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Soluble Epoxide Hydrolase Plays a Vital Role in Angiotensin II-Induced Lung Injury in Mice

Tao, Wei; Li, Ping-Song; Xu, Gang; Luo, Yi; Shu, Yu-Sheng; Tao, Yong-Zhong§; Yang, Liu-Qing§

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doi: 10.1097/SHK.0000000000001067
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Angiotensin II belongs to the rennin-angiotensin system that plays a vital role in several biological processes, such as maintaining blood pressure and inflammatory response (1, 2). In addition to its function in the regulation of the cardiovascular system, angiotensin II plays an important role in the pathogenesis of acute respiratory distress syndrome (ARDS) that remains a major challenge in critically ill patients (3–5). A mild form of ARDS is previously known as acute lung injury (ALI) (6). Increased angiotensin II levels have been reported in animal studies of ALI (4, 7, 8). Dampened lung injury was observed when angiotensin II receptor was blocked by its antagonist (7, 9–11). Moreover, administration of angiotensin II may induce lung injury in animal studies (12, 13). However, the potential mechanism that how angiotensin II aggravates lung injury still needs to be elucidated.

Excessive inflammation plays a central role in the pathophysiological mechanism of ARDS (5, 14, 15). Soluble epoxide hydrolase (sEH; Ephx2) has been suggested as a vital pharmacologic target for inflammation (16). sEH hydrolyzes epoxyeicosatrienoic acids (EETs) that have been shown to possess protective properties in inflammatory disorders (16, 17). Recent studies reported that inhibition of sEH is proved lung protective in a number of preclinic studies (18, 19). It has been reported that sEH plays a vital effect in the pathogenesis of ALI and is suggested as a potential pharmacological target (18). Angiotensin II is capable of modulating sEH expression via activation of activator protein-1 (AP-1) in an in vitro study (20). It seems that sEH may be a downstream factor of angiotensin II (20). In the present study, we sought to dissect the impact of sEH specifically in angiotensin II-induced lung injury, and to test the hypothesis that angiotensin II-triggered lung injury is sEH dependent.



Ephx2 gene knockout C57BL/6 mice (Ephx2−/−) were initially obtained from Meidesi Bioscience Co., Ltd (Wuhan, China) and backcrossed onto a C57BL/6 genetic background for more than 10 generations as previously described (21). Wild-type C57BL/6 mice were purchased from Meidesi Bioscience Co., Ltd (Wuhan, China). The mice were genotyped for Ephx2 via the PCR-based amplification of genomic DNA extracted from the tail as previously described (22). Briefly, PCR amplification was performed using the following three primers: Ephx2-sense for both genotypes—5′-TGG CAC GAC CCT AAT CTT AGG TTC-3′; Ephx2-antisense for the wild-type mice—5′-TGC ACG CTG GCA TTT TAA CAC CAG-3′; Ephx2-antisense for Ephx2 gene deficiency mice—5′-CCA ATG ACA AGA CGC TGG GCG-3′. The amplification conditions involved 30 cycles of 96°C for 20 s, 59°C for 30 s, and 72°C for 45 s. The Ephx2 gene knockout allele produces a 295-base pair band, whereas the wild-type allele produces a 338-base pair band. All animals used in the present study were 8 weeks old and 20 to 22 g body weight. Mice were kept in a 12 h light/dark cycle and had free access to standard chow and tap water.

Angiotensin II-induced lung injury

The present study conformed to the Guide for the Care and Use of Laboratory Animals by the US National Institutes of Health (NIH Publication, 8th Edition, 2011). Protocols for animal use were approved by the Animal Care and Use Committee of Yangzhou University. ALI was induced by angiotensin II (30 μL; Sigma-Aldrich) intratracheally instillation. Before use, angiotensin II was dissolved in normal saline at 10 μmol/L. Animals in control group received equivalent normal saline only. Briefly, animals were randomly divided into the following four groups (n = 10): wild-type mice treated with normal saline (control group), Ephx2 gene knockout mice treated with normal saline, wild-type mice treated with angiotensin II, and Ephx2 gene knockout mice treated with angiotensin II.

In additional groups of C57BL/6 wild-type mice, Losartan, an angiotensin II receptor 1 antagonist, was fed by oral gavage (25 mg/kg) 30 min before angiotensin II or normal saline challenge. Before use, Losartan was dissolved in phosphate-buffered saline (PBS). Equivalent PBS was administrated for control group.

Histological analysis

The left lung was infused with 4% buffered paraformaldehyde, embedded in paraffin, sectioned at 5-μm thickness, and stained with hematoxylin and eosin. Two pathologists blind to group assignment analyzed the samples and determined levels of lung injury according to Murakami's technique (23). Briefly, the lung section was graded on a scale of 0 to 4 (0, normal; 1, light; 2, moderate; 3, strong; 4, intense) for infiltration of inflammatory cells, edema, congestion, and hemorrhaging.

