Intervention effect of lipoxygen receptor agonist BML-111 on acute liver injury in rats and its mechanism

doi:10.12047/j.cjap.5990.2020.105

Abstract

Abstract: Objective: To investigate the effect and mechanism of lipoxygen on acute liver injury. Methods: Twenty-four SD rats were randomly divided into 4 groups (n=6): normal control group: subcutaneous injection of olive oil at a dose of 1.8 ml/kg; model group: subcutaneous injection of 40% carbon tetrachloride(CCL4)oil (olive oil as a solvent) at a dose of 3 ml/kg; BML-111 treatment group: Lipoxin receptor agonist BML-111 was injected subcutaneously at a dose of 1 mg/kg, and treated in the same model group after 30 minutes; BOC-2 blocker group: Lipoxin receptor blocker BOC-2 was injected subcutaneously at a dose of 50 μg/kg. After 30 minutes, the treatment was the same as BML-111 group. HE staining was used to observe the pathological changes of liver tissues to judge the liver injury. Serological detection was used to determine the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST); The myeloperoxidase (MPO) activity in rat liver tissue was detected by kit method; the contents of of angiotensin converting enzyme (ACE) , Angiotensin converting enzyme 2 (ACE2), angiotensin II (AngII) and angiotensin 1-7 (Ang- (1-7)) were detected by ELISA. Western Blot was used to detect the protein contents of Ang II and Ang- (1-7) in liver tissue. Results: The treatment group had less liver damage than the model group and the blocker group; BML-111 decreased the levels of ACE and AngII in serum of rats with CCL4 injury (P＜0.01) and increased the levels of ACE2 and Ang- (1 in serum -7) content (P＜0.01). BML-111 increased the content of Ang- (1-7) in liver tissue and decreased the content of AngII in CCL4 injured rat tissue. Conclusion: The results showed that the intervention effect and mechanism of lipoxygen receptor agonist BML-111 on acute liver injury in rats may be related to the regulation of AngII and Ang-(1-7).

Key words: lipoxin, acute liver injury, carbon tetrachloride, RASS, rat

CLC Number:

R575.2
R-332

HU Quan-dong, YANG Yu-juan, YU Shan-shan. Intervention effect of lipoxygen receptor agonist BML-111 on acute liver injury in rats and its mechanism[J]. CJAP, 2020, 36(5): 494-498.

