title: SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation.
abstract: Asthma is a chronic condition with unknown pathogenesis, and recent evidence suggests that enhanced airway epithelial chloride (Cl-) secretion plays a role in the disease. However, the molecular mechanism underlying Cl- secretion and its relevance in asthma pathophysiology remain unknown. To determine the role of the solute carrier family 26, member 9 (SLC26A9) Cl- channel in asthma, we induced Th2-mediated inflammation via IL-13 treatment in wild-type and Slc26a9-deficient mice and compared the effects on airway ion transport, morphology, and mucus content. We found that IL-13 treatment increased Cl- secretion in the airways of wild-type but not Slc26a9-deficient mice. While IL-13-induced mucus overproduction was similar in both strains, treated Slc26a9-deficient mice exhibited airway mucus obstruction, which did not occur in wild-type controls. In a study involving healthy children and asthmatics, a polymorphism in the 3' UTR of SLC26A9 that reduced protein expression in vitro was associated with asthma. Our data demonstrate that the SLC26A9 Cl- channel is activated in airway inflammation and suggest that SLC26A9-mediated Cl- secretion is essential for preventing airway obstruction in allergic airway disease. These results indicate that SLC26A9 may serve as a therapeutic target for airway diseases associated with mucus plugging.
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center, Member of the German Center for Lung Research, University of Heidelberg, Heidelberg, Germany.
authors.forename: Pinelopi
authors.initials: P
authors.lastname: Anagnostopoulou
authors.forename: Brigitte
authors.initials: B
authors.lastname: Riederer
authors.forename: Julia
authors.initials: J
authors.lastname: Duerr
authors.forename: Sven
authors.initials: S
authors.lastname: Michel
authors.forename: Aristea
authors.initials: A
authors.lastname: Binia
authors.forename: Raman
authors.initials: R
authors.lastname: Agrawal
authors.forename: Xuemei
authors.initials: X
authors.lastname: Liu
authors.forename: Katrin
authors.initials: K
authors.lastname: Kalitzki
authors.forename: Fang
authors.initials: F
authors.lastname: Xiao
authors.forename: Mingmin
authors.initials: M
authors.lastname: Chen
authors.forename: Jolanthe
authors.initials: J
authors.lastname: Schatterny
authors.forename: Dorothee
authors.initials: D
authors.lastname: Hartmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.forename: Manoocher
authors.initials: M
authors.lastname: Soleimani
authors.forename: Ursula
authors.initials: U
authors.lastname: Seidler
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
mesh_terms: D020413:3' Untranslated Regions; D000402:Airway Obstruction / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D017920:Antiporters / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001249:Asthma / Q000235:genetics* / Q000503:physiopathology; D001991:Bronchitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D002118:Calcium / Q000494:pharmacology; D002648:Child; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000502:physiology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D018793:Interleukin-13 / Q000633:toxicity; D017136:Ion Transport / Q000502:physiology*; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism*; D000076988:Sulfate Transporters; D018418:Th2 Cells / Q000276:immunology; D014136:Tracheitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*
chemical_list: D020413:3' Untranslated Regions; D017920:Antiporters; D002712:Chlorides; D018793:Interleukin-13; C533708:Slc26a9 protein, mouse; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D002118:Calcium