DIFFERENTIAL EXPRESSION OF PCSK9 MODULATES INFECTION, INFLAMMATION, AND COAGULATION IN A MURINE MODEL OF SEPSIS
DIFFERENTIAL EXPRESSION OF PCSK9 MODULATES INFECTION, INFLAMMATION, AND COAGULATION IN A MURINE MODEL OF SEPSIS
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DOI：
10.1097/shk.0000000000000682
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发表时间：
2016-12-01
期刊：
影响因子：
3.1
通讯作者：
Liaw, Patricia C.
中科院分区：
文献类型：
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作者：
Dwivedi, Dhruva J.;Grin, Peter M.;Liaw, Patricia C.
蛋白转化酶subtilisin/kexin type 9 （PCSK9）靶向脂蛋白受体降解，从而减少肝脏脂质清除。PCSK9抑制降低了脓毒症小鼠的死亡率，可能是由于脂蛋白受体浓度增加而增加了肝脏对病原体脂质的清除。然而，PCSK9在脓毒症中的体内过表达尚未得到研究。因此，本研究旨在评估PCSK9差异表达对脓毒症全身性感染、炎症和凝血的影响。方法：对过表达PCSK9的野生型、PCSK9敲除型（KO）和转基因（Tg）小鼠进行假手术或盲肠结扎穿刺（CLP）。测定肺、腹膜腔液和血液中的细菌负荷。肺、肝、肾脏器病理检查。术后6 h检测肺髓过氧化物酶活性、血浆丙氨酸转氨酶（ALT）、肌酐、游离DNA （cfDNA）、蛋白C、凝血酶-抗凝血酶（TAT）复合物、白细胞介素(IL)-6、IL-10浓度。评估CLP后16小时的发病率。结果：小鼠中PCSK9的过表达增加了脓毒症期间肝脏和肾脏病理、血浆IL-6、ALT和TAT浓度，而PCSK9 KO小鼠在clp诱导的脓毒症期间表现出细菌负荷、肺和肝脏病理、髓过氧化物酶活性、血浆IL-10和cfDNA的减少。所有脓毒症小鼠的血浆蛋白C水平均降低，但PCSK9 Tg小鼠的蛋白C比值相对于正常小鼠显著降低。在过表达PCSK9的脓毒症小鼠中，呼吸困难、发绀和整体表情评分最高，而PCSK9 KO小鼠在脓毒症期间保持核心体温。结论：这些研究结果表明，PCSK9缺乏对全身细菌传播、器官病理和组织炎症具有保护作用，特别是在肺和肝脏，而PCSK9过表达加剧了早期败血症的多器官病理以及高凝和促炎状态。
Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets lipoprotein receptors for degradation, thereby reducing hepatic lipid clearance. PCSK9 inhibition reduces mortality in septic mice, presumably through increased hepatic clearance of pathogen lipids due to increased lipoprotein receptor concentrations. However, PCSK9 overexpression in vivo has not been studied in sepsis. Therefore, this study aimed to evaluate the effects of differential PCSK9 expression on systemic infection, inflammation, and coagulation in sepsis. Methods: Wild-type, PCSK9 knockout (KO), and transgenic (Tg) mice that overexpress PCSK9 were subjected to sham surgery or cecal ligation and puncture (CLP). Bacterial loads were measured in lungs, peritoneal cavity fluid, and blood. Organ pathology was assessed in lungs, liver, and kidneys. Lung myeloperoxidase activity, and plasma concentrations of alanine aminotransferase (ALT), creatinine, cell-free DNA (cfDNA), protein C, thrombin-antithrombin (TAT) complexes, interleukin (IL)-6, and IL-10 were also measured 6 h postoperatively. Morbidity was assessed for 16 h following CLP. Results: Overexpression of PCSK9 in mice increased liver and kidney pathology, plasma IL-6, ALT, and TAT concentrations during sepsis, whereas PCSK9 KO mice exhibited reduced bacterial loads, lung and liver pathology, myeloperoxidase activity, plasma IL-10, and cfDNA during CLP-induced sepsis. All septic mice had reduced plasma levels of protein C, but the protein C ratio relative to normal was significantly decreased in PCSK9 Tg mice. Dyspnea, cyanosis, and overall grimace scores were greatest in septic mice overexpressing PCSK9, whereas PCSK9 KO mice retained core body temperature during sepsis. Conclusion: These findings demonstrate that PCSK9 deficiency confers protection against systemic bacterial dissemination, organ pathology, and tissue inflammation, particularly in the lungs and liver, while PCSK9 overexpression exacerbates multi-organ pathology as well as the hypercoagulable and pro-inflammatory states in early sepsis.