Li Xiu-juan, Fu Hong-yu, Yi Wen-jing, Zhao Yan-jun, Wang Jun, Li Jin-bao, Wang Jia-feng, Deng Xiao-ming
Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China.
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.
J Surg Res. 2015 Feb;193(2):902-8. doi: 10.1016/j.jss.2014.09.013. Epub 2014 Sep 22.
The controversial results from different studies suggested that leukocyte recruitment mediated by leukotriene B4 (LTB4) and its receptor might improve pathogen clearance, but might also aggravate organ injury during sepsis. The present study was performed to compare the effect of BLT1 ligand LTB4 and its antagonist U-75302 on the development of sepsis.
Sepsis in mice was induced by cecal ligation and puncture (CLP). The mice were allocated into sham group, CLP group, U-75302 group, and LTB4 group. In the latter three groups, CLP mice were treated by intraperitoneal saline, U-75302, and LTB4, respectively. Their effect on the progression of sepsis were compared by histopathologic tests, level of systemic cytokines, counts of immune cells and bacterial clearance, and survival rate.
The histopathologic tests showed that U-75302 attenuated lung injury, whereas LTB4 aggravated liver injury. LTB4 increased the plasma levels of interleukin-6, tumor necrosis factor-α, and U-75302 increased the level of plasma interleukin-10. LTB4 increased whereas U-75302 reduced the neutrophil numbers in the peritoneal lavage fluid. LTB4 also increased the number of peritoneal and splenic CD4(+) and CD8(+) T cells. Bacterial clearance in blood and peritoneal lavage fluid was significantly enhanced in the LTB4 group. Both U-75302 and LTB4 did not change the survival rate significantly compared with vehicle, but mortality in the LTB4 group was significantly higher than in the U-75302 group. Dose response analyses were also performed to compare the effect of U-75302 and LTB4 at different doses. Different doses of both agents did not influence the survival rate of CLP mice.
U-75302 attenuates sepsis-induced organ injury, whereas LTB4 increases the leukocyte recruitment toward infection site, but LTB4 showed a more lethal effect than U-75302 during polymicrobial sepsis.
不同研究得出的有争议结果表明，白三烯B4（LTB4）及其受体介导的白细胞募集可能会改善病原体清除，但也可能加重脓毒症期间的器官损伤。本研究旨在比较BLT1配体LTB4及其拮抗剂U-75302对脓毒症发展的影响。
通过盲肠结扎和穿刺（CLP）诱导小鼠脓毒症。将小鼠分为假手术组、CLP组、U-75302组和LTB4组。在后三组中，CLP小鼠分别腹腔注射生理盐水、U-75302和LTB4。通过组织病理学检查、全身细胞因子水平、免疫细胞计数和细菌清除情况以及生存率来比较它们对脓毒症进展的影响。
组织病理学检查显示，U-75302减轻了肺损伤，而LTB4加重了肝损伤。LTB4增加了白细胞介素-6、肿瘤坏死因子-α的血浆水平，而U-75302增加了血浆白细胞介素-10的水平。LTB4增加了腹腔灌洗液中的中性粒细胞数量，而U-75302减少了该数量。LTB4还增加了腹腔和脾脏中CD4(+)和CD8(+) T细胞的数量。LTB4组血液和腹腔灌洗液中的细菌清除率显著提高。与溶剂对照组相比，U-75302和LTB4均未显著改变生存率，但LTB4组的死亡率显著高于U-75302组。还进行了剂量反应分析，以比较不同剂量的U-75302和LTB4的效果。两种药物的不同剂量均未影响CLP小鼠的生存率。
U-75302减轻脓毒症诱导的器官损伤，而LTB4增加白细胞向感染部位的募集，但在多微生物脓毒症期间，LTB4显示出比U-75302更致命的作用。
