Adiponectin treatment attenuates inflammatory response during early sepsis in obese mice.
Adiponectin treatment attenuates inflammatory response during early sepsis in obese mice.
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DOI：
10.2147/jir.s119021
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发表时间：
2016
影响因子：
4.5
通讯作者：
Vachharajani V
中科院分区：
文献类型：
--
作者：
Wang X;Buechler NL;Yoza BK;McCall CE;Vachharajani V
病态肥胖会增加危重患者的护理成本。脓毒症是非冠心病重症监护病房中死亡的主要原因。微循环中循环细胞与内皮细胞的相互作用是任何炎症的速率决定因素；肥胖进一步加剧了这些相互作用。脂联素缺乏与肥胖患者心血管风险增加有关。我们已经证明脂联素缺乏会增加早期脓毒症的微血管功能障碍。在本研究中，我们研究了脂联素替代疗法对患有早期败血症的营养性肥胖小鼠的影响。我们在饮食诱导肥胖（DIO）与对照饮食（CTRL）小鼠中使用败血症的盲肠结扎和穿刺模型，使用或不使用脂联素治疗。我们研究了早期脓毒症脑微循环中的白细胞/血小板粘附。我们还研究了脂联素对游离脂肪酸（FFA）喂养和脂多糖刺激的骨髓源性巨噬细胞（BMDM）的影响，以进行机制研究。与假手术组相比，早期脓毒症 DIO 和 CTRL 小鼠的脑微循环中白细胞和血小板粘附增加；此外，DIO-脓毒症组的细胞粘附显着高于CTRL-脓毒症组。脂联素替代减少了 CTRL 和 DIO 小鼠的白细胞/血小板粘附。在 FFA 喂养的 BMDM 中，脂联素治疗降低了肿瘤坏死因子-α mRNA 表达，并增加了 Sirtuin-1 (SIRT1) mRNA 表达。此外，使用 SIRT1 敲除小鼠的 BMDM，我们发现脂联素治疗通过 SIRT1 依赖性和非依赖性途径降低了 FFA 喂养的 BMDM 的炎症反应。脂联素替代可减轻 DIO 脓毒症小鼠的微血管炎症。从机制上讲，脂联素治疗 FFA 喂养的小鼠巨噬细胞可通过 SIRT1 依赖性和非依赖性途径减弱炎症反应。
Morbid obesity increases the cost of care in critically ill patients. Sepsis is the leading cause of death in noncoronary intensive care units. Circulating cell–endothelial cell interactions in microcirculation are the rate-determining factors in any inflammation; obesity increases these interactions further. Adiponectin deficiency is implicated in increased cardiovascular risk in obese patients. We have shown that adiponectin deficiency increases microvascular dysfunction in early sepsis. In the present study, we investigated the effect of adiponectin replacement on nutritionally obese mice with early sepsis. We used cecal ligation and puncture model of sepsis in mice with diet-induced obesity (DIO) vs control diet (CTRL), with or without adiponectin treatment. We studied leukocyte/platelet adhesion in the cerebral microcirculation in early sepsis. We also studied the effect of adiponectin on free fatty acid (FFA)-fed and lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDM) for mechanistic studies. Leukocyte and platelet adhesion increased in the cerebral microcirculation of DIO and CTRL mice with early sepsis vs. sham; moreover cell adhesion in DIO-sepsis group was significantly higher than in the CTRL-sepsis group. Adiponectin replacement decreased leukocyte/platelet adhesion in CTRL and DIO mice. In FFA-fed BMDM, adiponectin treatment decreased tumor necrosis factor-alpha mRNA expression and increased sirtuin-1 (SIRT1) mRNA expression. Furthermore, using BMDM from SIRT1 knockout mice, we showed that the adiponectin treatment decreased inflammatory response in FFA-fed BMDM via SIRT1-dependent and -independent pathways. Adiponectin replacement attenuates microvascular inflammation in DIO-sepsis mice. Mechanistically, adiponectin treatment in FFA-fed mouse macrophages attenuates inflammatory response via SIRT1-dependent and -independent pathways.