Effects of a Soluble Epoxide Hydrolase Inhibitor on Lipopolysaccharide-Induced Acute Lung Injury in Mice

Tao, Wei; Li, Pingsong; Yang, Liuqing; Ma, Yong-Bo

doi:10.1371/journal.pone.0160359

Cited by 32 publications

(22 citation statements)

References 23 publications

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“…Cisplatin-induced renal apoptosis was attenuated by a sEH inhibitor via EETs dependent mechanisms [6]. Moreover, LPS-induced ALI was dampened by a sEH inhibitor in a preclinical research [4]. In the present study, pulmonary inflammation and injury was significantly reduced in Semen Cassiae treated group.…”

Section: Discussionsupporting

confidence: 50%

Attenuation of acute lung injury in a rat model by Semen Cassiae

Chen

Zhang

et al. 2017

BMC Complement Altern Med

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BackgroundAcute lung injury (ALI) is an inflammatory disorder. Semen Cassiae has potent anti-inflammatory activities. The aim of our study was to investigate whether Semen Cassiae plays a protective effect on lipopolysaccharide (LPS)-induced ALI and, if so, to elucidate its potential mechanism.MethodsMale Sprague–Dawley rat lungs were injured by intratracheal instillation of LPS. Rats were treated with Semen Cassiae or vehicle 3 h after LPS challenge. Samples were harvested 24 h post-LPS administration. We also investigated the effects of Semen Cassiae on LPS stimulation in RAW 264.7 cells.ResultsLPS administration markedly induced pulmonary edema and polymorphonuclear neutrophil influxes. These changes were significantly attenuated in Semen Cassiae treated group. Moreover, Semen Cassiae markedly reduced pulmonary interleukin (IL)-6, tumor necrosis factor (TNF)-α, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels. The pulmonary soluble epoxide hydrolase (sEH) activity and the DNA binding activity of Nuclear factor (NF)-κB were significantly inhibited in Semen Cassiae treated group. Furthermore, Semen Cassiae treatment significantly increased epoxyeicosatrienoic acids (EETs), and heme oxygenase-1 (HO-1) activity. Our in vitro study demonstrates that Semen Cassiae treatment may inhibit LPS induced IκBα phosphorylation and NF-κB p65 nucleus translocation.Conclusion Semen Cassiae protects LPS-induced ALI in rats. Semen Cassiae can be developed as a novel treatment for ALI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-017-1747-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 50%

Attenuation of acute lung injury in a rat model by Semen Cassiae

Chen

Zhang

et al. 2017

BMC Complement Altern Med

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“…In line with the major role of sEH in EET hydrolysis, inhibition of sEH or genetic deletion of Ephx2 , the gene encoding for sEH, results in increased EET levels and modifications of various EET-mediated physiological effects including blood pressure (Sinal et al 2000 ; Sun et al 2014 ), inflammation (Bettaieb et al 2014 ; Kim et al 2015 ; Tao et al 2016 ), and inflammatory pain (Inceoglu et al 2006 ). In contrast to sEH inhibitors, which elaborated over recent years (Morisseau et al 1999 ; Ulu et al 2012 ), the available mEH inhibitors have the disadvantage that they are either highly unstable [2-nonylsulfanyl-propanamide (NSPA) and elaidamide each contain an amide group and are readily metabolized by amide hydrolases (Morisseau et al 2008 )] or highly toxic (1,1,1-trichloropropene oxide, TCPO), which prevents their application in vivo.…”

Section: Introductionmentioning

confidence: 95%

Beyond detoxification: a role for mouse mEH in the hepatic metabolism of endogenous lipids

