Preclinical evaluation of EPHX2 inhibition as a novel treatment for inflammatory bowel disease.

Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by cytochrome P450 epoxygenation of arachidonic acid, which are metabolized by EPHX2 (epoxide hydrolase 2, alias soluble epoxide hydrolase or sEH). EETs have pleiotropic effects, including anti-inflammatory activity. Using a Connectivity Map (CMAP) approach, we identified an inverse-correlation between an exemplar EPHX2 inhibitor (EPHX2i) compound response and an inflammatory bowel disease patient-derived signature. To validate the gene-disease link, we tested a pre-clinical tool EPHX2i (GSK1910364) in a mouse disease model, where it showed improved outcomes comparable to or better than the positive control Cyclosporin A. Up-regulation of cytoprotective genes and down-regulation of proinflammatory cytokine production were observed in colon samples obtained from EPHX2i-treated mice. Follow-up immunohistochemistry analysis verified the presence of EPHX2 protein in infiltrated immune cells from Crohn's patient tissue biopsies. We further demonstrated that GSK2256294, a clinical EPHX2i, reduced the production of IL2, IL12p70, IL10 and TNFα in both ulcerative colitis and Crohn's disease patient-derived explant cultures. Interestingly, GSK2256294 reduced IL4 and IFNγ in ulcerative colitis, and IL1ß in Crohn's disease specifically, suggesting potential differential effects of GSK2256294 in these two diseases. Taken together, these findings suggest a novel therapeutic use of EPHX2 inhibition for IBD.

Acute cardio-respiratory changes induced by hyperpnoea using a respiratory muscle trainer.

The aim of this study was to examine the cardio-respiratory effects of voluntary hyperpnoea using a respiratory muscle trainer (RMT) with three different sized rebreathing bags. In particular, the effects of hyperpnoea on inspired and end-tidal gas concentrations were determined. Seven adult males completed three 30 min bouts of hyperpnoea using optimal, oversized and undersized rebreathing bags. Inspired (F(I)) and expired end-tidal (F(ET)) O2 and CO2 concentrations, arterial O2 saturation (S(AO2)) and heart rate were measured during hyperpnoea. Before and after a bout of hyperpnoea, pulmonary function and blood pressure (BP) were assessed. Data were analysed using a two-way repeated-measures ANOVA, with p < 0.05 considered significant. Three subjects experienced discomfort during hyperpnoea and stopped after 20 min. During hyperpnoea, the F(ETCO2) was maintained at 4.6 +/- 0.7% irrespective of bag size. The increase in F(ICO2) over time reached 0.5 +/- 0.5% at 20 min. The F(IO2) fell to 19.4 +/- 0.8% at 20 min, and S(AO2) decreased to 97%. Heart rate and systolic BP increased slightly, but independently of rebreathing bag volume. No changes in pulmonary function or diastolic BP were found. It is concluded that the RMT maintained a constant F(ETCO2) at the expense of a mild hypoxia. The acute effects of hyperpnoea on the cardio-respiratory system are generally mild, but not always tolerable for 30 min.