Ertel W, Jarrar D, Jochum M, Thiele V, Kenney J, Faist E, Schildberg F W
Department of Surgery, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Arch Surg. 1994 Jan;129(1):90-7; discussion 97-8. doi: 10.1001/archsurg.1994.01420250102013.
The proteolytic enzyme elastase released by granulocytes (polymorphonuclear leukocytes [PMN]) in high concentrations during sepsis causes degradation of essential plasma proteins, endothelial damage, and tissue edema. This may result in organ dysfunction and organ failure during sepsis, since increased elastase plasma levels correlate with the mortality rate of patients with sepsis. In vitro studies demonstrated a regulatory role of inflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin 1 beta [IL-1 beta], IL-8]) upregulating protease release by PMN. In this light, the interactions between cytokine release by macrophages and altered elastase secretion during sepsis remain to be determined.
An ex vivo model consisting of lipopolysaccharide stimulation of human whole blood as a relevant physiological milieu was used. Heparinized blood was obtained from 20 patients with sepsis syndrome (APACHE II [Acute Physiology and Chronic Health Evaluation II] score 28.5 +/- 1.2 points [mean +/- SD]) on days 0 through 3, 5, 7, and 10 after sepsis diagnosis and from 20 control patients without infection. Blood was incubated with lipopolysaccharide (1 mg/L) for 8 hours. Plasma levels of elastase, TNF-alpha, IL-1 beta, and IL-8 were determined using enzyme-linked immunosorbent assay or bioassay (TNF-alpha), respectively.
Elastase plasma levels in whole blood from patients with sepsis were increased up to 188% (P < .01) above normal, while the release of TNF-alpha (-87%), IL-1 beta (-91%), and IL-8 (-51%) was markedly (P < .01) decreased compared with control patients. Neutralization of TNF-alpha or IL-1 beta did not attenuate the increased release of elastase.
These data indicate an increased release of elastase by PMN despite a reduced secretion of PMN-activating cytokines. Although priming effects of TNF-alpha, IL-1 beta, and IL-8 on protease secretion in vivo cannot be excluded completely, other mediators or mechanisms may be involved in the upregulation of detrimental protease release during sepsis.
在脓毒症期间，粒细胞（多形核白细胞[PMN]）释放的蛋白水解酶弹性蛋白酶浓度过高，会导致必需血浆蛋白降解、内皮损伤和组织水肿。这可能会导致脓毒症期间器官功能障碍和器官衰竭，因为弹性蛋白酶血浆水平升高与脓毒症患者的死亡率相关。体外研究表明，炎性细胞因子（肿瘤坏死因子-α[TNF-α]、白细胞介素1β[IL-1β]、IL-8）具有调节作用，可上调PMN释放蛋白酶。有鉴于此，脓毒症期间巨噬细胞释放细胞因子与弹性蛋白酶分泌改变之间的相互作用仍有待确定。
使用由脂多糖刺激人全血组成的体外模型作为相关生理环境。在脓毒症诊断后的第0天至第3天、第第5天、第7天和第10天，从20例脓毒症综合征患者（急性生理学与慢性健康状况评分II[APACHE II]评分为28.5±1.2分[平均值±标准差]）和20例无感染的对照患者中获取肝素化血液。将血液与脂多糖（1mg/L）孵育8小时。分别使用酶联免疫吸附测定法或生物测定法（TNF-α）测定弹性蛋白酶、TNF-α、IL-1β和IL-8的血浆水平。
脓毒症患者全血中的弹性蛋白酶血浆水平比正常水平升高了188%（P<.01），而与对照患者相比，TNF-α（-87%）、IL-1β（-91%）和IL-8（-51%）的释放明显（P<.01）减少。中和TNF-α或IL-1β并不能减弱弹性蛋白酶释放增加的情况。
这些数据表明，尽管PMN激活细胞因子的分泌减少，但PMN释放的弹性蛋白酶增加。尽管不能完全排除TNF-α、IL-1β和IL-8对体内蛋白酶分泌的启动作用，但其他介质或机制可能参与了脓毒症期间有害蛋白酶释放的上调。
