高压氧对失血性休克复苏后炎症反应的影响

目的观察高压氧对大白鼠失血性休克复苏后炎症反应的影响并探讨其作用机制。方法Wistar大鼠随机分为三组：高压氧治疗组、休克组和对照组。建立大鼠失血性休克模型,自体血和生理盐水复苏后应用2．0绝对大气压高压氧治疗,于休克前、休克后、复苏后和复苏后24h取血检测血红细胞SOD、血浆卧限a、血浆iNOS值,并进行统计学（one-way ANOVA plus SNK）分析。观察复苏后24h大鼠肝、肠、肺组织病理改变并进行病理损伤评分。结果复苏后24h高压氧治疗组血红细胞SOD值高于休克组,高压氧治疗组血浆iNOS值和TNFoa值低于休克组,差异具有统计学意义（P〈0．05）。病理损伤评分：高压氧治疗组病理损伤与休克组相比减轻,差异具有统计学意义（P〈0．05）。结论 高压氧可能通过增强机体清除活性氧和自由基、阻止炎症介质的产生,进而减轻大鼠失血性休克复苏后的炎症反应和组织脏器的病理损伤。     

高渗氯化钠溶液复苏对失血性休克大鼠T淋巴细胞亚群的早期影响

目的 探讨高渗氯化钠溶液(HS)复苏对失血性休克大鼠T淋巴细胞亚群的早期影响及其意义.方法 将18只SD大鼠制作成重度失血性休克模型,随机分为假手术组(Sham组)、高渗氯化钠溶液复苏组(HS组)和等渗盐水复苏组(NS组),每组6只,采用双抗体标记流式细胞分析技术测定休克前及复苏/急救后各组大鼠的外周血CD4+、CD8+的百分率及二者比值CD4+/CD8+.结果 在失血性休克/复苏/急救后的早期阶段,HS组和NS组大鼠的外周血CD4+细胞亚群表达均显著升高(P＜0.05),HS组大鼠的外周血CD8+细胞亚群表达也有所升高,而NS组大鼠的外周血CD8+细胞亚群表达则无明显改变,从而导致NS组大鼠的外周血CD4+/CD8+比值较Sham组和HS组明显增高,差异具有统计学意义(P＜0.05).结论 在重度失血性休克大鼠模型中,与NS复苏相比较,HS复苏能明显减轻复苏后早期的免疫炎症调节功能紊乱,有助于维持T细胞的辅助-抑制免疫炎症调节网络的平衡.     

高渗盐溶液联合己酮可可碱用于失血性休克早期复苏的研究现状

失血性休克液体复苏时如何减轻复苏后器官损伤是该领域近年来的研究热点.已有研究显示高渗盐溶液联合己酮可可碱用于失血性休克早期复苏时不仅能迅速提高有效循环血量、改善组织灌注,还能有效地减轻复苏后器官损伤,这为入院后进一步的治疗提供了良好的救治基础.这种复苏液联合"复苏药物"的模式为临床失血性休克患者的院前急救提供了新的思路,有进一步深入研究的价值.     

早期复苏中高渗盐胶体对小肠黏膜形态学的影响

目的 观察高渗盐复合胶体液在失血性休克早期复苏中对小肠黏膜形态学特征的影响.方法 36只SD大鼠随机分为三组,通过控制性颈动脉放血制成失血性休克模型,分别应用相同容量的乳酸钠林格氏液、7.5%高渗盐水和琥珀酸明胶的混合液、ATP-MgCl2-乳酸钠林格氏液进行液体复苏,复苏结束后2 h处死动物,取末端回肠,常规固定切片染色,以光学图像分析法观察比较复苏后回肠黏膜的黏膜厚度和绒毛长度以及回肠黏膜上皮损伤指数等.结果 三组复苏方案之间的回肠黏膜损伤指数比较有显著性差异（P＜0.05）,高渗盐明胶组的回肠黏膜损伤指数最小.三组复苏方案之间的回肠黏膜厚度和绒毛长度比较均无显著性差异.结论 高渗盐复合胶体溶液在控制性失血性休克的早期复苏中对回肠黏膜的形态学损伤较小,能相对较好地保护肠黏膜物理屏障.     

