Document Detail


The potassium channel KCa3.1 as new therapeutic target for the prevention of obliterative airway disease.
MedLine Citation:
PMID:  23325003     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Xiaoqin Hua; Tobias Deuse; Yi-Je Chen; Heike Wulff; Mandy Stubbendorff; Ralf Köhler; Hiroto Miura; Florian Länger; Hermann Reichenspurner; Robert C Robbins; Sonja Schrepfer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Transplantation     Volume:  95     ISSN:  1534-6080     ISO Abbreviation:  Transplantation     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-17     Completed Date:  2013-03-07     Revised Date:  2014-01-28    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  285-92     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bronchiolitis Obliterans / genetics,  immunology,  metabolism,  pathology,  prevention & control*
Cell Proliferation / drug effects
Disease Models, Animal
Enzyme-Linked Immunospot Assay
Genetic Therapy*
Intermediate-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors*,  deficiency,  genetics,  metabolism*
Isoantibodies / blood
Lymphocyte Activation / drug effects
Macrophages / drug effects,  immunology,  metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Knockout
Potassium Channel Blockers / pharmacology*
Pyrazoles / pharmacology*
Respiratory Mucosa / drug effects,  metabolism,  pathology
Th1 Cells / drug effects,  immunology,  metabolism
Th2 Cells / drug effects,  immunology,  metabolism
Time Factors
Trachea / drug effects*,  immunology,  metabolism,  pathology,  transplantation
Grant Support
ID/Acronym/Agency:
R01 GM076063/GM/NIGMS NIH HHS; R01 GM076063/GM/NIGMS NIH HHS; R01 HL080173/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Intermediate-Conductance Calcium-Activated Potassium Channels; 0/Isoantibodies; 0/Kcnn4 protein, mouse; 0/Potassium Channel Blockers; 0/Pyrazoles; 0/TRAM 34
Comments/Corrections

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