Barber A E, Coyle S M, Marano M A, Fischer E, Calvano S E, Fong Y, Moldawer L L, Lowry S F
Department of Surgery, New York Hospital, Cornell Medical Center, NY 10021.
J Immunol. 1993 Mar 1;150(5):1999-2006.
Previous experimental data have demonstrated that steroid pretreatment regulates endotoxin-elicited cytokine production. The timing of such hypercortisolemia also appears to be a major determinant of both the systemic and the cytokine response to infectious stimuli. Our study was undertaken to further study the in vivo influence of glucocorticoid infusion concurrent with and before endotoxin exposure in man. A total of 23 normal human subjects were given endotoxin (LPS) alone or pretreated with hydrocortisone infusion for 6 h immediately before and concomitant to LPS administration; or rendered hypercortisolemic for a 6-h period waiting 6, 12, or 144 h before LPS administration. LPS administration was followed by significant elevations in temperature (1.9 +/- 0.3 degrees C), pulse (29 +/- 6 bpm), and resting energy expenditure (26.2 +/- 0.4 kcal/kg/day) as well as epinephrine (236 +/- 59 pg/ml), cortisol (296 +/- 29), and C-reactive protein (4.2 +/- .03 mg/dl) as compared with base-line values. Levels of TNF and IL-6 that were not detectable before LPS administration, peaked, respectively, at 90 and 120 min after LPS (155 +/- 4 pg/ml, 12 +/- 1 U/ml). Glucocorticoids when given immediately before and concomitant with LPS significantly attenuated the temperature (0.8 +/- 0.01 degrees C) and pulse rate response (10 +/- 3 bpm) seen after LPS alone as well as suppressing peak levels of epinephrine (78 +/- 14 pg/ml) and C-reactive protein (undetected). TNF remained undetectable in this group although the IL-6 response (14 +/- 1 U/ml) was unchanged. With a 6-h interval between hydrocortisone infusion and LPS challenge, changes in temperature, pulse, resting energy expenditure, and hormone levels were similar to those seen after LPS alone whereas TNF remained undetectable and IL-6 levels were similar to subjects receiving LPS alone. Subjects receiving LPS after 12 or 144 h after hydrocortisone infusion displayed hemodynamic and hormonal responses similar to the LPS alone group, yet mounted significantly greater circulating levels of both IL-6 (117 +/- 14 U/ml, 160 +/- 51 U/ml at 12 and 144 h) and TNF (609 +/- 173, 671 +/- 132 pg/ml at 12 and 144 h) to those observed after LPS alone. We conclude that antecedent periods of hypercortisolemia participate in regulation of the hemodynamic, hormonal, and cytokine responses to endotoxin and that a complex temporal relationship between hypercortisolemia and LPS induced cytokine and systemic responses exists.
先前的实验数据表明，类固醇预处理可调节内毒素诱导的细胞因子产生。这种高皮质醇血症的时机似乎也是对感染性刺激的全身反应和细胞因子反应的主要决定因素。我们开展这项研究是为了进一步研究在人体中内毒素暴露前后同时输注糖皮质激素的体内影响。共有23名正常人类受试者，分别单独给予内毒素（LPS），或在LPS给药前立即并同时给予氢化可的松输注预处理6小时；或在LPS给药前6、12或144小时使其处于高皮质醇血症状态6小时。给予LPS后，与基线值相比，体温（1.9±0.3℃）、脉搏（29±6次/分钟）、静息能量消耗（26.2±0.4千卡/千克/天）以及肾上腺素（236±59皮克/毫升）、皮质醇（296±29）和C反应蛋白（4.2±0.03毫克/分升）均显著升高。LPS给药前无法检测到的TNF和IL-6水平，分别在LPS给药后90分钟和120分钟达到峰值（155±4皮克/毫升，12±1单位/毫升）。在LPS给药前立即并同时给予糖皮质激素可显著减弱单独给予LPS后出现的体温（0.8±0.01℃）和脉搏率反应（10±3次/分钟），同时抑制肾上腺素（78±14皮克/毫升）和C反应蛋白（未检测到）的峰值水平。该组中TNF仍无法检测到，尽管IL-6反应（14±1单位/毫升）未改变。氢化可的松输注与LPS激发之间间隔6小时，体温、脉搏、静息能量消耗和激素水平的变化与单独给予LPS后相似，而TNF仍无法检测到，IL-6水平与单独接受LPS的受试者相似。在氢化可的松输注后12或144小时接受LPS的受试者表现出与单独给予LPS组相似的血流动力学和激素反应，但与单独给予LPS后相比，循环中IL-6（12小时和144小时分别为117±14单位/毫升，160±51单位/毫升）和TNF（12小时和144小时分别为609±173，671±132皮克/毫升）的水平显著更高。我们得出结论，先前的高皮质醇血症期参与对内毒素的血流动力学、激素和细胞因子反应的调节，并且高皮质醇血症与LPS诱导的细胞因子和全身反应之间存在复杂的时间关系。
