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.

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Metabolic Syndrome (MetS), Type 2 Diabetes (T2DM) and obesity related sleep disorders like Sleep Disordered Breathing (SDB) share common features including visceral adiposity, impaired glycaemic control and increased cardiovascular disease (CVD) risk. As sub-clinical inflammation is considered a key player in these conditions they are thought to be interrelated. We aimed to further investigate this putative interrelationship. In a multi-ethnic population with a spectrum of glucose tolerance (sub-study of the ADDITION-study), we report that abdominal obesity underpins the association between SDB and systemic inflammation. South Asians with SDB had significantly higher levels of leptin, poorer glycaemic control but lower levels of oxidative stress than their Caucasian counterparts. These data suggest that the pathogenesis of SDB is different between these ethnic groups and may aid in understanding why South Asians are at increased risk of T2DM and CVD. Furthermore, SDB is independently associated with increased likelihood of MetS. However, no differences in cardiovascular markers, inflammatory biomarkers or anthropometric measures were observed between those with excessive daytime sleepiness or sleep disturbances as determined by the Epworth Sleepiness Scale and the Sleep Assessment Questionnaire, respectively. This suggests that these questionnaires are broad and insensive in identifying these sleep parameters. Obstructive Sleep Apnoea (OSA) is a severe form of SDB which can be successfully treated with Continuous Positive Airway Pressure (CPAP). Reported results on the effects of CPAP therapy on glycaemic control are inconsistent thus no difinative conclusion could be made from the systematic review carried out to answer this research question. Thus 'The Leicester Sleep and Sugar Study' was conducted to further establish whether CPAP-therapy impacts glycaemic control or systemic inflammation in subjects with established T2DM and newly diagnosed OSA. We report a clinically significant improvement in glycaemic control (HbA1c -0.8%) and a significant reduction in waist circumference with improved psychological well being 6 months post CPAP-therapy. It is evident that OSA is associated with T2DM and MetS although the direction of cause and effect has not been elucidated to date. The results reported here suggest that OSA negatively impacts on glycaemic control. Additionally we report a possible ethnic difference in the pathophysiology of SDB with inflammation playing a key role. Further research is required in this area to further establish these findings.

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