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The Role of the K⁺ Channel KCa3.1 in Idiopathic Pulmonary Fibrosis

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posted on 2013-03-27, 11:34 authored by Katy Morgan Roach
Idiopathic pulmonary fibrosis (IPF) is a common disease with a median survival of only 3 years. There is no effective treatment. IPF is characterized by myofibroblast accumulation and progressive lung scarring. The Ca²⁺-activated K⁺ channel KCa3.1 modulates the activity of several structural and inflammatory cells which play important roles in model diseases characterized by tissue remodelling and fibrosis. We hypothesise that KCa3.1-dependent cell processes are a common denominator in IPF. KCa3.1 expression and function were examined in human myofibroblasts derived from IPF and non-fibrotic (NFC) donors. Myofibroblasts grown in vitro were characterised by western blot, immunofluorescence, RT-PCR and patch clamp electrophysiology to determine KCa3.1 channel expression. Wound healing, collagen secretion and contraction assays were performed using the pro-fibrotic mediators TGFβ1 and bFGF and two specific KCa3.1 blockers (TRAM-34, ICA-17043 [Senicapoc]). Both NFC and IPF myofibroblasts expressed KCa3.1 channel mRNA and protein. Using the KCa3.1 channel opener 1-EBIO, KCa3.1 ion currents were elicited in 59% of NFC and 77% of IPF myofibroblasts tested (P=0.0411). These currents were blocked by TRAM-34 (200 nM). The 1-EBIO-induced currents were significantly larger in IPF cells compared to NFC cells (P=0.0078). TGFβ1 and bFGF increased KCa3.1 channel expression. TRAM-34 and ICA-17043 dose-dependently attenuated wound healing, TGFβ1-dependent collagen secretion and bFGF- and TGFβ1-dependent contraction. We show for the first time that human lung myofibroblasts express the KCa3.1 K⁺ channel. KCa3.1 channel block attenuates pro-fibrotic myofibroblast function. These findings raise the possibility that blocking the KCa3.1 channel will inhibit pathological myofibroblast function in IPF, and thus offer a novel approach to IPF therapy.

History

Supervisor(s)

Bradding, Peter

Date of award

2013-03-01

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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