A calcium-activated chloride channel blocker inhibits goblet cell metaplasia and mucus overproduction.
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.
Zhou
Yuhong
Y
Genaera Corporation, 5110 Campus Drive, Plymouth Meeting, PA 19462, USA.
Shapiro
Michael
M
Dong
Qu
Q
Louahed
Jamila
J
Weiss
Christine
C
Wan
ShanHong
S
Chen
Qiming
Q
Dragwa
Carl
C
Savio
Dawn
D
Huang
Minxue
M
Fuller
Catherine
C
Tomer
Yaniv
Y
Nicolaides
Nicholas C
NC
McLane
Michael
M
Levitt
Roy C
RC
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
C492109:CLCA1 protein, human; D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D005782:Gels; D009077:Mucins; D009088:Mucoproteins; D009544:Niflumic Acid