Rose S, Baumann H, Jahreis G P, Sayeed M M
Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois 60153, USA.
Shock. 1994 Feb;1(2):87-93. doi: 10.1097/00024382-199402000-00002.
This study assessed the hepatic acute phase response and cellular Ca2+ regulation in septic animals and in hepatoma cell lines in vitro. Sepsis was induced in male Sprague-Dawley rats by implanting in their abdominal cavities fecal pellets impregnated with live Escherichia coli and Bacteroides fragilis. 8 h after implantations, rats were treated with diltiazem (1.2 mg/kg) or superoxide dismutase (SOD) (5 x 10(3) units/kg). After 24 h, plasma acute phase proteins (APP) were determined by immunoelectrophoresis, and hepatic APP-mRNAs by Northern blot hybridization. Effects of diltiazem, verapamil, or SOD on hepatic cells were determined in rat Reuber H-35 and human HepG2 hepatoma cells. Sepsis induced a significant increase in plasma APP and their hepatic mRNAs. Diltiazem and SOD reduced the sepsis-induced elevations in plasma lactate, the febrile response and mortality. APP expression in H-35 and HepG2 cells, stimulated by interleukin 1 (IL-1), IL-6, and dexamethasone, was inhibited by diltiazem or verapamil but not SOD. The results suggest that a heightened hepatic APP response in septic animals accompanies systemic/metabolic derangements and a significant animal mortality. Because diltiazem was previously shown to prevent sepsis-related disturbances in hepatic cellular Ca2+ regulation, its mediation of decrease in APP, systemic/metabolic response, and mortality may be effected through modifications in cellular Ca2+ regulation. The data from hepatoma cells show an attenuation of the AAP can result from direct effects of a calcium blocker. However, whether the blocker primarily modifies cellular Ca2+ regulation and secondarily effects APP gene expression, or directly effects gene expression remains unknown.
本研究评估了脓毒症动物及体外肝癌细胞系中的肝脏急性期反应和细胞钙调节。通过向雄性Sprague-Dawley大鼠腹腔内植入含活大肠杆菌和脆弱拟杆菌的粪便颗粒诱导脓毒症。植入后8小时，大鼠接受地尔硫䓬（1.2毫克/千克）或超氧化物歧化酶（SOD）（5×10³单位/千克）治疗。24小时后，通过免疫电泳测定血浆急性期蛋白（APP），通过Northern印迹杂交测定肝脏APP-mRNA。在地鼠Reuber H-35和人HepG2肝癌细胞中测定地尔硫䓬、维拉帕米或SOD对肝细胞的作用。脓毒症导致血浆APP及其肝脏mRNA显著增加。地尔硫䓬和SOD降低了脓毒症诱导的血浆乳酸升高、发热反应和死亡率。白介素1（IL-1）、IL-6和地塞米松刺激的H-35和HepG2细胞中的APP表达被地尔硫䓬或维拉帕米抑制，但未被SOD抑制。结果表明，脓毒症动物肝脏APP反应增强伴随着全身/代谢紊乱和显著的动物死亡率。由于先前已证明地尔硫䓬可预防肝脏细胞钙调节中与脓毒症相关的紊乱，其对APP降低、全身/代谢反应和死亡率的介导作用可能是通过细胞钙调节的改变来实现的。肝癌细胞的数据表明，钙通道阻滞剂的直接作用可导致AAP减弱。然而，该阻滞剂是主要改变细胞钙调节继而影响APP基因表达，还是直接影响基因表达尚不清楚。
