Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis
Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis
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DOI：
10.1159/000442976
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发表时间：
2016-01-01
影响因子：
5.3
通讯作者：
Walley, Keith R.
中科院分区：
文献类型：
--
作者：
Boyd, John H.;Fjell, Christopher D.;Walley, Keith R.
目的：我们最近发现，PCSK 9减少了内毒素的清除，因此是感染期间先天免疫应答的关键调节因子。然而，人类脓毒症期间的血浆PCSK 9水平及其与结局的关系尚不清楚。我们的目的是确定血浆PCSK 9水平和内毒素清除率之间的关系，然后将PCSK 9水平与脓毒症患者队列中急性器官衰竭的发生相关。研究方法：使用人肝细胞，我们确定了PCSK 9能够降低培养的人肝细胞对大肠杆菌内毒素摄取的阈值。在加拿大温哥华的圣保罗医院的一个单中心观察队列中，我们招募了200名患者，他们激活了急诊科的脓毒症方案，并在分诊时和整个入院期间测量了血浆PCSK 9和脂质水平。结果是败血症引起的心血管或呼吸衰竭的发展。结果如下：我们回顾了文献，并确定血浆中PCSK 9的正常人体范围为170-220 ng/ml，而250 ng/ml及以上的水平降低了E。大肠杆菌内毒素清除培养的人肝细胞。在脓毒症患者中，与新发呼吸衰竭和心血管衰竭相关的中位水平分别为370（250-500）和380（270-530）ng/ml，而在未继续发展为任何器官衰竭的患者中为270（220-380）ng/ml（分别为p = 0.003和0.005）。结论：脓毒症患者血浆PCSK 9水平显著升高。在正常水平下，PCSK 9对肝细胞细菌内毒素清除没有影响，但随着水平升高，清除受到进行性抑制。在脓毒症期间，PCSK 9水平与随后的多器官衰竭的发展高度相关。抑制PCSK 9活性是治疗脓毒症和脓毒性休克的一个有吸引力的靶点。(C)2016 S. Karger AG，巴塞尔
Purpose: We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during human sepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. Methods: Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce Escherichia coli endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. Results: We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced E. coli endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270-530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). Conclusions: Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock. (C) 2016 S. Karger AG, Basel