The potassium channel KCa3.1 as New therapeutic target for the prevention of obliterative airway disease

Xiaoqin Hua, Tobias Deuse, Yi-Je Chen, Heike Wulff, Mandy Stubbendorff, Ralf Köhler, Hiroto Miura, Florian Länger, Hermann Reichenspurner, Robert C. Robbins, Sonja Schrepfer

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)285-292
Number of pages8
JournalTransplantation
Volume95
Issue number2
DOIs
StatePublished - Jan 27 2013

Keywords

  • Chronic rejection
  • Heterotopic tracheal transplantation.
  • KCa3.1
  • Obliterative airway disease
  • TRAM-34

ASJC Scopus subject areas

  • Transplantation

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    Hua, X., Deuse, T., Chen, Y-J., Wulff, H., Stubbendorff, M., Köhler, R., Miura, H., Länger, F., Reichenspurner, H., Robbins, R. C., & Schrepfer, S. (2013). The potassium channel KCa3.1 as New therapeutic target for the prevention of obliterative airway disease. Transplantation, 95(2), 285-292. https://doi.org/10.1097/TP.0b013e318275a2f4