Soluble Epoxide Hydrolase Inhibitor Attenuates Inflammation and Airway Hyperresponsiveness in Mice

Abstract

Control of airway inflammation is critical in asthma treatment. Soluble epoxide hydrolase (sEH) has recently been demonstrated as a novel therapeutic target for treating inflammation, including lung inflammation. We hypothesized that pharmacological inhibition of sEH can modulate the inflammatory response in a murine ovalbumin (OVA) model of asthma. BALB/c mice were sensitized and exposed to OVA over 6 weeks. A sEH inhibitor (sEHI) was administered for 2 weeks. Respiratory system compliance, resistance, and forced exhaled nitric oxide were measured. Lung lavage cell counts were performed, and selected cytokines and chemokines in the lung lavage fluid were measured. A LC/MS/MS method was used to measure 87 regulatory lipids mediators in plasma, lung tissue homogenates, and lung lavage fluid. The pharmacological inhibition of sEH increased concentrations of the antiinflammatory epoxy eicosatrienoic acids and simultaneously decreased the concentrations of the proinflammatory dihydroxyeicosatrienoic acids and dihydroxyoctadecenoic acids. All monitored inflammatory markers, including FeNO levels, and total cell and eosinophil numbers in the lung lavage of OVA-exposed mice were reduced by sEHI. The type 2 T helper cell (Th2) cytokines (IL-4, IL-5) and chemokines (Eotaxin and RANTES) were dramatically reduced after sEHI administration. Resistance and dynamic lung compliance were also improved by sEHI. We demonstrated that sEHI administration attenuates allergic airway inflammation and airway responsiveness in a murine model. sEHI may have potential as a novel therapeutic strategy for allergic asthma.Keywords: soluble epoxide hydrolase; asthma; inflammation; lipid mediators; type 2 T helper cell cytokines Clinical RelevanceWe demonstrated that inhibition of soluble epoxide hydrolase attenuates allergic airway inflammation and airway responsiveness in a murine model. Therefore, sEH inhibitors may have potential as a novel therapeutic strategy for allergic asthma.Three hundred million people worldwide suffer from episodic or persistent asthma (1). The cornerstones of treatment for persistent asthma are inhaled corticosteroids and b-agonist bronchodilators; however, a significant minority of patients with asthma does not respond well to these therapies (2). Thus, there are ongoing efforts to develop novel treatment strategies (3), such as specific antagonists of type 2 T helper cell (Th2) cytokines and mediators.

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

“…GSK2256294 demonstrates picomolar activity toward sEH, effectively increases in vivo EET/DHET and epoxyoctadecenoic acid/dihydroxyoctadecenoic acid ratios, and reduces cell counts of macrophages, neutrophils, and keratinocyte chemoattractant cells of smoke-exposed rodents (Podolin et al, 2013). These observations are consistent with several studies demonstrating the efficacy of sEH inhibitors at reducing inflammation and general lung injury from smoke exposure (Smith et al, 2005;Wang et al, 2012) and asthma (Yang et al, 2015).…”

Soluble epoxide hydrolase inhibitor 1-trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl) urea attenuates bleomycin-induced pulmonary fibrosis in mice

“…The lung vasculature is known to be a rich source of lipid mediator biosynthesis from AA, and EETs have been previously described as the predominant eicosanoids in human lungs upon stimulation with the Ca 2+ ionophore A23187 challenge (Kiss, et al, 2010). EETs in the lung are involved in many pulmonary diseases, such as asthma (Norton, et al, 2012, Yang, et al, 2015), cigarette smoke extract-induced lung injury (Yu, et al, 2015), lung ischemia-reperfusion injury (Chen, et al, 2015), and pulmonary hypertension (Revermann, et al, 2009). A recent study showed that EETs could inhibit the expression of α-SMA and TGF-β1/SMADs, protect the remnant kidney in nephrectomized rat via the inhibition of fibrosis (Zhao, et al, 2012).…”

CYP450-derived oxylipins mediate inflammatory resolution

“…There has been great recent interest in the therapeutic potential of sEH inhibitors as novel antiinflammatories. sEH inhibitors or genetic disruption of sEH in mice reduces inflammation in models of endotoxin-induced pulmonary inflammation (22), ischemia-reperfusion injury (33,34), subarachnoid hemorrhage (35), and the murine ovalbumin model of asthma (36), and in more chronic models including atherogenic diet-induced fatty liver disease and adipose tissue (37) and atherosclerosis (38,39). In contrast, the expression and roles of epoxy-oxylipins during inflammatory resolution have not been investigated.…”