Lung wet to dry (W/D) weight ratio

Lungs were harvested 24 h after angiotensin II challenge, and weighed immediately to obtain the wet lung weight. Then, the lungs were dried in a 70°C incubator for 3 days to obtain dry lung weight.

Enzyme-linked immunosorbent assay (ELISA) analysis

The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and albumin concentration in cell-free BALF were measured using ELISA (R&D Systems, Minneapolis, Minn), according to the manufacturer's instructions. Myeloperoxidase (MPO) activity in lung homogenates was measured by using ELISA kits (Sigma Chemicals, St. Louis, Mo) according to the manufacturers’ manual. The binding activity of nuclear factor (NF)-κB p65 to DNA was measured in nuclear extract of lung tissues using an ELISA-based TranAm NF-κB p65 transcription factor assay kit (Active Motif, Carlsbad, Calif) according to the manufacturer's instructions. The levels of EETs and sEH activity in lung homogenates were measured using a 14,15-EET/dihydroxyeicosatrienoic acids (DHETs) ELISA kit (Detroit R&D, Detroit, Mich) according to the manufacturers’ manual.

Measurement of AP-1 activity

The activity of AP-1 in nuclear extractions from the lung was determined with a commercial AP-1 filter plate assay kit according to the manufacturers’ manual (Signosis, Santa Clara, Calif).

Neutrophils counting in bronchoalveolar lavage fluid (BALF)

After the administration of angiotensin II for 24 h, all mice were euthanized before BALF collection. BALF was collected by cannulating the upper part of the trachea, by lavage 3 times with 1.0 mL PBS (pH 7.2). The fluid recovery rate was about 90%. BALF was centrifuged at 700 × g for 5 min at 4°C. The sedimented cells were resuspended in PBS to obtain counts of neutrophils by using a hemocytometer.

Quantitative real-time RT-PCR

Total RNA in isolated mice pulmonary tissues was extracted using TRIzol (Invitrogen, Calif). The mRNA was reverse-transcribed into cDNA using a Prime Script RT Reagent Kit (Takara, Otsu, Shiga, Japan) in accordance with manufacturer's instructions. Then, the expression levels of sEH gene mRNAs were measured as previously described (20). The nucleotide sequences of the primers were as follows: sEH, 5′-TGCCATCCTCACCAACAC-3′ (sense) and 5′-ACGGACCCTGGGCTTTAC-3′ (antisense); β-actin (internal control), 5′-TGACCGGGTCACCCACACTGTGCCCATCTA-3′ (sense) and 5′-CTAGAAGCATTTGCGGTGGACGATGGAGGG-3′ (antisense).

Western blot analysis

Isolated mice pulmonary tissues were lysed, and protein concentrations were measured by using the BCA protein assay kit (Pierce, Rockford, Ill). Cell lysates were resolved by 10% SDS/PAGE and transferred to a nitrocellulose membrane. sEH and β-actin proteins were detected by use of a polyclonal anti-sEH (Santa Cruz Biotechnology, Santa Cruz, Calif) and an anti-β-actin followed by an HRP-conjugated secondary antibody. The protein bands were visualized by the ECL detection system (Amersham, Arlington Heights, Ill), and the densities of the bands were quantified by use of Scion Image software (Scion, Frederick, Md).

Survival study

The survival rate was performed using additional animals (n = 20 in each group). C57BL/6 wild-type mice were treated with Losartan (25 mg/kg/d) or PBS 30 min before angiotensin II or normal saline challenge and observed at 24-h intervals to assess survival. Observation was continued up to 10 days.

Data analysis

Statistical analysis was performed using SPSS18.0. All values were expressed as mean ± SEM. One-way analysis of variance followed by Bonferroni's post hoc test was used for multiple comparisons. Two-tailed Student t test was used for comparison between two groups. No statistical method was used to estimate sample size. The sample size of the present study is consistent with previous publications (a minimum of n = 6 mice). Pulmonary histological scores were analyzed with the Kruskal–Wallis nonparametric test followed by Dunn's pairwise comparison. Kaplan–Meier method was used to estimate the survival rate. Results were considered statistically significant at P < 0.05.


