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Mechanisms of fibrosis in respiratory disease
S139 The K+ channel KCa3.1 is a novel target for the treatment of idiopathic pulmonary fibrosis
  1. M C Shepherd1,
  2. S R Sabir1,
  3. C McSharry1,
  4. H Wulff2,
  5. P Bradding3
  1. 1Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK
  2. 2Department of Pharmacology, University of California, Davis, USA
  3. 3Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester., Leicester, UK

Abstract

Introduction and objectives Idiopathic pulmonary fibrosis (IPF) is common, largely unresponsive to treatment with a median survival of 3 years. New therapies are urgently required. IPF is characterised by proliferation of pulmonary mesenchymal cells through epithelial mesenchymal transition, resident fibroblast proliferation and circulating fibrocyte recruitment. We have previously demonstrated that the potassium channel KCa3.1 regulates lung mesenchymal cell proliferation, is up-regulated by TGFβ, an important driver of IPF, and is present in fibrocytes in peripheral blood. We tested the hypotheses that KCa3.1 is up-regulated in IPF using the bleomycin-induced pulmonary fibrosis murine model and that KCa3.1 inhibition reduces pulmonary fibrosis.

Methods Prophylactic (Day -3) and daily thereafter, sub-cutaneous TRAM-34, a specific KCa3.1 inhibitor, was administered to C57BL/6 mice later exposed to nasal bleomycin (Day 0) and culled on day +21. Mice exposed to PBS or bleomycin acted as negative and positive controls. The primary endpoint was histological fibrosis score. Inflammation was assessed by bronchoalveolar lavage. Collagen deposition and KCa3.1 expression were assessed by Masson's trichrome staining and qPCR.

Results Bleomycin-induced pulmonary fibrosis characterised by thickened alveolar septae, architectural destruction and collagen deposition. Co-administration of TRAM-34 significantly reduced pulmonary fibrosis (Modified Ashcroft's score +/− SEM: 4.8+/−0.8 bleomycin group vs 2.6+/−0.6 TRAM-34 group: p=0.02). Bleomycin increased lung KCa3.1 (55-fold versus PBS control) and collagen Iα mRNA (fourfold) expression (n=3 in each case). Mice receiving bleomycin lost more weight (2.39 vs 0 g) and had greater mortality than those co-administered TRAM-34. BAL cellularity did not differ between the groups. Collagen staining was reduced in the TRAM-34 group.

Conclusions KCa3.1 expression is increased in a model of pulmonary fibrosis and inhibition with TRAM-34 significantly improves pathological outcome. The mechanism is likely to involve the modulation of cells involved in the fibrotic process. Previous clinical studies have shown KCa3.1 inhibition to be safe in humans and our study provides a rationale for a clinical trial of KCa3.1 inhibitors in human IPF.

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