盐酸戊乙奎醚结合液体复苏抑制失血性休克大鼠小肠黏膜凋亡的研究

目的 探讨盐酸戊乙奎醚结合液体复苏对失血性休克大鼠小肠黏膜细胞凋亡的影响.方法 32只SD大鼠,制成重度失血性休克模型,分成对照组、假手术组、液体复苏组和盐酸戊乙奎醚结合液体复苏组,每组8只.采用流式细胞仪和FITC-Annexin V/PI荧光染色法检测和比较失血/复苏/急救后各组大鼠小肠黏膜细胞凋亡的发生情况.结果 无论采取治疗措施,经历了失血性休克和复苏的大鼠,其小肠黏膜细胞均存在显著的细胞凋亡情况.液体复苏组和盐酸戊乙奎醚结合液体复苏组大鼠的小肠黏膜细胞凋亡率明显高于对照组和假手术组,差异均有统计学意义（P均＜0.05）.同时,与液体复苏组相比较,盐酸戊乙奎醚结合液体复苏组大鼠的小肠黏膜细胞凋亡率明显降低,差异有统计学意义（P＜0.05）. 结论 盐酸戊乙奎醚结合液体复苏能有效抑制失血性休克大鼠肠道黏膜细胞的凋亡,从而减少失血/复苏对肠道黏膜完整性的损害,可能有助于改善预后.     

不同时间输注红细胞悬液对大鼠失血性休克复苏的影响

目的探讨红细胞悬液延迟输注30 min对大鼠失血性休克复苏的影响。方法 24只Wistar大鼠随机分为假手术(SHAM)、RBC 1和RBC 2组(n=8),RBC 1和RBC 2组制备重度失血性休克大鼠模型,先后采用晶胶复合液和红细胞悬液复苏,RBC 2组红细胞悬液延迟输注30 min;监测生理、血气等指标。结果与RBC1组相比,RBC 2组平均动脉压(MAP)和体温恢复延迟,RBC 1组复苏结束后2组MAP分别为(116.99±11.06)和(73.72±14.34)mm Hg(P0.01);RBC 1组复苏结束后30 min,2组MAP分别为(103.07±9.59)和(120.61±10.73)mmHg(P0.01)。RBC 1组复苏结束后120 min RBC 1组体温(37.28±0.80)℃明显低于RBC 2组(38.83±0.58)℃(P0.01)。与SHAM组相比,RBC 1和RBC 2组休克后pH、PCO2、BE和ctHb明显降低,PO2明显升高;复苏后PCO23 h,RBC 1和RBC 2组碱剩余(BE)值明显低于SHAM组。结论在失血性休克液体复苏的基础上,红细胞悬液延迟输注30 min对失血性休克大鼠模型的生理、血气等指标无明显影响。提示紧急救治中输血准备工作耗时可能不影响失血性休克的复苏效果。     

Effects of different resuscitation fluids on the rheologic behavior of red blood cells,blood viscosity and plasma viscosity in experimental hemorrhagic shock

Background

Hemorrhagic shock is associated with severe rheological abnormalities. We hypothesized that in the setting of hemorrhagic shock, resuscitation can alter hemorheological characteristics dramatically, and different fluids cause different effects. The aim of this study was to investigate whether the type of fluid administered has an impact on hemorheological characteristics at the early stage of resuscitation in a rodent model of hemorrhagic shock.

Methods

Animals were randomized into five groups: (1) sham hemorrhage (SHAM); (2) shock and sham resuscitation (SHOCK); (3) shock and resuscitation with normal saline 32 ml/kg (NS); (4) shock and resuscitation with 7.5% hypertonic saline 4 ml/kg (HS); (5) shock and resuscitation with 7.5% hypertonic saline/6% Dextran 70 4 ml/kg (HSD). Hemorheological characteristics were measured at 60 min after resuscitation.

Results

Results showed that NS resuscitation deteriorated red blood cell (RBC) deformability compared with the SHOCK group. The HS group showed improved RBC deformability compared with the NS group, although the differences were not statistically significant. There were significant improvements of RBC deformability at all shear rates in the HSD group compared with the NS group. Whole blood and plasma viscosities decreased significantly in the SHOCK group compared with the SHAM group. At shear rates of 60 and 150 s⁻¹, the NS group decreased whole blood viscosity compared with the SHOCK group. The HSD group showed elevated plasma viscosity compared with the SHOCK, NS and HS groups.

Conclusion

These results suggested that at the early stage of hemorrhagic shock resuscitation, hypertonic–hyperoncotic resuscitation could improve RBC deformability compared with isotonic crystalloid resuscitation. Dextran 70 could elevate plasma viscosity to nearly baseline level. These effects of hypertonic–hyperoncotic resuscitation could be beneficial to maintain microcirculation.     

