Resistin production does not affect outcomes in a mouse model of acute surgical sepsis.
Resistin production does not affect outcomes in a mouse model of acute surgical sepsis.
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DOI：
10.1371/journal.pone.0265241
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Lang CH
中科院分区：
文献类型：
--
作者：
Bonavia AS;Chroneos ZC;Ruiz-Velasco V;Lang CH
由于血液中抵抗素浓度与脓毒症患者的病情严重程度密切相关，抵抗素已被认为是脓毒症的一种病理生理介质。体外数据表明，人类抵抗素直接损害中性粒细胞迁移和细胞内细菌杀灭，尽管这些发现在体内的意义尚不清楚。本研究的目的是：(1)验证人类抵抗素在临床相关的外科脓毒症小鼠模型中的表达，(2)评估脓毒症引起的抵抗素变化与感染和器官功能障碍标志物的相关性，以及(3)研究人类抵抗素的表达是否会改变体内的免疫功能或疾病结局。10 7只雄性C57BL/6小鼠在小鼠抵抗素基因敲除背景下获得了人抵抗素基因及其启动子元件(Retn+/−/−，或Retn+)转基因小鼠。比较了年龄匹配的转基因小鼠和基因敲除小鼠的结果。急性脓毒症定义为盲肠结扎穿孔(CLP)后最初24小时。测量与人类序贯器官衰竭评估(SOFA)评分相关的生理和实验室参数，并评估血液和腹膜腔内天然免疫细胞的数量/功能。CLP显著增加循环中人抵抗素水平。在Retn+和RKO小鼠之间，脓毒症引起的白细胞减少的严重程度是相似的。抵抗素与脓毒症后6h中性粒细胞活性氧生成增加、循环中性粒细胞减少、腹膜Ly6chi单核细胞增多有关。然而，脓毒症小鼠的腹膜内细菌生长、器官功能障碍和小鼠存活与抵抗素的产生没有区别。体外抵抗素诱导的中性粒细胞功能损害似乎不会转化为CLP后脓毒症严重程度的增加或体内较差的预后。
Because of the strong correlation between the blood concentration of circulating resistin and the illness severity of septic patients, resistin has been proposed as a mediator of sepsis pathophysiology. In vitro data indicate that human resistin directly impairs neutrophil migration and intracellular bacterial killing, although the significance of these findings in vivo remain unclear. The objectives of the present study were: (1) to validate the expression of human resistin in a clinically relevant, murine model of surgical sepsis, (2) to assess how sepsis-induced changes in resistin correlate with markers of infection and organ dysfunction, and (3) to investigate whether the expression of human resistin alters immune function or disease outcomes in vivo. 107 male, C57BL/6 mice transgenic for the human resistin gene and its promoter elements (Retn+/−/−, or Retn+) were generated on a Retn−/− (mouse resistin knockout, or Rko) background. Outcomes were compared between age-matched transgenic and knockout mice. Acute sepsis was defined as the initial 24 h following cecal ligation and puncture (CLP). Physiologic and laboratory parameters correlating to the human Sequential Organ Failure Assessment (SOFA) Score were measured in mice, and innate immune cell number/function in the blood and peritoneal cavity were assessed. CLP significantly increased circulating levels of human resistin. The severity of sepsis-induced leukopenia was comparable between Retn+ and Rko mice. Resistin was associated with increased production of neutrophil reactive oxygen species, a decrease in circulating neutrophils at 6 h and an increase in peritoneal Ly6Chi monocytes at 6 h and 24 h post-sepsis. However, intraperitoneal bacterial growth, organ dysfunction and mouse survival did not differ with resistin production in septic mice. Ex vivo resistin-induced impairment of neutrophil function do not appear to translate to increased sepsis severity or poorer outcomes in vivo following CLP.
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