Bisoendial Radjesh J, Birjmohun Rakesh S, Akdim Fatima, van 't Veer Cornelis, Spek C Arnold, Hartman Daniel, de Groot Els R, Bankaitis-Davis Danute M, Kastelein John J P, Stroes Erik S G
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Am J Med. 2009 Jun;122(6):582.e1-9. doi: 10.1016/j.amjmed.2008.11.032.
Consistent epidemiologic evidence suggests that acute infections increase the risk for acute cardiovascular events. We tested in humans whether activation of peripheral leukocytes in reaction to the administration of recombinant human C-reactive protein (rhCRP) may provide a mechanism for infectious diseases to promote atherosclerotic disease.
By using quantitative real-time polymerase chain reaction analysis, whole-blood expression profiles were analyzed for 95 inflammatory markers before and after infusion of 1.25 mg/kg rhCRP in 5 male volunteers. Relevant transcript levels were measured at baseline and 4 and 8 hours after rhCRP-infusion. CRP caused significant up-regulation of matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-1, plasminogen activator urokinase, macrophage inflammatory protein 1 alpha, and nuclear factor of kappa B inhibitor mRNAs in peripheral leukocytes. mRNA up-regulation of MMP-9 and MCP-1 was 17- and 11-fold, respectively. The corresponding increase in plasma protein levels of MMP-9 (78+/-32 ng/mL to 109+/-41 ng/mL; P=.014) and MCP-1 (312+/-92 pg/mL to 2590+/-898 pg/mL; P=.007) closely mirrored mRNA findings. Also, in whole-blood culture stimulation assays, CRP induced proinflammatory changes. Notably, heat inactivation abolished the capacity of CRP to evoke these proinflammatory changes, excluding a role for contaminants within the purified CRP preparation.
CRP elicits activation of peripheral leukocytes with ensuing secretion of plaque-destabilizing mediators. These findings are consistent with the hypothesis that infectious diseases trigger manifestations of atherosclerosis, in which CRP elevation might contribute to the onset of cardiovascular events.
一致的流行病学证据表明，急性感染会增加急性心血管事件的风险。我们在人体中测试了重组人C反应蛋白（rhCRP）给药后外周白细胞的激活是否可能为传染病促进动脉粥样硬化疾病提供一种机制。
通过定量实时聚合酶链反应分析，在5名男性志愿者中，于输注1.25mg/kg rhCRP前后对95种炎症标志物进行全血表达谱分析。在基线以及rhCRP输注后4小时和8小时测量相关转录水平。CRP导致外周白细胞中基质金属蛋白酶（MMP）-9、单核细胞趋化蛋白（MCP）-1、尿激酶型纤溶酶原激活剂、巨噬细胞炎性蛋白1α和核因子κB抑制因子mRNA显著上调。MMP-9和MCP-1的mRNA上调分别为17倍和11倍。MMP-9（78±32ng/mL至109±41ng/mL；P = 0.014）和MCP-1（312±92pg/mL至2590±898pg/mL；P = 0.007）血浆蛋白水平的相应升高与mRNA结果密切相符。此外，在全血培养刺激试验中，CRP诱导促炎变化。值得注意的是，热灭活消除了CRP引发这些促炎变化的能力，排除了纯化的CRP制剂中污染物的作用。
CRP引发外周白细胞激活，随后分泌破坏斑块稳定性的介质。这些发现与传染病引发动脉粥样硬化表现的假说一致，其中CRP升高可能促成心血管事件的发生。
