title: A calcium-activated chloride channel blocker inhibits goblet cell metaplasia and mucus overproduction.
abstract: We have previously shown that expression of a Ca2+-activated Cl- channel (mCLCA3 in mice and bCLCA1 in humans) is up-regulated along with goblet cell metaplasia and mucus overproduction in the lungs of interleukin 9 (IL9) transgenic mice, and in human primary lung cultures by IL4, IL13 and IL9. We show here that hCLCA1 expression in NCI-H292 cells specifically induces soluble gel-forming mucin production. Moreover, niflumic acid (NFA), a blocker of hCLCA1-dependent Cl- efflux, inhibits MUC5A/C production in these cells. NFA treatment during natural antigen-exposure, where mCLCA3 is greatly up-regulated in the lung, significantly reduces airway inflammation, goblet cell metaplasia and mucus overproduction in vivo. These data suggest that this Ca2+-activated Cl- channel plays an important role in epithelial-regulated inflammatory responses, including goblet cell metaplasia, and represents a potential novel therapeutic target for the control of mucus overproduction in chronic pulmonary disorders.
authors.affiliation: Genaera Corporation, 5110 Campus Drive, Plymouth Meeting, PA 19462, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Michael
authors.initials: M
authors.lastname: Shapiro
authors.forename: Qu
authors.initials: Q
authors.lastname: Dong
authors.forename: Jamila
authors.initials: J
authors.lastname: Louahed
authors.forename: Christine
authors.initials: C
authors.lastname: Weiss
authors.forename: ShanHong
authors.initials: S
authors.lastname: Wan
authors.forename: Qiming
authors.initials: Q
authors.lastname: Chen
authors.forename: Carl
authors.initials: C
authors.lastname: Dragwa
authors.forename: Dawn
authors.initials: D
authors.lastname: Savio
authors.forename: Minxue
authors.initials: M
authors.lastname: Huang
authors.forename: Catherine
authors.initials: C
authors.lastname: Fuller
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Tomer
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Nicolaides
authors.forename: Michael
authors.initials: M
authors.lastname: McLane
authors.forename: Roy C
authors.initials: RC
authors.lastname: Levitt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects* / Q000502:physiology; D003433:Crosses, Genetic; D005782:Gels; D020397:Goblet Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007158:Immunologic Techniques; D007249:Inflammation; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009077:Mucins / Q000096:biosynthesis / Q000737:chemistry; D009088:Mucoproteins / Q000187:drug effects* / Q000502:physiology; D009544:Niflumic Acid / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility
chemical_list: C492109:CLCA1 protein, human; D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D005782:Gels; D009077:Mucins; D009088:Mucoproteins; D009544:Niflumic Acid