Abstract Objective To study the effect of early intervention with lipoxin A4 (LXA4) on septic mice. Methods Healthy male Balb/c mice aged 6-8 weeks were randomly divided into sham-operation group, sepsis group, 1-hour intervention group (intervention at 1 hour after sepsis), and 6-hour intervention group (intervention at 6 hours after sepsis) (n=8 each). A sepsis model was prepared by cecal ligation and puncture. The intervention groups received LXA4 at 0.01 μg/g body weight 1 or 6 hours after the model was established. Blood was taken from eyeballs at 24 hours after operation. Peritoneal lavage fluid and liver and lung tissue samples were collected. The bacterial colonies of whole blood and peritoneal lavage fluid were counted by dilution plating. The serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) were determined by cytometric bead array. The serum level of high mobility group box-1 (HGMB1) was determined using ELISA. The percentages of macrophages and neutrophils in peritoneal lavage fluid were determined by flow cytometry. Paraffin sectioning and hematoxylin-eosin staining were performed for the liver and lung tissue samples to observe pathological damage. Results Compared with the sham-operation group, the sepsis group had a significantly decreased percentage of macrophages and a significantly increased percentage of neutrophils in peritoneal lavage fluid (P < 0.05), as well as significantly increased serum levels of IL-6, TNF-α, MCP-1, and HMGB1 (P < 0.05); in addition, the sepsis group showed more vacuolar degeneration, hepatocyte swelling, and inflammatory cell infiltration in liver tissue, and more capillary congestion, pulmonary septal thickening, inflammatory cell infiltration, and partial tissue destruction in lung tissue. Compared with the sepsis group, the 1-hour and 6-hour intervention groups had a significantly increased percentage of macrophages in peritoneal lavage fluid (P < 0.05) and significantly reduced bacterial load in whole blood (P < 0.05), serum levels of IL-6, TNF-α, MCP-1, and HMGB1 (P < 0.05), and degree of liver and lung tissue damage and inflammatory cell infiltration, but there was no significant difference in the percentage of neutrophils and bacterial load in peritoneal lavage fluid (P > 0.05). Compared with the 6-hour intervention group, the 1-hour intervention group had a significantly decreased serum level of HMGB1 (P < 0.05), but there was no significant difference in other indicators between the two groups (P > 0.05). Conclusions Early intervention with LXA4 may attenuate liver and lung injuries in septic mice, which may be explained by the decrease in serum levels of IL-6, TNF-α, MCP-1, and HMGB1, and it also may reduce the bacterial dissemination in the whole blood of septic mice, which may be explained by the increase in the percentage of peritoneal macrophages.
Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a new definition and assessing new clinical criteria for septic shock:for the third international consensus definitions for sepsis and septic shock (Sepsis-3)[J]. JAMA, 2016, 315(8):775-787.
[2]
Weiss SL, Fitzgerald JC, Pappachan J, et al. Global epidemiology of pediatric severe sepsis:the sepsis prevalence, outcomes, and therapies study[J]. Am J Respir Crit Care Med, 2015, 191(10):1147-1157.
English JT, Norris PC, Hodges RR, et al. Identification and profiling of specialized pro-resolving mediators in human tears by lipid mediator metabolomics[J]. Prostaglandins Leukot Essent Fatty Acids, 2017, 117:17-27.
[5]
Poorani R, Bhatt AN, Dwarakanath BS, et al. COX-2, aspirin and metabolism of arachidonic, eicosapentaenoic and docosahexaenoic acids and their physiological and clinical significance[J]. Eur J Pharmacol, 2016, 785:116-132.
[6]
Romano M, Cianci E, Simiele F, et al. Lipoxins and aspirin-triggered lipoxins in resolution of inflammation[J]. Eur J Pharmacol, 2015, 760:49-63.
[7]
Ei-Tanbouly GS, Ei-Awady MS, Megahed NA, et al. The lipoxin A4 agonist BML-111 attenuates acute hepatic dysfunction induced by cecal ligation and puncture in rats[J]. Naunyn Schmiedebergs Arch Pharmacol, 2017, 390(4):361-368.
