First Department of Medicine, University Medical Centre Mannheim (UMM), Faculty of Medicine Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
BMC Infect Dis. 2012 Sep 14;12:217. doi: 10.1186/1471-2334-12-217.
The adipokine leptin regulates energy expenditure, vascular function, bone and cartilage growth as well as the immune system and systemic inflammatory response. Several activating effects towards T cells, monocytes, endothelium cells and cytokine production have been reported suggesting a protective role of leptin in the setting of an acute systemic inflammation. However, the pathophysiological role of leptin during severe sepsis is currently not elucidated in detail. This study aims to investigate leptin expression in cultured human adipocytes within an inflammatory model and in patients suffering from severe sepsis and evaluates treatment effects of drotrecogin alpha (activated) (DAA), the recombinant form of human activated protein C.
In an in-vitro inflammatory model of adipocyte cell-culture the effect of DAA on leptin mRNA expression was evaluated. Synthesis of mRNA was measured by quantitative polymerase chain reaction (qPCR). Additionally, supernatants of these adipocytes as well as serum levels of adiponectin were measured in blood of 104 severe septic patients by ELISA-method. 26 patients were treated with DAA (DAA+), 78 patients were not treated with DAA (DAA-).
Stimulation of human adipocytes with TNF alpha over 6 and 24 hours resulted in a significant decrease by 46% and 59% of leptin mRNA transcripts compared to un-stimulated controls (p < 0.05). Leptin levels of supernatants of adipocyte culture decreased by 25% and 23% (p < 0.05) after incubation with TNF alpha after 6 and 24 hours. Incubation with DAA at 50 ng/ml DAA and 5 μg/ml doubled mRNA expression significantly at 24 hours (p < 0.05) but not at 6 hours. From day 1 to day 3 of sepsis, leptin levels increased in DAA+ compared to DAA- patients (p<0.10).
Leptin appears to be involved in the pathogenesis of a systemic inflammatory response during sepsis. Administration of DAA significantly increased leptin expression. The specific mechanism or even benefit of DAA towards leptin needs further ongoing research.
脂肪因子瘦素调节能量消耗、血管功能、骨骼和软骨生长以及免疫系统和全身炎症反应。有报道称瘦素对 T 细胞、单核细胞、内皮细胞和细胞因子产生有几种激活作用，这表明瘦素在急性全身炎症中具有保护作用。然而，目前尚未详细阐明瘦素在严重脓毒症中的病理生理作用。本研究旨在研究炎症模型培养的人脂肪细胞中的瘦素表达，并评估重组人激活蛋白 C （Drotrecogin Alpha，活化型）（DAA）治疗严重脓毒症患者的疗效。
在体外脂肪细胞培养炎症模型中，评估 DAA 对瘦素 mRNA 表达的影响。通过实时定量聚合酶链反应（qPCR）测量 mRNA 的合成。此外，通过 ELISA 法测量 104 例严重脓毒症患者血液中的这些脂肪细胞上清液和脂联素的血清水平。26 例患者接受 DAA 治疗（DAA+），78 例患者未接受 DAA 治疗（DAA-）。
用 TNFα刺激人脂肪细胞 6 小时和 24 小时后，与未刺激对照相比，瘦素 mRNA 转录本分别显著下降 46%和 59%（p<0.05）。用 TNFα孵育 6 小时和 24 小时后，脂肪细胞培养上清液中的瘦素水平分别下降 25%和 23%（p<0.05）。用 50ng/ml DAA 和 5μg/ml DAA 孵育 24 小时可使 mRNA 表达显著增加一倍（p<0.05），但在 6 小时内无此作用。在脓毒症的第 1 天到第 3 天，与 DAA-患者相比，DAA+患者的瘦素水平升高（p<0.10）。
瘦素似乎参与了脓毒症全身炎症反应的发病机制。DAA 的给药显著增加了瘦素的表达。DAA 对瘦素的具体作用机制甚至益处需要进一步的研究。
