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LPS-induced mucin expression in human sinus mucosa can be attenuated by hCLCA inhibitors

Medical Clinic, Research Center Borstel, Borstel, Germany, hphauber{at}web.de

Torsten Goldmann

Department of Pathology, Research Center Borstel, Borstel, Germany

Ekkehard Vollmer

Department of Pathology, Research Center Borstel, Borstel, Germany

Barbara Wollenberg

Clinic of Otolaryngology, University Hospital Schleswig Holstein Campus Lübeck, Lübeck, Germany

Hsiao-Ling Hung

Genaera Corporation, Plymouth Meeting, Pennsylvania, USA

Roy C. Levitt

Genaera Corporation, Plymouth Meeting, Pennsylvania, USA

Peter Zabel

Medical Clinic, Research Center Borstel, Borstel, Germany

Background: hCLCA1 is a member of the calcium-activated chloride channel family and is associated with disease-inducible mucus expression. Niflumic acid (NFA) and a closely related chemical structure are reported inhibitors of calcium-activated chloride channels and endotoxin-inducible mucus expression in the mouse. Therefore, we tested the hypothesis that hCLCA1 may be involved in lipopolysaccharide (LPS) induced mucin up-regulation in human airways. We also investigated the effect of NFA and MSI-2216 on LPS-induced mucin up-regulation.

Materials and Methods : Explanted human airways and the muco-epidermoid cell line Calu-3 were stimulated with LPS. Different concentrations of NFA or MSI-2216 were added to LPS-stimulated airway mucosa and Calu-3 cells. Expression of hCLCA1 and MUC5AC mRNA and protein was quantified in human airways using real-time PCR and PAS staining. In addition, immunohistochemistry was performed for quantification of inflammatory cells (lymphocytes, monocytes, eosinophils, and neutrophils) in the submucosa of the airways. Expression of hCLCA1 protein in Calu-3 cells was analysed by FACS.

Results: LPS significantly induced hCLCA1 and MUC5AC mRNA and protein expression in human airway mucosa (P < 0.05). NFA and MSI-2216 significantly decreased LPS-induced mucus expression in explanted airway mucosa in a dose-dependent manner (P < 0.05). In Calu-3 cells, LPS significantly increased hCLCA1 surface expression whereas intracellular expression was significantly decreased (P < 0.05). In Calu-3 cells, NFA and MSI-2216 also significantly reduced MUC5AC mRNA expression (P < 0.05).

Conclusions: These data suggest that hCLCA1 may play a role in LPS-induced mucin expression in human airway mucosa. Calcium-activated chloride channel inhibitors significantly decreased LPS-induced mucus expression both ex vivo and in vitro . Therefore, blocking of hCLCA1 may offer a therapeutic approach to reduce bacterial-induced mucus hypersecretion.

Key Words: Airway • hCLCA1 • LPS • mucus • niflumic acid

Journal of Endotoxin Research, Vol. 13, No. 2, 109-116 (2007)
DOI: 10.1177/0968051907079168


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