[8]
Chen QF, Kuang XD, Yuan QF, et al. Lipoxin A4 attenuates LPS-induced acute lung injury via activation of the ACE2-Ang-(1-7)-Mas axis[J]. Innate Immun, 2018, 24(5):285-296.
[9]
Walker J, Dichter E, Lacorte G, et al. Lipoxin A4 increases survival by decreasing systemic inflammation and bacterial load in sepsis[J]. Shock, 2011, 36(4):410-416.
[10]
Wu B, Walker JA, Temmermand D, et al. Lipoxin A4 promotes more complete inflammation resolution in sepsis compared to stable lipoxin A4 analog[J]. Prostaglandins Leukot Essent Fatty Acids, 2013, 89(1):47-53.
[11]
Rinaldi SF, Catalano RD, Wade J, et al. 15-epi-lipoxin A4 reduces the mortality of prematurely born pups in a mouse model of infection-induced preterm birth[J]. Mol Hum Reprod, 2015, 21(4):359-368.
[12]
Eisen DP, Reid D, McBryde ES. Acetyl salicylic acid usage and mortality in critically ill patients with the systemic inflammatory response syndrome and sepsis[J]. Crit Care Med, 2012, 40(6):1761-1767.
[13]
Ueda T, Fukunaga K, Seki H, et al. Combination therapy of 15-epi-lipoxin A4 with antibiotics protects mice from Escherichia coli-induced sepsis*[J]. Crit Care Med, 2014, 42(4):e288-e295.
[14]
Rittirsch D, Huber-Lang MS, Flierl MA, et al. Immunodesign of experimental sepsis by cecal ligation and puncture[J]. Nat Protoc, 2009, 4(1):31-36.
Gentile LF, Moldawer LL. HMGB1 as a therapeutic target for sepsis:it's all in the timing![J]. Expert Opin Ther Targets, 2014, 18(3):243-245.
[22]
Zheng S, Weng Q, Wu W, et al. Blood purification treatment initiated at the time of sepsis diagnosis effectively attenuates serum HMGB1 upregulation and improves patient prognosis[J]. Exp Ther Med, 2017, 14(4):3029-3035.
[23]
Ahn MY, Hwang JS, Lee SB, et al. Curcumin longa extract-loaded nanoemulsion improves the survival of endotoxemic mice by inhibiting nitric oxide-dependent HMGB1 release[J]. Peer J, 2017, 5:e3808.
[24]
Li Z, Ma QQ, Yan Y, et al. Edaravone attenuates hippocampal damage in an infant mouse model of pneumococcal meningitis by reducing HMGB1 and iNOS expression via the Nrf2/HO-1 pathway[J]. Acta Pharmacol Sin, 2016, 37(10):1298-1306.
[25]
Singh A, Feng Y, Mahato N, et al. Role of high-mobility group box 1 in patients with acute obstructive suppurative cholangitis-induced sepsis[J]. J Inflamm Res, 2015, 8:71-77.
[26]
Wang XW, Karki A, Zhao XJ, et al. High plasma levels of high mobility group box 1 is associated with the risk of sepsis in severe blunt chest trauma patients:a prospective cohort study[J]. J Cardiothorac Surg, 2014, 9:133.
[27]
Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis:a novel understanding of the disorder and a new therapeutic approach[J]. Lancet Infect Dis, 2013, 13(3):260-268.
[28]
Timmermans K, Kox M, Vaneker M, et al. Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients[J]. Intensive Care Med, 2016, 42(4):551-561.
[29]
Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans[J]. J Exp Med, 2011, 208(13):2581-2590.
[30]
Wu B, Walker J, Spur B, et al. Effects of Lipoxin A4 on antimicrobial actions of neutrophils in sepsis[J]. Prostaglandins Leukot Essent Fatty Acids, 2015, 94:55-64.
[31]
Wu B, Capilato J, Pham MP, et al. Lipoxin A4 augments host defense in sepsis and reduces Pseudomonas aeruginosa virulence through quorum sensing inhibition[J]. FASEB J, 2016, 30(6):2400-2410.
