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DOI: 10.1055/s-0029-1247062
Identifying the potassium channel KCa3.1 as new therapeutic target to prevent chronic airway allograft rejection
Background: Currently there is no effective therapy to prevent obliterative airway disease (OAD) which is the most common cause of morbidity and mortality after lung transplantations. In this study we investigated the relevance of the KCa3.1 channel for OAD and examined the antiproliferative effects of the new KCa3.1 channel blocker TRAM34 after tracheal transplantation in a murine model.
Methods: Trachea from CBA donors were heterotopically transplanted in the greater omentum of C57Bl6 mice (n=6 per group). Recipients were treated for 28 days with TRAM34 (120mg/kg/d i.p.) or left untreated. The KCa3.1 -/- mouse on C57Bl6-background was used as control group. Grafts were harvested and tracheal segments were processed for histological evaluation by computer morphometry determining degree of luminal obliteration and percentage of respiratory epithelium coverage.
Results: Since submucosal and epithelial tissues form the inner lining of the cartilage, the value for luminal obliteration in syngeneic tracheas obtained with this method corresponds to 13.2±3.9%, whereas allogeneic grafts showed a mean obliteration of 92±7% (p<0.001). Luminal obliteration in the KCa3.1-/- group (60±29%) was significant lower than in the allogeneic group (p=0.007), which identifies the KCa3.1 channel as relevant target. The TRAM34 treatment group showed an obliteration of 61±28% (p=0.011 vs. no medication). There was no significant difference between the TRAM34 and the knockout group.
Conclusions: Our findings suggest that KCa3.1 channels are involved in the development of OAD and that TRAM34 holds promise to prevent OAD development.