Effect of sEH on angiotensin II-induced lung tissue specimen changes

No histological changes were observed in the control group and Ephx2 gene knockout mice challenged with normal saline (Fig. 1, a1 and a2). In keeping with previous studies (12, 13), alterations in the lung tissue specimens observed 24 h after angiotensin II administration showed edema-like formation and interstitial inflammatory cell infiltration in wild-type mice (Fig. 1a3). However, the angiotensin II-induced pulmonary histological changes were markedly reduced in Ephx2 gene knockout mice (Fig. 1a4). All of the lung injury scores included inflammation, edema, congestion, and hemorrhaging were significantly reduced in Ephx2 gene knockout mice (Fig. 1B).

Fig. 1:
(A) Histology of lung sections with hematoxylin and eosin staining from Ephx2 deficient (Ephx2−/−) or wild-type (WT) mice challenged with angiotensin II or normal saline (NS) for 24 h.

Effect of sEH on angiotensin II-induced pulmonary inflammation and edema

Neutrophils release neutrophil elastase and reactive oxygen species play an important role in ALI (24, 25). The angiotensin II-induced neutrophils infiltration in the lung that detected by MPO activity (Fig. 1C) in lung homogenates and neutrophils infiltration (Fig. 2A) in BALF was markedly dampened in Ephx2 gene knockout mice. The angiotensin II-induced lung edema that detected by W/D ration was significantly reduced in Ephx2 gene knockout mice (Fig. 2B). The albumin concentration in BALF was measured to investigate alveolar capillary protein leak. Our result indicated that angiotensin II-induced increasing of alveolar capillary protein leak was markedly improved in Ephx2 gene knockout mice (Fig. 2C). Proinflammatory cytokines chemotactical and activate inflammatory cells play a vital effect in ALI. Twenty-four hours after administration of angiotensin II, the levels of TNF-α (Fig. 2D) and IL-1β (Fig. 3A) were notably increased in wild-type mice. In Ephx2 gene knockout mice, the angiotensin II-induced elevation of proinflammatory cytokine was largely inhibited (Figs. 2D, 3A).

Fig. 2:
Ephx2 deficient (Ephx2−/−) or wild-type (WT) mice challenged with angiotensin II or normal saline (NS) for 24 h.
Fig. 3:
(A) Interleukin (IL)-1β in bronchoalveolar lavage fluid (BALF), (B) activator protein (AP)-1 activity, (C) nuclear factor (NF)-κB activity, (D) soluble epoxide hydrolase (sEH) activity, (E) epoxyeicosatrienoic acids (EETs) levels in lung homogenates in Ephx2 deficient (Ephx2−/−) or wild-type (WT) mice challenged with angiotensin II or normal saline (NS) for 24 h.

Effect of sEH on angiotensin II-induced AP-1 and NF-κB activation

In wild-type mice, the AP-1 was markedly activated by administration of angiotensin II (Fig. 3B). However, the angiotensin II-induced activation of AP-1 was notably dampened in Ephx2 gene knockout mice (Fig. 3B).

NF-κB activation is an important therapeutic target for ALI (15). Administration of angiotensin II significantly activated NF-κB in wild-type mice (Fig. 3C). This angiotensin II-induced activation of NF-κB was partially blocked in Ephx2 gene knockout mice (Fig. 3C).

Effect of angiotensin II on EETs levels and sEH activity

Twenty-four hours after administration of angiotensin II, the sEH activity was notably increased in wild-type mice (Fig. 3D). This angiotensin II-induced alteration in sEH activity was associated with a concomitant decrease in EETs levels (Fig. 3E). However, the EETs levels were markedly increased in Ephx2 gene knockout mice challenged with angiotensin II (Fig. 3E).

Effect of Losartan on angiotensin II-induced sEH expression and mortality

Angiotensin II significantly induced sEH both in mRNA and protein levels (Fig. 4, A and B). The angiotensin II-induced upregulation of sEH was markedly inhibited by Losartan (Fig. 4, A and B). Moreover, the mortality was markedly improved in Losartan-treated group compared with vehicle-treated animals (Fig. 4C).

Fig. 4:
In additional groups of C57BL/6 wild-type mice, Losartan (Los) or phosphate-buffered saline (PBS) was administrated by oral gavage 30 min before angiotensin II (Ang II) or normal saline (NS) challenge.


ARDS remains a serious clinical problem with significant morbidity and mortality (5). Angiotensin II plays a key role in the pathophysiological mechanism of ARDS (3, 7, 10, 11, 26). The present study showed that angiotensin II administration significantly increased sEH activity in wild-type mice. The elevated sEH activity was associated with aggravated pulmonary inflammation and edema. However, these changes were markedly dampened in sEH gene knockout mice. The results of the present study suggest that pulmonary inflammation and edema in angiotensin II-induced lung injury are mediated, at least in part, through the sEH.

