Niflumic acid and MSI-2216 reduce TNF-⍺–induced mucin expression in human airway mucosa - 18/08/11
, Patrick Daigneault, MD a, Saul Frenkiel, MD b, Francois Lavigne, MD c, Hsiao-Ling Hung, PhD d, Roy C. Levitt, PhD d, Qutayba Hamid, MD, PhD a
Reprint requests: Hans-Peter Hauber, MD, Department of Medicine, Research Centre Borstel, Parkallee 35, 23845 Borstel, Germany.Montreal, Quebec, Canada, Plymouth Meeting, Pa, and Borstel, Germany
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-⍺ 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-⍺ 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-⍺ 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-⍺–induced mucin expression could be decreased by NFA and MSI-2216. Inhibiting hCLCA1 may be a potential new approach to reduce mucus overproduction.
Le texte complet de cet article est disponible en PDF.Key words : Airway, explant model, hCLCA1, inhibition, laser capture microdissection, MSI-2216, MUC5AC, mucin, niflumic acid, TNF-⍺
Abbreviations used : ALAS-1, CF, COPD, EF-1⍺, hCLCA1, HKG, LCM, MUC, NFA, PAS, QRTPCR, rhTNF-⍺
Plan
| Supported by Genaera Corp and Canadian Institutes of Health Research Canada. Dr Hauber was supported by a GlaxoSmithKline/Canadian Lung Association/Canadian Institutes of Health Research fellowship and the Christiane Herzo Stiftung. Dr Daigneault is supported by the Sick Children Foundation, Toronto, Ontario, Canada. |
Vol 115 - N° 2
P. 266-271 - février 2005 Retour au numéro
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