高渗氯化钠溶液复苏抑制失血性休克大鼠肺细胞凋亡的初步研究

目的 探讨高渗氯化钠溶液(HS)复苏对失血性休克大鼠肺细胞凋亡的影响及其意义. 方法 将23只SD大鼠制作成重度失血性休克模型,随机分为假手术组(Sham组,8只)、高渗氯化钠溶液复苏组(HS组,9只)和等渗盐水复苏组(NS组,6只),采用流式细胞仪FITC-AnnexinV/PI荧光染色法定量测定休克/复苏后各组大鼠肺组织细胞的凋亡情况,并加以比较和分析. 结果 在失血性休克/复苏后的早期阶段,HS组和NS组大鼠的肺组织细胞即有大量凋亡发生,其肺细胞凋亡率均明显高于Sham组,差异有统计学意义(P＜0.01).同时,NS组大鼠的肺细胞凋亡率则显著高于HS组,差异有统计学意义(P＜0.01). 结论 在重度失血性休克大鼠模型中,与等渗盐水复苏相比较,高渗氯化钠溶液复苏能显著抑制失血/复苏后肺细胞的凋亡,有助于减轻休克后急性肺损伤,这可能也是高渗氯化钠溶液复苏肺保护作用的重要机制之一.     

Effects of arterial oxygen content on oxidative stress during resuscitation in a rat hemorrhagic shock model

Objective

To examine whether reactive oxygen species (ROS) production is affected by arterial oxygen content (CaO₂) in attempted resuscitation to restore blood pressure from hemorrhagic shock (HS) or not.

Methods

Under light anesthesia and spontaneous beating, 16 rats underwent HS for 80 min, during which 3.0 mL/100 g of blood was withdrawn, followed by resuscitation attempt for 70 min. At 80 min, rats were randomized into a high-CaO₂ group (Group 1, transfusion under fractional inspired oxygen (F_IO₂) of 1.0, n = 8) or a low-CaO₂ group (Group 2, fluid administration under F_IO₂ of 0.21, n = 8). In each group, either blood or lactate Ringer's (LR) solution was infused to maintain mean arterial pressure ≥75 mmHg under each F_IO₂ concentration. CaO₂, O₂ utilization coefficient (UC) and plasma %CoQ9 were compared between groups.

Results

Mean infused volume for attempted resuscitation was 7.6 ± 1.0 mL of blood in Group 1, and 31.4 ± 5.5 mL of LR solution in Group 2. At the end of resuscitation, CaO₂ was 18.5 ± 1.2 vol% in Group 1, almost double the 9.1 ± 0.8 vol% in Group 2 (P < 0.01). O₂ UC and %CoQ9 in all rats increased from baselines of 0.25 ± 0.12 and 7.6 ± 1.8% to 0.44 ± 0.13 and 9.7 ± 1.8% after resuscitation, respectively (P < 0.05 vs. baseline for each), but did not differ significantly between the groups.

Conclusion

In a rat HS model, attempted resuscitation to restore blood pressure increased O₂ UC as well as %CoQ9. However, the magnitude of %CoQ9 increase that represents ROS production is not affected by CaO₂ during resuscitation from HS.     

早期应用去甲肾上腺素的液体复苏方案对脓毒性休克大鼠肺脏的作用

目的 研究早期与延迟应用去甲肾上腺素的两种液体复苏方案对脓毒性休克大鼠肺损伤的影响.方法 60只Wistar大鼠随机(随机数字法)分成4组:健康对照组(A组,n=15),休克对照组(B组,n=15),传统液体复苏组(C组,n=15),早期应用去甲肾上腺素组(D组,n=15),所有大鼠给予经口气管插管机械通气,相同呼吸机模式及参数.LPS静脉注射建立脓毒性休克大鼠模型,C组于液体复苏0.5h后应用去甲肾上腺素,D组于液体复苏同时应用去甲肾上腺素,记录各组大鼠生命体征、补液量及去甲肾上腺素用量.2h后处死大鼠,进行血气分析,HE染色观察肺组织形态学变化,ELISA检测肺泡灌洗液及血清中炎性介质的表达,检测肺组织中髓过氧化物酶、超氧化物歧化酶及丙二醛表达.计量资料以均数±标准差((x)±s)表示,采用SPSS13.0统计软件分析,组间比较采用t检验,以P＜0.05为差异具有统计学意义.结果 早期应用去甲肾上腺素与传统补液方案比较明显减少了达到目标血压所需的补液量,使氧合指数进一步改善,同时降低了血乳酸水平(P＜0.05);HE染色结果显示早期应用去甲肾上腺素使肺水肿程度明显减轻,肺组织中炎性细胞侵润程度、肺泡充血情况得到明显改善;早期应用去甲肾上腺素和传统补液方案均使血清和肺泡灌洗液中的促炎介质白介素-6、白介素-8、肿瘤坏死因子-α表达水平下调,但早期应用去甲肾上腺素使促炎介质表达下降更为明显,与传统补液比较差异具有统计学意义(P＜0.05);早期应用去甲肾上腺素仅使髓过氧化物酶表达较传统补液组及休克对照组明显下降,两种补液方案对超氧化物歧化酶和丙二醛表达均无明显改善.结论 早期应用去甲肾上腺素的液体复苏方案与传统补液方案比较从多层面改善了脓毒性休克大鼠肺损伤的程度.     

高渗盐己酮可可碱复苏对失血性休克大鼠肺部炎症反应的影响

目的 探讨HSPTX(7.5%氯化钠+己酮可可碱)对失血性休克大鼠肺损伤的影响.方法 24只雄性SD大鼠随机(随机数字法)分为3组:假失血性休克(Sham)组,仅接受动静脉插管操作,不放血及复苏;大容量乳酸钠林格氏液(RL)复苏组,接受32 mL/kg RL;小容量高张液(7.5%氯化钠)+PTX复苏组,接受4 mL/kg 7.5%NaCL+25 mg/kg PTX,每组8只.测定各组动脉血氧分压(PaO2),pH值,二氧化碳分压(PaCO2),肺湿/干质量比值,测定血清丙二醛(MDA)含量以及超氧化物歧化酶(SOD)活性;检测支气管肺泡灌洗液(BALF)中性粒细胞比例及肺通透性指数,采用ELISA法测定灌洗液上清中肿瘤坏死因子-α(TNF-α)、白细胞介素1-β(IL-1β)含量.结果 与RL组相比,HSPTX组PaO2和pH值升高、PaCO2降低(P＜0.01),HSPTX组大鼠肺湿/干质量(W/D)及支气管肺泡灌洗液中上清中TNF-α、IL-1β含量均低于RL组(P＜0.01).结论 HSPTX复苏可减少失血性休克大鼠炎性细胞因子的表达,减轻由失血性休克诱发的急性肺损伤.     

糖皮质激素受体及核因子-κB在创伤休克大鼠肝脏中的作用

目的 探讨糖皮质激素受体(GR)、核因子-κB(NF-κB)在创伤失血性休克后肝组织中的变化、相互关系,及其对肝损伤的作用机制.方法 雄性健康Wistar大鼠96只,采用双侧股骨骨折伴失血性休克创伤模型,随机分成正常对照组6只,创伤休克组30只,GR阻断伴创伤休克组30只,NF-κB抑制伴创伤休克组30只.动态观察伤后0.5、2、4、6、8 h大鼠肝组织GR、NF-κB,肝脏病理,肝功能,血清TNF -α、IL-6等变化.GR采用免疫印迹法测定蛋白含量,NF-κB采用EMSA法测定结合活性,并进行计算机图像分析.结果 肝组织GR的蛋白含量在创伤失血性休克后2 h即开始下降,4 h明显低于正常对照(P<0.01),6 h降至最低,8 h仍显著低于正常(P<0.01);NF-κB的活性伤后迅速升高,伤后6 h达到高峰(P<0.01).光镜下伤后4～8 h肝窦内少许淤血,有散在炎性细胞浸润;血清TNF-α、IL-6、ALT、TB伤后4 h 开始增高.GR阻断后再致伤,NF-κB在伤后各个时相点的表达均较未阻断有明显增高,光镜下伤后2 h肝窦内即可见较多炎性细胞浸润,血清TNF-α、IL-6、ALT、TB在伤后2 h即有明显升高(P<0.01).抑制NF-κB再致伤后,GR在伤后肝组织中的表达增强,TNF-α、IL-6伤后各个时相点均迅速回落,光镜下伤后4～8 h肝细胞变性明显好转,肝窦内见淤血减轻,仅见少许淋巴细胞及中性粒细胞浸润;伤后4 h,血清ALT、TB即明显下降.结论 GR、NF-κB参与了严重创伤失血性休克后肝损伤的发生,阻断GR使NF-κB的表达增强,肝损害程度加重;抑制NF-κB使GR表达增加,肝损害程度减轻.提示GR及NF-κB在严重创伤休克后肝组织细胞损伤过程中关系密切并起着重要作用.     

Balanced vs unbalanced crystalloid resuscitation in a near-fatal model of hemorrhagic shock and the effects on renal oxygenation, oxidative stress, and inflammation

Background

The aim of the present study was to test the hypothesis that balanced crystalloid resuscitation would be better for the kidney than unbalanced crystalloid resuscitation in a rat hemorrhagic shock model.

Methods

Male Wistar rats were randomly assigned to four groups (n = 6/group): (1) time control; (2) hemorrhagic shock control; (3) hemorrhagic shock followed by unbalanced crystalloid resuscitation (0.9% NaCl); and (4) hemorrhagic shock followed by acetate and gluconate-balanced crystalloid resuscitation (Plasma Lyte). We tested the solutions for their effects on renal hemodynamics and microvascular oxygenation, strong-ion difference, systemic and renal markers of inflammation and oxidative stress including glycocalyx degradation as well as their effects on renal function.

Results

The main findings of our study were that: (1) both the balanced and unbalanced crystalloid solutions successfully restored the blood pressure, but renal blood flow was only recovered by the balanced solution although this did not lead to improved renal microvascular oxygenation; (2) while unbalanced crystalloid resuscitation induced hyperchloremia and worsened metabolic acidosis in hemorrhaged rats, balanced crystalloid resuscitation prevented hyperchloremia, restored the acid–base balance, and preserved the anion gap and strong ion difference in these animals; (3) in addition balanced crystalloid resuscitation significantly improved renal oxygen consumption (increased VO₂, decreased EFNa₊${\text{EF}}_{{\text{Na}}^{+}}$); and (4) however neither balanced nor unbalanced crystalloid resuscitation could normalize systemic inflammation or oxidative stress. Functional immunohistochemistry biomarkers showed improvement in L-FABP in favor of balanced solutions in comparison to the hemorrhagic group although no such benefit was seen for renal tubular injury (measured by NGAL) by giving either unbalanced or balanced solutions.

Conclusions

Although balanced crystalloid resuscitation seems superior to balanced crystalloid resuscitation in protecting the kidney after hemorrhagic shock and is certainly better than not applying fluid resuscitation, these solutions were not able to correct systemic inflammation or oxidative stress associated with hemorrhagic shock.     

不同复苏方式对失血性休克大鼠脑组织S100B及糖基化终产物受体的影响

目的 探讨不同复苏方式对未控制出血致失血性休克大鼠脑组织中晚期糖基化终产物受体(RAGE)及其配体S100B蛋白的影响.方法 54只SD大鼠随机分成空白对照(C)组、限制性液体复苏(LR)组、常规液体复苏(TR)组,模拟未控制出血的失血性休克大鼠模型,进行不同方式的液体复苏,分别经历造模休克期、急救复苏期、止血治疗期、观察期,并在观察期1、6及12 h采血、处死大鼠,检测各组大鼠脑组织S100B蛋白、RAGE含量以及血清丙二醛(MDA)和总超氧化物歧化酶(T-SOD)含量.结果 在观察期1h,S100B蛋白及RAGE在LR组、TR组高于C组(P＜0.01),到了观察期6、12h,S100B蛋白含量比较为TR组＞LR组＞C组,且差异有统计学意义(P＜0.01).而在观察期各个时间点,各组MDA在脑组织中含量比较均为LR组＞TR组＞C组,且各组之间比较差异有统计学意义(P＜0.01).而同样在观察期各个时间点,各组T-SOD在脑组织中含量比较均为C组＞LR组＞TR组,且各组之间比较差异有统计学意义(P＜0.01).结论 限制性液体复苏同常规液体复苏模式相比可使失血性休克大鼠脑组织S100B蛋白的表达减缓,S100B蛋白及RAGE表达可能跟机体氧化应激水平或缺血-再灌注损伤相关.     

Effects of various concentrations of inhaled oxygen on tissue dysoxia,oxidative stress,and survival in a rat hemorrhagic shock model

Objective

To test the hypothesis that a fractional inspired oxygen (F_IO₂) of 1.0 compared to 0.4 during hemorrhagic shock (HS) and fluid resuscitation (FR): mitigates tissue dysoxia; however, enhances the oxidative stress; therefore, offsets the benefit on survival.

Methods

Thirty rats underwent: HS for 75 min, during which 3.0 mL/100 g of blood was withdrawn, followed by FR for 75 min, during which 1.0 mL/100 g of shed blood and 3.0 mL/100 g of crystalloid solution were infused. Ten rats were randomized into one of three F_IO₂ (0.21 vs. 0.4 vs. 1.0) groups, and observed for survival until 72 h in each group. Hemodynamics, liver tissue PO₂ (P_TO₂), and, plasma antioxidants levels were also monitored.

Results

Oxygen inhalation increased mean arterial pressure (MAP) and decreased heart rate (HR) during HS and FR. Liver P_TO₂ was less than 10 Torr in all groups throughout HS; while it increased to average 26–35 Torr in oxygen groups during FR, it remained at 10 Torr with F_IO₂ 0.21 (P < 0.01). MAP, HR, and P_TO₂ did not differ significantly between oxygen groups. Plasma antioxidants levels did not differ among the three groups. All rats treated with oxygen, but eight of 10 rats with F_IO₂ 0.21 survived up to 72 h (NS).

Conclusions

Supplemental oxygen does not mitigate tissue dysoxia during HS, but does reduce tissue dysoxia without enhancing oxidative stress during subsequent FR. Increased F_IO₂ appears to prolong survival. These beneficial effects of supplemental oxygen do not differ between an F_IO₂ of 0.4 and 1.0.     

Effects of synthetic colloids on oxidative stress and inflammatory response in hemorrhagic shock: comparison of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin

Introduction

This study compared the effects of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin on oxidative stress and the inflammatory response in a rodent hemorrhagic shock model.

Methods

Sodium pentobarbital-anesthetized adult male Wistar rats (200 g to 220 g) were subjected to a severe volume-controlled hemorrhage using arterial blood withdrawal (30 mL/kg to 33 mL/kg) and resuscitated with a colloid solution at the same volume as blood withdrawal (hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, or succinylated gelatin). Arterial blood gas parameters were monitored. Malondialdehyde (MDA) content and myeloperoxidase (MPO) activity in the liver, lungs, intestine, and brain were measured two hours after resuscitation. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 in the intestine were also measured.

Results

Infusions of hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, significantly reduced MDA levels and MPO activity in the liver, intestine, lungs and brain, and it also inhibited the production of TNF-α in the intestine two hours after resuscitation. However, no significant difference between hydroxyethyl starch 200/0.5 and succinylated gelatin was observed.

Conclusions

Hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, treatment after hemorrhagic shock ameliorated oxidative stress and the inflammatory response in this rat model. No significant differences were observed after hydroxyethyl starch 200/0.5 or succinylated gelatin administration at doses of approximately 33 mL/kg.     

Pathogenic molecular mechanisms in an animal model of fulminant hepatic failure: rabbit hemorrhagic viral disease

In this study we sought to determine whether molecular mechanisms involved in the pathogenesis of fulminant hepatic failure are present in rabbits experimentally infected with rabbit hemorrhagic disease virus (RHDV). The activities of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, as well as bilirubin concentration, were found to be significantly increased 36 hours after infection. Infected animals also demonstrated significant decreases in factor VII activity, in the Fischer index, and in the deterioration of prothrombin time. The concentration of reduced glutathione was significantly decreased 36 hours after infection, and we noted a marked increase in the ratio of oxidized to reduced glutathione. Infected animals showed progressive decreases in liver activity of the antioxidant enzyme superoxide dismutase. Expression of hepatocyte growth factor and c-met was found to be progressively reduced from 24 hours after infection, during which time we detected no modification in messenger RNA (mRNA) levels of transforming growth factor (TGF)-alpha. TFG-beta 1 was overexpressed 24 and 36 hours after infection, and 36 hours after infection we detected a significant increase in TNF-alpha mRNA levels. Experimental RHDV infection also induced marked activation of nuclear factor-kappaB and a significant increase in inducible nitric oxide synthase mRNA levels from 24 hours after infection. Data obtained from this animal model support its usefulness in the investigation of potential novel therapeutical modalities aimed at neutralizing reactive oxygen species and hepatocyte growth inhibitors or enhancing hepatocyte responsiveness to mitogens.