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KCa3.1 as a potential new target for the prevention of chronic allograft vasculopathy and airway allograft rejection
Author(s) -
Chen YiJe Jay,
Hua Xiaoqin,
Schrepfer Sonja,
Köhler Ralf,
Wulff Heike
Publication year - 2011
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.25.1_supplement.1042.12
Subject(s) - medicine , adventitia , transplantation , pathology , sirolimus , mononuclear cell infiltration , lung transplantation , inflammation , infiltration (hvac) , lung , immunology , surgery , physics , thermodynamics
The Ca + ‐activated K + channel KCa3.1 is critically involved in the activation of T cells, macrophages, proliferating vascular smooth muscle cells and fibroblasts. KCa3.1 has therefore been suggested as a potential therapeutic target for diseases where activation and excessive proliferation of one or more of these cell types is involved in the pathology. We here evaluated the KCa3.1 blocker TRAM‐34 in two models of chronic allograft rejection. In an obliterative airway disease model, where tracheas from CBA mice were heterotopically transplanted into the greater omentum of C57Bl6 mice, both genetic deficiency and pharmacological blockade of KCa3.1 with TRAM‐34 reduced luminal obliteration and significantly suppressed IFN‐gamma and IL4 in Elispot assays. We further performed orthotopic aortic transplantations in the PVG‐to‐ACI rat model and evaluated chronic allograft vasculopathy after 120 days. TRAM‐34 dose‐dependently reduced aortic luminal occlusion, adventitia area and mononuclear cell infiltration. Its effectiveness was comparable to the m‐Tor inhibitor rapamycin (0.3 mg/kg). Our findings suggest that KCa3.1 channels are involved in the pathology of obliterative airway disease, a major complication after lung‐transplantation, and chronic allograft vasculopathy, which remains one the major obstacles to long‐term functioning of solid organ transplants. Supported by NIH (RO1GM076063)