et al. 2017

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Microsomal and soluble epoxide hydrolase (mEH and sEH) fulfill apparently distinct roles: Whereas mEH detoxifies xenobiotics, sEH hydrolyzes fatty acid (FA) signaling molecules and is thus implicated in a variety of physiological functions. These epoxy FAs comprise epoxyeicosatrienoic acids (EETs) and epoxy-octadecenoic acids (EpOMEs), which are formed by CYP epoxygenases from arachidonic acid (AA) and linoleic acid, respectively, and then are hydrolyzed to their respective diols, the so-called DHETs and DiHOMEs. Although EETs and EpOMEs are also substrates for mEH, its role in lipid signaling is considered minor due to lower abundance and activity relative to sEH. Surprisingly, we found that in plasma from mEH KO mice, hydrolysis rates for 8,9-EET and 9,10-EpOME were reduced by 50% compared to WT plasma. This strongly suggests that mEH contributes substantially to the turnover of these FA epoxides—despite kinetic parameters being in favor of sEH. Given the crucial role of liver in controlling plasma diol levels, we next studied the capacity of sEH and mEH KO liver microsomes to synthesize DHETs with varying concentrations of AA (1–30 μM) and NADPH. mEH-generated DHET levels were similar to the ones generated by sEH, when AA concentrations were low (1 μM) or epoxygenase activity was curbed by modulating NADPH. With increasing AA concentrations sEH became more dominant and with 30 μM AA produced twice the level of DHETs compared to mEH. Immunohistochemistry of C57BL/6 liver slices further revealed that mEH expression was more widespread than sEH expression. mEH immunoreactivity was detected in hepatocytes, Kupffer cells, endothelial cells, and bile duct epithelial cells, while sEH immunoreactivity was confined to hepatocytes and bile duct epithelial cells. Finally, transcriptome analysis of WT, mEH KO, and sEH KO liver was carried out to discern transcriptional changes associated with the loss of EH genes along the CYP-epoxygenase–EH axis. We found several prominent dysregulations occurring in a parallel manner in both KO livers: (a) gene expression of Ephx1 (encoding for mEH protein) was increased 1.35-fold in sEH KO, while expression of Ephx2 (encoding for sEH protein) was increased 1.4-fold in mEH KO liver; (b) Cyp2c genes, encoding for the predominant epoxygenases in mouse liver, were mostly dysregulated in the same manner in both sEH and mEH KO mice, showing that loss of either EH has a similar impact. Taken together, mEH appears to play a leading role in the hydrolysis of 8,9-EET and 9,10-EpOME and also contributes to the hydrolysis of other FA epoxides. It probably profits from its high affinity for FA epoxides under non-saturating conditions and its close physical proximity to CYP epoxygenases, and compensates its lower abundance by a more widespread expression, being the only EH present in several sEH-lacking cell types.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-017-2060-4) contains supplementary material, which is available to authorized users.

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“…into rats causes a significant increase in plasma level of potent vasodilator nitric oxide (NO) within 3 h [ 32 ]; however, some reports suggest that this effect does not have to translate into lowering blood pressure [ 25 ]. As we mentioned, recent findings showed that AUDA significantly elevates levels of vasorelaxing EETs in LPS-treated mice [ 34 ]. In regard to interactions between EETs and NO, both appear to act independent; nevertheless, it was proved that EETs activate endothelial isoform of nitric oxide synthase (eNOS) [ 8 ].…”

Section: Discussionmentioning

confidence: 93%

“…Moreover, in comparison with vehicle (LPS-treated group), administration of AUDA (10 mg/kg i.p.) markedly increased EET level and dampened the activation of nuclear factor (NF)-κB in LPS-challenged mice [ 34 ]. These findings are consistent with the previous reports indicating that EETs prevent amplification of inflammatory signaling pathways by inhibition of transcription factor NF-κB and IκB kinase [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

The weakening effect of soluble epoxide hydrolase inhibitor AUDA on febrile response to lipopolysaccharide and turpentine in rat

et al. 2017

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A still growing body of evidence suggests the importance of epoxyeicosatrienoic acids (EETs) in the regulation of inflammatory response; therefore, drugs that stabilize their levels by targeting the soluble epoxide hydrolase (sEH), an enzyme responsible for their metabolism, are currently under investigation. The effect of sEH inhibitors on molecular components of fever mechanism, i.e., on synthesis of pro-inflammatory cytokines or prostaglandins, has been repeatedly proven; however, the hypothesis that sEH inhibitors affect febrile response has never been tested. The aim of this study was to examine if sEH inhibition affects core body temperature (Tb) as well as Tb changes during febrile response to infectious (lipopolysaccharide; LPS) or non-infectious (turpentine; TRP) stimuli. Male Wistar rats were implanted intra-abdominally with miniature biotelemeters to monitor Tb. A potent sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) was suspended in olive oil and administrated into animals in the intraperitoneal (i.p.) dose of 15 mg/kg, which, as we showed, has no significant influence on normal Tb. We have found that AUDA injected 3 h after LPS (50 μg/kg i.p.) significantly weakened febrile rise of Tb. Moreover, injection of sEH inhibitor 7 h after turpentine (administrated subcutaneously in a dose of 100 μL/rat) markedly reduced the peak period of aseptic fever. Obtained results provide first experimental evidence that sEH inhibitors possess anti-pyretic properties. Therefore, medicines targeting sEH enzymatic activity should be considered as a complement to the arsenal of topical medications used to treat fever especially in clinical situations when non-steroidal anti-inflammatory drugs are ineffective.

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Effects of a Soluble Epoxide Hydrolase Inhibitor on Lipopolysaccharide-Induced Acute Lung Injury in Mice

Cited by 32 publications

References 23 publications

Attenuation of acute lung injury in a rat model by Semen Cassiae

Attenuation of acute lung injury in a rat model by Semen Cassiae

Beyond detoxification: a role for mouse mEH in the hepatic metabolism of endogenous lipids

The weakening effect of soluble epoxide hydrolase inhibitor AUDA on febrile response to lipopolysaccharide and turpentine in rat

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