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Th2 driven anion conductance in airway epithelium is lost in the mCLCA3 knockout mouse
Author(s) -
Loewen Matthew E,
Mortimer James R,
Hanrahan John W,
Xanthoudakis Steven
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a348-a
Subject(s) - knockout mouse , mucus , ovalbumin , mucociliary clearance , cystic fibrosis transmembrane conductance regulator , chloride channel , chemistry , gene knockout , immunology , respiratory epithelium , bronchoalveolar lavage , endocrinology , medicine , microbiology and biotechnology , respiratory system , lung , biology , immune system , biochemistry , gene , ecology
Ion transport creates the osmotic drive for appropriate airway hydration, which is essential for mucociliary clearance, the primary lung defense mechanism. Microbial insult or immunological dysregulation results in a strong, Th2‐driven cytokine response, which stimulates fluid secretion and the clearance of mucus and microbes. This response is primarily mediated by an increase in calcium activated chloride conductance. mCLCA3, a putative regulator of calcium activated chloride channels, is highly up‐regulated in asthma. We used mCLCA3 knockout mice to assess the role of this gene in Th2‐induced conductance. Physiologic properties of homozygous, heterozygous knockout mice and wild type mCLCA3 littermates were compared in two preclinical models of asthma. Cohorts were challenged with either recombinant IL‐13 by intranasal administration or whole‐body exposure to ovalbumin (OVA), and short‐circuit current was measured across freshly excised tracheas. The Th2 driven increase in DIDS‐sensitive calcium activated chloride conductance was dependent on mCLCA3 gene dose. Genechip analysis of OVA‐treated knockout and littermate control mice did not reveal any changes in the expression of known channel proteins. Reduced Cl conductance in the mCLCA3 KOs may reduce airway hydration and mucus clearance, thereby explaining, in part, the increase in mucus found in bronchoaveolar lavage of the mCLCA3 knockout mouse under Th2‐challenged conditions. Supported in part by NSERC and the Breathe program of the Canadian CF Foundation and CIHR.