Angiotensin II is proposed as a harmful factor for ARDS (3, 7, 26). Nevertheless, the underlying mechanism is still not well defined. Previous study reported that angiotensin II impaired the integrity of pulmonary microvascular endothelial barrier through inhibiting the VE-cadherin expression that proposed to have vital roles in maintaining the barrier function (27). Angiotensin II triggered pulmonary permeability edema formation through inhibition of alpha-epithelial sodium channel expression (8). A previous study reported that administration of exogenous angiotensin II induces pulmonary edema through angiotensin II receptor-dependent downregulation of cAMP level and dysregulation of epithelial sodium channel expression (12). Our results showed that angiotensin II-induced lung injury was markedly dampened in sEH gene knockout mice. This result suggests that the angiotensin II-induced lung injury is mediated, at least in part, through the sEH. Our result provides the first evidence that sEH plays a pivotal role in the pathogenesis of angiotensin II-induced lung injury.

The sEH is suggested to be involved in the rennin-angiotensin system (28). Angiotensin II has been reported to upregulate sEH protein in the kidney (29) and aortic intima (20). Our result indicates that angiotensin II also induces sEH in the lung. The mechanism that how angiotensin II induced the upregulation of sEH expression has been well studied in a previous in vitro research (20). Previous studies reported that angiotensin II activated AP-1 and NF-κB (30, 31). However, the AP-1, but not NF-κB, within the sEH promoter region is the functional element responsive for angiotensin II activation of she (20). In the present study, both AP-1 and NF-κB were activated 24 h after angiotensin II challenge. The sEH activity was markedly increased in response to angiotensin II challenge in wild-type mice. Moreover, the angiotensin II-induced lung injury was notably dampened when the sEH gene was deleted. These results suggest the sEH as an important downstream factor of angiotensin II. Various investigators have demonstrated the importance of sEH in inflammatory disorders (7, 16, 18, 19, 32). sEH gene deficiency protects mice form cerulein- and arginine-induced acute pancreatitis (32). Treated with an inhibitor of sEH is protective hearts against ischemia reperfusion injury (33). Cisplatin-induced renal damage is dampened in sEH inhibitor-treated mice as well as sEH gene deficiency mice (34). Inhibition of sEH may reduce lipopolysaccharide-induced ALI and has been suggested as a potential therapeutic target for ALI (18). However, the potential proinflammatory effect mechanism of sEH is complicated. EETs are the substrates of sEH. Inhibition of sEH may save EETs that is proposed to have anti-inflammatory role (17, 28). Increased EETs have been reported in a lipopolysaccharide-induced ALI animal model treated with an sEH inhibitor (18). Consistent with previous reports, the EETs were significantly increased in sEH gene knockout mice challenged with angiotensin II. Elevation of EETs via inhibition of sEH or exogenous EETs administration has protective effect on the lung (19). Blocked NF-κB activation has been reported in a number of animal studies that treated with sEH inhibitors or sEH gene deletion (32, 35). In the present study, the NF-κB p65 DNA binding activity was largely blocked in sEH gene knockout mice. The inflammatory effect of sEH seems to be associated with reduction of EETs and activation of NF-κB signaling pathway.

Previous study has shown that an angiotensin II receptor 1 antagonist, Losartan, blocks angiotensin II-induced she (20). Indeed, the angiotensin II-induced upregulation of sEH both in mRNA and protein levels was notably dampened when Losartan was administrated. Moreover, the mortality was improved by Losartan treatment. These results suggest that the angiotensin II receptor 1-mediated upregulation of sEH plays an important role in angiotensin II-induced ALI. Our result provides a novel mechanism that Losartan reduces lung injury by blocking angiotensin II-induced upregulation of sEH.

Our results suggest that although deletion of sEH gene significantly reduced angiotensin II-induced pulmonary edema and inflammation, the perimeters of edema and inflammation in sEH gene deficient mice were still markedly increased compared with control. This result indicates that other mechanisms are involved in the angiotensin II-induced lung injury. Activation of NF-κB plays an important role in ARDS (15). Angiotensin II activates NF-κB in cell studies (20, 36, 37). In the present study, angiotensin II markedly activated the NF-κB both in wild-type and sEH gene knockout mice. The activation of NF-κB may contribute to the pulmonary inflammation and edema in sEH gene knockout mice. Potential mechanisms that involved in the angiotensin II-induced lung injury are still need to be elucidated.


Angiotensin II-induced lung injury was improved in sEH gene deleted mice. The angiotensin II-triggered pulmonary inflammation is mediated, at least in part, through the sEH.


The authors thank H.X. Miao for outstanding technical support for mouse studies, and also thank Q. Xiao and Y.X. Chen for experimental assistance and valuable discussions.


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Acute respiratory distress syndrome; angiotensin II; soluble epoxide hydrolase

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