Abstract：Objective To study the protective effect of lipoxin A4 (LXA4) against sepsis induced by lipopolysaccharide (LPS) in rats with obesity and its effect on the expression of Toll-like receptor 4 (TLR4) and TNF receptor-associated factor 6 (TRAF6) in the liver.Methods A total of 60 male Sprague-Dawley rats aged three weeks were randomly divided into a normal group and an obesity group, with 30 rats in each group. A rat model of obesity was established by high-fat diet. Each of the two groups was further randomly divided into control group, sepsis group, and LXA4 group, and 8 rats were selected from each group. The rats in the control, sepsis, and LXA4 groups were treated with intraperitoneal injection of normal saline, LPS, and LXA4+LPS respectively. Twelve hours later, blood samples were collected from the heart and liver tissue samples were also collected. ELISA was used to measure the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Western blot was used to measure the protein expression of TLR4 and TRAF6 in liver tissue. Quantitative real-time PCR was used to measure the mRNA expression of TLR4 and TRAF6.Results After being fed with high-fat diet for 6 weeks, the obesity group had signifcantly higher average weight and Lee's index than the normal group (P < 0.05). Compared with the normal group, the obesity group had signifcant increases in the serum levels of IL-6 and TNF-α (P < 0.05). In the normal group or the obesity group, the sepsis subgroup had signifcant increases in the serum levels of IL-6 and TNF-α compared with the control subgroup (P < 0.05), while the LXA4 subgroup had signifcant reductions in the two indices compared with the sepsis subgroup (P < 0.05). Compared with the normal group, the obesity group had signifcant increases in the protein and mRNA expression of TLR4 and TRAF6 (P < 0.05). In the normal group or the obesity group, the sepsis subgroup had signifcant increases in the protein and mRNA expression of TLR4 and TRAF6 compared with the control subgroup (P < 0.05). Compared with the sepsis subgroup, the LXA4 subgroup had signifcant reductions in the protein and mRNA expression of TLR4 and TRAF6 (P < 0.05).Conclusions LXA4 can reduce the serum levels of IL-6 and TNF-α and alleviate inflammatory response. LXA4 can inhibit the expression of TLR4 and TRAF6 in the liver of septic rats, possibly by inhibiting the TLR4 signaling pathway.
JIANG Wei-Wei,GAO Li-Li,WU Ming et al. Effect of lipoxin A4 on the expression of Toll-like receptor 4 and TNF receptorassociated factor 6 in the liver of obese rats with sepsis[J]. CJCP, 2018, 20(7): 578-584.
Juonala M, Magnussen CG, Berenson GS, et al. Childhood adiposity, adult adiposity, and cardiovascular risk factors[J]. N Engl J Med, 2011, 365(20):1876-1885.
[2]
Reilly JJ, Kelly J. Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood:systematic review[J]. Int J Obes (Lond), 2011, 35(7):891-898.
[3]
Masoodi M, Kuda O, Rossmeisl M, et al. Lipid signaling in adipose tissue:connecting inflammation & metabolism[J]. Biochim Biophys Acta, 2015, 1851(4):503-518.
[4]
Cullberg KB, Larsen JØ, Pedersen SB, et al. Effects of LPS and dietary free fatty acids on MCP-1 in 3T3-L1 adipocytes and macrophages in vitro[J]. Nutr Diabetes, 2014, 4:e113.
[5]
Li Q, Tian Y, Wang ZF, et al. Involvement of the spinal NALP1 inflammasome in neuropathic pain and aspirin-triggered-15-epilipoxin A4 induced analgesia[J]. Neuroscience, 2013, 254:230-240.
[6]
Wu R, Zhou W, Chen S, et al. Lipoxin A4 suppresses the development of endometriosis in an ALX receptor-dependent manner via the p38 MAPK pathway[J]. Br J Pharmacol, 2014, 171(21):4927-4940.
[7]
Wu H, Zhao G, Jiang K, et al. Plantamajoside ameliorates lipopolysaccharide-induced acute lung injury via suppressing NF-κB and MAPK activation[J]. Int Immunopharmacol, 2016, 35:315-322.
[8]
Guo Z, Hu Q, Xu L, et al. Lipoxin A4 reduces inflammation through formyl peptide receptor 2/p38 MAPK signaling pathway in subarachnoid hemorrhage rats[J]. Stroke, 2016, 47(2):490-497.
Börgeson E, Johnson AM, Lee YS, et al. Lipoxin A4 attenuates obesity-induced adipose inflammation and associated liver and kidney disease[J]. Cell Metab, 2015, 22(1):125-137.
Rosenfeld ME. Inflammation and atherosclerosis:direct versus indirect mechanisms[J]. Curr Opin Pharmacol, 2013, 13(2):154-160.
[15]
Pal D, Dasgupta S, Kundu R, et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance[J]. Nat Med, 2012, 18(8):1279-1285.
[16]
Ma C, Jiang Y, Zhang X, et al. Isoquercetin ameliorates myocardial infarction through anti-inflammation and antiapoptosis factor and regulating TLR4-NF-κB signal pathway[J]. Mol Med Rep, 2018, 17(5):6675-6680.
[17]
Jiang K, Guo S, Zhang T, et al. Downregulation of TLR4 by miR-181a provides negative feedback regulation to lipopolysaccharide-induced inflammation[J]. Front Pharmacol, 2018, 9:142.
Börgeson E, McGillicuddy FC, Harford KA, et al. Lipoxin A4 attenuates adipose inflammation[J]. FASEB J, 2012, 26(10):4287-4294.
[20]
Lv W, Lv C, Yu S, et al. Lipoxin A4 attenuation of endothelial inflammation response mimicking pancreatitis-induced lung injury[J]. Exp Biol Med (Maywood), 2013, 238(12):1388-1395.
[21]
Serhan CN, Hamberg M, Samuelsson B. Lipoxins:novel series of biologically active compounds formed from arachidonic acid in human leukocytes[J]. Proc Natl Acad Sci U S A, 1984, 81(17):5335-5339.
[22]
Cattaneo F, Parisi M, Ammendola R. Distinct signaling cascades elicited by different formyl peptide receptor 2(FPR2) agonists[J]. Int J Mol Sci, 2013, 14(4):7193-7230.
