University of Hamburg, University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Lab (TSI), Cardiovascular Research Center Hamburg (CVRC),Hamburg, Germany.
Transplantation. 2013 Jan 27;95(2):285-92. doi: 10.1097/TP.0b013e318275a2f4.
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.
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.
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.
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.
钙激活钾通道 KCa3.1 对 T 细胞的激活以及平滑肌细胞和成纤维细胞的增殖至关重要。我们试图研究 KCa3.1 是否有助于闭塞性气道疾病 (OAD) 的发病机制，以及敲除或药物阻断是否可以预防 OAD 的发展。
CBA 供体的气管异位移植到 C57Bl/6J 野生型或 KCa3.1 小鼠的大网膜中。C57Bl/6J 受体未接受治疗或接受 KCa3.1 阻断剂 TRAM-34（120mg/kg/天）治疗。术后第 5 天或第 28 天进行组织病理学和免疫测定。
术后第 5 天，未治疗的同种异体移植物中可见的粘膜下 T 细胞和巨噬细胞浸润，在 KCa3.1 和 TRAM-34 组中明显减少。此外，KCa3.1 敲除或阻断可显著降低系统性 Th1 激活，轻度降低 Th2 激活。28 天后，未治疗受者的同种异体气管移植物管腔闭塞率从 89%±21%降低至 53%±26%（P=0.010）和 59%±33%（P=0.032），分别在 KCa3.1 和 TRAM-34 治疗的动物中。同种移植物的气道上皮在同基因移植物中大部分保留，在 KCa3.1 和 TRAM-34 组中大部分破坏，在未治疗的同种移植物中不存在。同种异体移植物在未治疗的受者中引发抗体反应，在 KCa3.1 动物中明显减少。KCa3.1 在 T 细胞、气道上皮细胞和成纤维细胞中均有检测到。TRAM-34 剂量依赖性地抑制野生型 C57B/6J 脾细胞的增殖，但对 KCa3.1 脾细胞无任何作用。
我们的研究结果表明，KCa3.1 通道参与 OAD 的发病机制，KCa3.1 阻断有望减少 OAD 的发展。
