The potassium channel KCa3.1 as new therapeutic target for the prevention of obliterative airway disease
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The potassium channel KCa3.1 as new therapeutic target for the prevention of obliterative airway disease. / Hua, Xiaoqin; Deuse, Tobias; Chen, Yi-Je; Wulff, Heike; Stubbendorff, Mandy; Köhler, Ralf; Miura, Hiroto; Länger, Florian; Reichenspurner, Hermann; Robbins, Robert C; Schrepfer, Sonja.
In: TRANSPLANTATION, Vol. 95, No. 2, 27.01.2013, p. 285-292.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The potassium channel KCa3.1 as new therapeutic target for the prevention of obliterative airway disease
AU - Hua, Xiaoqin
AU - Deuse, Tobias
AU - Chen, Yi-Je
AU - Wulff, Heike
AU - Stubbendorff, Mandy
AU - Köhler, Ralf
AU - Miura, Hiroto
AU - Länger, Florian
AU - Reichenspurner, Hermann
AU - Robbins, Robert C
AU - Schrepfer, Sonja
PY - 2013/1/27
Y1 - 2013/1/27
N2 - 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.
AB - 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.
KW - Animals
KW - Bronchiolitis Obliterans/genetics
KW - Cell Proliferation/drug effects
KW - Disease Models, Animal
KW - Enzyme-Linked Immunospot Assay
KW - Genetic Therapy
KW - Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors
KW - Isoantibodies/blood
KW - Lymphocyte Activation/drug effects
KW - Macrophages/drug effects
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Inbred CBA
KW - Mice, Knockout
KW - Potassium Channel Blockers/pharmacology
KW - Pyrazoles/pharmacology
KW - Respiratory Mucosa/drug effects
KW - Th1 Cells/drug effects
KW - Th2 Cells/drug effects
KW - Time Factors
KW - Trachea/drug effects
U2 - 10.1097/TP.0b013e318275a2f4
DO - 10.1097/TP.0b013e318275a2f4
M3 - SCORING: Journal article
C2 - 23325003
VL - 95
SP - 285
EP - 292
JO - TRANSPLANTATION
JF - TRANSPLANTATION
SN - 0041-1337
IS - 2
ER -