title: The potassium channel KCa3.1 as new therapeutic target for the prevention of obliterative airway disease.
abstract: BACKGROUND
  The calcium-activated potassium channel KCa3.1 is critically involved in T-cell activation as well as in the proliferation of smooth muscle cells and fibroblasts. We sought to investigate whether KCa3.1 contributes to the pathogenesis of obliterative airway disease (OAD) and whether knockout or pharmacologic blockade would prevent the development of OAD.
  
  
  METHODS
  Tracheas from CBA donors were heterotopically transplanted into the omentum of C57Bl/6J wild-type or KCa3.1 mice. C57Bl/6J recipients were either left untreated or received the KCa3.1 blocker TRAM-34 (120 mg/kg/day). Histopathology and immunologic assays were performed on postoperative day 5 or 28.
  
  
  RESULTS
  Subepithelial T-cell and macrophage infiltration on postoperative day 5, as seen in untreated allografts, was significantly reduced in the KCa3.1 and TRAM-34 groups. Also, systemic Th1 activation was significantly and Th2 mildly reduced by KCa3.1 knockout or blockade. After 28 days, luminal obliteration of tracheal allografts was reduced from 89%±21% in untreated recipients to 53%±26% (P=0.010) and 59%±33% (P=0.032) in KCa3.1 and TRAM-34-treated animals, respectively. The airway epithelium was mostly preserved in syngeneic grafts, mostly destroyed in the KCa3.1 and TRAM-34 groups, and absent in untreated allografts. Allografts triggered an antibody response in untreated recipients, which was significantly reduced in KCa3.1 animals. KCa3.1 was detected in T cells, airway epithelial cells, and myofibroblasts. TRAM-34 dose-dependently suppressed proliferation of wild-type C57B/6J splenocytes but did not show any effect on KCa3.1 splenocytes.
  
  
  CONCLUSIONS
  Our findings suggest that KCa3.1 channels are involved in the pathogenesis of OAD and that KCa3.1 blockade holds promise to reduce OAD development.
authors: University of Hamburg, University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Lab (TSI), Cardiovascular Research Center Hamburg (CVRC),Hamburg, Germany.
authors: Xiaoqin
authors: X
authors: Hua
authors: Tobias
authors: T
authors: Deuse
authors: Yi-Je
authors: YJ
authors: Chen
authors: Heike
authors: H
authors: Wulff
authors: Mandy
authors: M
authors: Stubbendorff
authors: Ralf
authors: R
authors: Köhler
authors: Hiroto
authors: H
authors: Miura
authors: Florian
authors: F
authors: Länger
authors: Hermann
authors: H
authors: Reichenspurner
authors: Robert C
authors: RC
authors: Robbins
authors: Sonja
authors: S
authors: Schrepfer
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D058501:Enzyme-Linked Immunospot Assay; D015316:Genetic Therapy; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007518:Isoantibodies / Q000097:blood; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014132:Trachea / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D007518:Isoantibodies; C496925:Kcnn4 protein, mouse; D026902:Potassium Channel Blockers; D011720:Pyrazoles; C411671:TRAM 34