O'Callaghan David J P, O'Dea Kieran P, Scott Alasdair J, Takata Masao, Gordon Anthony C
1Section of Anesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom. 2Department of Critical Care, Imperial College Healthcare NHS Trust, London, United Kingdom.
Crit Care Med. 2015 Jul;43(7):1375-85. doi: 10.1097/CCM.0000000000000992.
To determine the effect of severe sepsis on monocyte tumor necrosis factor-α-converting enzyme baseline and inducible activity profiles.
Observational clinical study.
Mixed surgical/medical teaching hospital ICU.
Sixteen patients with severe sepsis, 15 healthy volunteers, and eight critically ill patients with noninfectious systemic inflammatory response syndrome.
None.
Monocyte expression of human leukocyte antigen-D-related peptide, sol-tumor necrosis factor production, tumor necrosis factor-α-converting enzyme expression and catalytic activity, tumor necrosis factor receptor 1 and 2 expression, and shedding at 48-hour intervals from day 0 to day 4, as well as p38-mitogen activated protein kinase expression. Compared with healthy volunteers, both sepsis and systemic inflammatory response syndrome patients' monocytes expressed reduced levels of human leukocyte antigen-D-related peptide and released less sol-tumor necrosis factor on in vitro lipopolysaccharide stimulation, consistent with the term monocyte deactivation. However, patients with sepsis had substantially elevated levels of basal tumor necrosis factor-α-converting enzyme activity that were refractory to lipopolysaccharide stimulation and this was accompanied by similar changes in p38-mitogen activated protein kinase signaling. In patients with systemic inflammatory response syndrome, monocyte basal tumor necrosis factor-α-converting enzyme, and its induction by lipopolysaccharide, appeared similar to healthy controls. Changes in basal tumor necrosis factor-α-converting enzyme activity at day 0 for sepsis patients correlated with Acute Physiology and Chronic Health Evaluation II score and the attenuated tumor necrosis factor-α-converting enzyme response to lipopolysaccharide was associated with increased mortality. Similar changes in monocyte tumor necrosis factor-α-converting enzyme activity could be induced in healthy volunteer monocytes using an in vitro two-hit inflammation model. Patients with sepsis also displayed reduced shedding of monocyte tumor necrosis factor receptors upon stimulation with lipopolysaccharide.
Monocyte tumor necrosis factor-α-converting enzyme catalytic activity appeared altered by sepsis and may result in reduced shedding of tumor necrosis factor receptors. Changes seemed specific to sepsis and correlated with illness severity. A better understanding of how tumor necrosis factor-α-converting enzyme function is altered during sepsis will enhance our understanding of sepsis pathophysiology, which will help in the assessment of patient inflammatory status and ultimately may provide new strategies to treat sepsis.
确定严重脓毒症对单核细胞肿瘤坏死因子-α转换酶基线水平及诱导活性谱的影响。
观察性临床研究。
外科/内科混合教学医院重症监护病房。
16例严重脓毒症患者、15名健康志愿者以及8例患有非感染性全身炎症反应综合征的危重症患者。
无。
从第0天至第4天，每隔48小时检测单核细胞人类白细胞抗原-D相关肽的表达、可溶性肿瘤坏死因子的产生、肿瘤坏死因子-α转换酶的表达及催化活性、肿瘤坏死因子受体1和2的表达及脱落情况，以及p38丝裂原活化蛋白激酶的表达。与健康志愿者相比，脓毒症患者和全身炎症反应综合征患者的单核细胞在体外脂多糖刺激下，人类白细胞抗原-D相关肽的表达水平均降低，可溶性肿瘤坏死因子的释放量也减少，这与单核细胞失活现象相符。然而，脓毒症患者的基础肿瘤坏死因子-α转换酶活性显著升高，且对脂多糖刺激不敏感，同时p38丝裂原活化蛋白激酶信号传导也有类似变化。在全身炎症反应综合征患者中，单核细胞基础肿瘤坏死因子-α转换酶及其对脂多糖的诱导反应与健康对照相似。脓毒症患者第0天基础肿瘤坏死因子-α转换酶活性的变化与急性生理与慢性健康状况评分系统II评分相关，而肿瘤坏死因子-α转换酶对脂多糖反应减弱与死亡率增加有关。使用体外双打击炎症模型可在健康志愿者单核细胞中诱导出类似的单核细胞肿瘤坏死因子-α转换酶活性变化。脓毒症患者在脂多糖刺激下，单核细胞肿瘤坏死因子受体的脱落也减少。
脓毒症似乎改变了单核细胞肿瘤坏死因子-α转换酶的催化活性，并可能导致肿瘤坏死因子受体脱落减少。这些变化似乎是脓毒症特有的，且与疾病严重程度相关。更好地了解脓毒症期间肿瘤坏死因子-α转换酶功能如何改变，将增进我们对脓毒症病理生理学的理解，有助于评估患者的炎症状态，并最终可能为治疗脓毒症提供新策略。