References

[1] Serhan CN. Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: an update and role in anti-inflammation and pro-resolution[J]. Prostaglandins Other Lipid Mediators, 2002,10 (68-69): 433-455.
[2] Jin H, Li YH, Xu JS, et al. Lipoxin A4 analog attenuates morphine antinociceptive tolerance, withdrawal-induced hyperalgesia, and glial reaction and cytokine expression in the spinal cord of rat[J]. Neuroscience, 2012, 19 (208): 1-10.
[3] Zhou XY, Yu ZJ, Yan D, et al. BML-11, a lipoxin receptor agonist, protected carbon tetrachloride-induced hepatic fibrosis in rats[J]. Inflammation, 2013, 36(5): 1101-1106.
[4] Hao H, Liu M, Wu P, et al. Lipoxin A4 and its analog suppress hepatocellular carcinoma via remodeling tumor microenvironment[J]. Cancer Lett, 2011, 309(1): 85-94.
[5] El-Agamy DS, Makled MN, Gamil NM. Protective effects of BML-111 against acetaminophen-induced acute liver injury in mice[J]. J Physiol Biochem, 2014, 70(1): 141-149.
[6] Yan D, Liu HL, Yu ZJ, et al. BML-111 Protected LPS/D-GalN-induced acute liver injury in rats[J]. Int J Mol Sci, 2016, 17(7): 1111-1124.
[7] Bataller R, Sancho-Bru P, Gines P, et al. Liver fibrogenesis: a new role for the renin-angiotensin system[J]. Antioxid Redox Signal, 2005, 7(9-10): 1346-1355.
[8] Vilas-Boas WW, Ribeiro-Oliveira AJr, Pereira RM, et al. Relationship between angiotensin-(1-7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis[J]. World J Gastroenterol, 2009, 15(20): 2512-2519.
[9] Li YS, Ni SY, Meng Y, et al. Angiotensin II facilitates fibrogenic effect of TGF-beta1 through enhancing the down-regulation of BAMBI caused by LPS: a new pro-fibrotic mechanism of angiotensin II[J]. PLoS One, 2013, 8(10): 762-789.
[10]Lee KC, Hsieh YC, Yang YY, et al. Aliskiren reduces hepatic steatosis and epididymal fat mass and increases skeletal muscle insulin sensitivity in high-fat diet-fed mice[J]. Sci Rep, 2016, 6(6): 188-199.
[11]Ning ZW, Zhang WY, Li Y, et al. Inhibitory effect of angiotensin (1-7) on hepatic sinusoid angiogenesis in bile duct ligation-induced hepatic fibrosis of rats[J]. Chin J Hepatol, 2013, 21(12): 907-913.
[12]赵鑫, 苟小军, 陈龙, 等. 花旗松素预防CCl4致大鼠急性肝损伤的代谢组学研究[J]. 上海中医药杂志, 2017, 51(8): 82-86.
[13]Chiang N, Serhan CN, Dahlen SE, et al. The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo[J]. Pharmacol Rev, 2006, 58(3): 463-487.
[14]崔桂玉, 白剑, 刘喜成, 等. 丹参对非酒精性脂肪肝Th17细胞及相关细胞因子的影响[J]. 中国应用生理学杂志, 2019, 35(6): 517-522.
[15]邵毅英, 范玉琪, 魏璨, 等. CaSR表达在大鼠糖尿病性肝硬化损伤和纤维化发生中的作用[J]. 中国应用生理学杂志, 2020, 36 (1): 1-5.
[16]Chen QF, Hao H, Zhou XY, et al. BML-111, a lipoxin receptor agonist, protects against acute injury via regulating the renin angiotensin- aldosterone system[J]. Prostaglandins Other Lipid Mediators, 2019, 11(140): 9-17.
[17]Hu QD, Hu ZZ, Chen QF, et al. BML-111 equilibrated ACE-Ang II-AT1R and ACE2-Ang-(1-7)-Mas axis to protect hepatic fibrosis in rats[J]. Prostaglandins Other Lipid Mediators, 2017, 8(131) : 75-82.
[18]Hao Y, Liu Y. Osthole alleviates bleomycin-induced pulmonary fibrosis via modulating angiotensin-converting enzyme 2/angiotensin-(1-7) axis and decreasing inflammation responses in rats[J]. Biol Pharm Bull, 2016, 39(4): 457-65.
[19]Recknagel RO, Glende EA, Dolak JA, et al. Mechanisms of carbon tetrachloride toxicity[J]. Pharmacol Ther, 1989, 43(1): 139-154.
[20]Cao X,Yang F, Shi T, et al. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis[J]. Sci Rep, 2016 , 6(1): 29-37.
[21]Murugan D,Lau YS,Lau CW, et al. Angiotensin 1-7 protects against angiotensin II-induced endoplasmic reticulum stress and endothelial dysfunction via Mas receptor[J]. PLoS One, 2016 , 11(1): 1-12.
[22]Reza HM ,Tabassum N, Sagor MA, et al. Angiotensin-converting enzyme inhibitor prevents oxidative stress, inflammation, and fibrosis in carbon tetrachloride -treated rat liver[J]. Toxicol Mech Methods, 2016, 26(1): 46-53.
[23]Supe S, Kohse F, Gembardt F, et al. Therapeutic time window for angiotensin-(1-7) in acute lung injury[J]. Br J Pharmacol, 2016, 173(10): 1618-1628.