors.lastname: Frenkiel
authors.forename: Francois
authors.initials: F
authors.lastname: Lavigne
authors.forename: Hsiao-Ling
authors.initials: HL
authors.lastname: Hung
authors.forename: Roy C
authors.initials: RC
authors.lastname: Levitt
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology*; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002908:Chronic Disease; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007834:Lasers; D008565:Membrane Proteins; D055271:Mucin 5AC; D009077:Mucins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009093:Mucus / Q000187:drug effects; D009544:Niflumic Acid / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D012852:Sinusitis / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C492109:CLCA1 protein, human; D002121:Calcium Channel Blockers; D018118:Chloride Channels; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; C524678:MUC5AC protein, human; D008565:Membrane Proteins; D055271:Mucin 5AC; D009077:Mucins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009544:Niflumic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases