失血性休克大鼠血浆代谢组学与肝脏基因组学研究
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摘要
研究背景:
无论是战时还是平时,失血性休克(hemorrhagic shock,HS)均是引起急诊创伤病例死亡的首要因素。随着人们对HS发生、发展病理生理机制认识的日渐深入以及多种救治措施的综合应用,使得HS的救治效果大为改善,救治成功率不断提高。但临床急诊中仍有部分患者,即使救治及时、控制出血、联合应用多种救治措施,却仍然难以摆脱死亡的威胁。原因之一在于HS是一种全身性、多系统、多器官参与的严重综合征,其有效救治的“黄金时间”非常短暂,另外其病程进展的病理生理机制尚未彻底阐明,救治措施尚需进一步完善。
HS发生后,“炎性瀑布”及多器官功能衰竭是导致病人死亡的主要因素之一,而“炎性瀑布”及多器官功能衰竭与物质及能量代谢的变化密切相关。HS状态下机体的代谢异常,包括糖类、脂类、氨基酸、维生素及核酸等物质,而每种物质的代谢不是彼此孤立的,而是相互联系,或相互转换,或相互依存,构成统一的整体。系统生物学的研究方法—代谢组学可以高通量检测复杂代谢产物并能筛选出变化最为显著的一种或几种代谢物的变化,为系统分析HS中的物质及能量代谢变化提供了可能。目前在HS研究领域,尚未见有关血浆代谢组学的研究报道。
物质及能量的代谢变化与器官及组织的病理生理变化息息相关,密不可分。而肝脏被誉为“物质代谢中枢”,同时也是HS发生后受累最为严重的器官之一。因此,HS状态肝脏基因组的差异表达,可能是血浆代谢组变化的分子基础之一,将为探讨血浆代谢组变化的可能机制提供佐证。研究目的及方法:
本研究以HS大鼠为研究模型,应用1H-NMR分析方法,观测HS大鼠血浆代谢组的变化,并用主成分分析(PCA)的方法筛选代谢组主成分(PC);根据筛选出的PC,深入分析PC的变化规律,以期为HS病程进展的监测提供新的靶标;利用大鼠全基因组芯片对HS大鼠肝脏基因表达谱进行分析,以期从基因水平探讨HS代谢变化的分子基础,希望发现新的HS损伤因素,为阐明HS的病理生理机制提供参考依据;并根据代谢组主成分对HS大鼠施行相应的干预措施,观察其对大鼠HS损伤的改善及代谢异常的纠正效果,以期为HS损伤的防治提供新的线索。
研究内容及结果分析
1. HS大鼠模型的建立手术后从股动脉放血,以控压模式分别制作重度HS(SHS)及中度HS(MHS)大鼠模型。记录失血量,并在SHS模型制成后60min内,每10min记录一次平均动脉压(MAP);MHS模型制成后120min内,每10min记录一次平均动脉压(MAP)。结果显示SHS模型60min内MAP为51.25±10.77mmHg,失血量占总血量的百分比为45.31±5.34%;MHS模型120min内MAP为80.87±7.42mmHg,失血量占总血量的百分比为32.37±3.36%。建立的HS模型稳定性好,符合HS模型的要求。
2.基于1H-NMR的HS大鼠血浆代谢组学分析应用核磁共振仪(1H-NMR)对HS及对照(Control, C)组大鼠血浆代谢组进行检测;用PCA的方法,筛选出代谢组的PC。结果显示两组间血浆代谢物含量差异明显。对PC相对应的代谢物谱峰进一步分析表明,与对照组比较,休克组血浆中乳酸、VLDL、LDL、以及不饱和脂肪酸等代谢物发生了明显变化。
3. HS大鼠血浆脂类代谢分析根据主成分分析的结果提示,分别对重度HS、中度HS及中度HS不同时相大鼠血浆脂类水平进行了进一步分析,包括游离脂肪酸(FFA)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、脂类介质—血栓素B2(TXB2)、6-酮-前列腺素F1a(6-Keto-PGF1a)及8-异前列腺素F2a(8-iso-PGF2a)。实验结果显示:①HS大鼠与C组大鼠比较:血浆FFA、TC、HDL-C及HDL-C/LDL-C(H/L)比值均显著降低,TG、LDL-C明显上升;随着HS程度的加重FFA、TG、TC水平及H/L比值呈下降趋势;随着HS时间的延长,FFA水平及H /L比值呈进行性下降,TG呈先上升后下降的趋势。②HS大鼠与C组大鼠比较:血浆TXB2及8-iso-PGF2a水平及TXB2/6-keto-PGF1a(T/K)比值明显上升,且随着HS程度的加重三指标的升高幅度愈加显著;6-Keto-PGF1a水平明显下降,且随着HS程度的加重下降幅度愈加显著。随着HS时间的延长, TXB2、8-iso-PGF2a及T/K比值呈先下降再上升的趋势;而6-Keto-PGF1a呈先上升再下降的趋势。
4. HS大鼠肝脏基因组学分析利用Affymetrix Rat 230A芯片对大鼠肝脏基因表达进行分析。结果显示HS组与C组比较,共出现差异表达上调基因256条,其中具有明确生物学功能的基因107条;下调基因47条,其中具有明确生物学功能的基因13条。根据基因的生物学功能,差异表达基因主要为:物质转运相关基因、转录调节相关基因、信号转导相关基因、应激反应相关基因、代谢相关基因、发育相关基因、细胞粘附相关基因、细胞增殖、分化及周期调控相关基因、细胞凋亡等。其中与脂类代谢相关的基因有10条,包括SCD1、FASN、ACLY、ELOVL6、HMGCR、CYP7A1、CYP4A12、EGR1、NR1i3及LCN2等,占已知功能差异表达基因的8.33%(10/120)。
5.脂肪乳干预对HS大鼠的影响根据前面实验结果提示,设对照组、重度HS组及重度HS脂肪乳干预组。分别对各组大鼠存活时间及存活率及平均动脉压(MAP)进行比较;对各组大鼠肝、脾、肾及肠系膜淋巴结细菌培养及菌落计数,比较肠道细菌移位情况;分别对各组血浆肿瘤坏死因子(TNF-a)进行检测,以了解干预措施对炎症反应的影响;对各组血浆TG、TC、HDL-C、LDL-C及FFA进行测定,以了解干预措施对脂类代谢水平的影响。结果显示重度HS脂肪乳干预组与HS组比较,大鼠存活时间明显延长,120min及180min存活率显著提高;在观察期MAP明显升高;大鼠肝、脾、肾及肠系膜淋巴结四部位的细菌移位量明显降低;血浆TNF-a的水平显著降低;血浆TG及FFA水平明显提高,而HDL-C、LDL-C水平及H /L比值无显著变化。
综上说明HS状态,脂类代谢明显异常,尤其是作为能量底物的FFA随HS程度加重或/和时间的延长而显著降低,而TG随HS时间的延长呈先上升后下降的趋势,提示机体的代偿机制难以纠正能量供应的相对不足;肝脏差异表达基因中,有10条与脂类代谢相关,可能是脂类代谢变化的分子基础;脂肪乳干预能显著提高HS大鼠血浆FFA及TG水平,明显延长HS大鼠的存活时间,显著降低炎症反应,提示脂肪乳干预可能是纠正或缓解HS的有效措施之一。
结论:
1. HS大鼠血浆代谢组与对照组比较存在显著性差异,其PC为脂类及乳酸;
2. HS大鼠与对照组大鼠比较:血浆FFA、TC、HDL-C及H/L比值均显著降低,TG、LDL-C明显上升;随着HS程度的加重FFA、TG、TC水平及H/L比值呈下降趋势;随着HS时间的延长,FFA水平及H/L比值呈进行性下降,TG呈先上升后下降的趋势。
3. HS大鼠与对照组比较:血浆TXB2及8-iso-PGF2a水平及T/K比值明显上升,且随着HS程度的加重三指标的升高幅度愈加显著;6-Keto-PGF1a水平明显下降,且随着HS程度的加重下降幅度愈加显著。随着HS时间的延长, TXB2、8-iso-PGF2a及T/K比值呈先下降再上升的趋势;而6-Keto-PGF1a呈先上升再下降的趋势。
4. HS大鼠肝脏基因组呈现多基因差异表达,与脂类代谢相关基因有10条,占已知功能差异表达基因的8.33%(10/120)。
5.脂肪乳干预大鼠抗HS能力提高,其存活时间明显延长,120min及180min存活率显著提高,肠道细菌移位量降低,血浆FFA及TG水平显著升高,TNF-a水平显著降低。
6.本研究结果提示血浆脂类水平异常可能是失血性休克病程进展的重要标志之一,对脂类代谢进行干预可能是纠正或缓解HS的有效措施之一。
Background:
Hemorrhagic shock(HS) is generally precipitated by traumatic event that results in an acute loss of blood from the intravascular space. It remains a major cause of death and disability in battlefield injuries, as well as in civilian trauma. With the deeper recognition of mechanism and development of treatment for HS, treatment success rate tend to ascend in recent years. But many of these people with severe HS will reach hospitals in salvageable condition but will still die. One of the reasons is that the syndrome of hemorrhagic shock in humans leads to cardiovascular failure and death by impairing the several important organs including heart, liver, spleen, lung, kidney and brain. Another reason for the continued deaths from injury is an incomplete understanding of the human response to hemorrhagic shock, and new therapeutic approaches need to be explored.
The main factors leading HS to refractory are cascade effects and multiple organ dysfunction syndrome, and they are correlated with variations of substance and energy metabolism. The rapid development of HS is accompanied by a series of abnormal metabolism implicated in many different pathways, such as sugar, lipid, amino acid, vitamin, nucleotide and other metabolism. 1H-nuclear magnetic resonance (1H-NMR)-based metabonomic approach is a newly developed technology that can be exploited to be a useful tool for disease diagnosis. And it has been widely used in many fields, but no report is found in HS so far.
The liver is responsible for maintaining homeostasis in the body and is the main source of energy to peripheral organs. Hence, it is readily susceptible to the ischemic injury associated with hemorrhagic shock. Disturbances in liver function profoundly affect other body systems leading to multiple organ failure and death. Therefore, the elucidation of hepatic responses to shock is of great importance in the pathogenesis and treatment of HS.
Objective and methods:
First, to detect the plasma metabonomic profile of rats subjected to HS and Control group by 1H-NMR analyzer. The 1H-NMR spectra of two groups is analyzed and the principal components(PC) are recognized by principal components analysis(PCA). Second, to analysis the PC detailed. Third, to detect differential gene expressions in mouse liver of HS and Control group used Affymetrix Gene Chip Rat 230 2.0 Array. Finally, to evaluate the effect of fat emulsion(FE) on rats subjected to HS.
Contents and results:
1. Establish rat model in HS
After rat model being operated and lying quietly for 10 minutes, Hemorrhage was performed through the femoral arterial catheter. The total amount of blood withdrawn and the mean artery blood pressure(MAP) was recorded. The amount of blood withdrawn were 45.31±5.34% and 32.37±3.36% of total blood respectively in model of severe HS(SHS) and moderate HS(MHS); the MAP were 51.25±10.77mmHg and 80.87±7.42mmHg respectively in SHS and MHS.
2. Analysis of plasma metabonomics of Rats Subjected to HS based on 1H-NMR.
Plasma was collected and its 1H-NMR spectra were acquired. The metabonomic profile of two groups were able to be distinguished after the data being processed by principal components analysis(PCA). The remarkable differenceso?f plasma metabonomic profile between two groups were lactate and lipids,such as very low density lipoprotein(VLDL), low density lipoprotein(LDL) and unsaturated fatty acid.
3. Analysis of plasma lipid profile of rats subjected to HS.
Following the results indicated by PCA, plasma lipid profile of rat subjected to SHS and MHS were measured, such as free fatty acids(FFA), total cholesterol(TC), triglyceride(TG), high density lipoprotein cholesterol(HDL-C), low density lipoprotein cholesterol(LDL-C), thromboxane B2(TXB2), 6-keto-prostaglandin Fla(6-Keto-PGF1a) and 8-iso-prostaglandin F2a (8-iso-PGF2a).
Results of plasma lipid profile:
①Compared with Control, the levels of FFA、TC、HDL-C and the ratio of HDL-C/LDL-C(H/L) decreased, and the levels of TG、LDL-C increased significantly. The severer of the HS was, the more the levels of FFA、TG、TC and H/L decreased. The longer the time of HS lasting, the more the FFA levels and H/L decreased. With the time of HS lasting, the levels of TG increased first, then decreased.
②Compared with Control, the levels of TXB2, 8-iso-PGF2a and the ratio of TXB2/6-keto-PGF1a(T/K) increased, and the severer of HS was, the more the items increased. The levels of 6-Keto-PGF1a decreased, and the severer of HS was, the more the items decreased. Compared among three group of MHS-30, MHS-60 and MHS-120, the levels of TXB2, 8-iso-PGF2a and the ratio of T/K decreased first, then increased in MHS-120. The levels of 6-Keto-PGF1a increased first, then decreased in MHS-120.
4. Hepatic gene expression of rats subjected to hemorrhagic shock.
Hepatic gene expression profiles of each group were detected by Affymetrix Gene Chip Rat 230 2.0 Array and 9 genes were selected to undergo semi-quantitative RT-PCR. The gene chip arrays results showed that 303 genes expression in the HS group was significantly different from the Control group; and of the 303 genes, 256 genes were up-regulated and 47 genes were down-regulated. Their biological function of 107 up-regulated genes and 13 down-regulated genes were known. Differentially expressed genes were categorized based on the best available information regarding their biological functions. Genes with multiple functions were assigned to a single category. These included many genes of transport, transcription, signaling, response to stress, metabolism, biosynthesis, development, cell adhesion, proliferation, differentiation, cell cycle and apoptosis. 10 genes of them were related with lipid metabolism, such as SCD1、FASN、ACLY、ELOVL6、HMGCR、CYP7A1、CYP4A12、EGR1、NR1i3 and LCN2, which occupied 8.33% of genes whose biological function were known.
5. Effect of fat emulsion(FE) on rats subjected to HS.
60 male Wistar rats were randomly divided into a Control group, HS group, and HS-F group, with 20 rats in each group. The survival time, survival rate and mean artery blood pressure(MAP) were recorded. The bacteria translocation of liver, spleen, kidney and mesenteric lymph nodes were detected. The levels of serum TNF-a, FFA, TG, TC, HDL-C and LDL-C were measured. Result: compared with the HS group, survival time prolonged and elevated survival rate in 120min and 180min increased significantly in the HS-F group; the MAP was increased significantly; bacterial translocation was lower in HS-F rats; serum levels of TNF-a were lower in HS-F rats compared with HS rats, and those of FFA and TG were elevated in HS-F rats compared with HS rats, but no difference of HDL-C and LDL-C was shown between them.
Conclusion:
1. The remarkable differences of plasma metabonomic profile between two groups were lactate and lipids.
2. The serum levels of FFA, TC, TG, HDL-C, LDL-C and the ratio of H/L were closely related to the severity and the lasting time of HS.
3. The serum levels of TXB2, 6-Keto-PGF1a, 8-iso-PGF2a and the ratio of T/K were closely related to the severity and the lasting time of HS.
4. Multiple hepatic genes differentially expressed in rats subjected to HS, and 10 genes were related to lipid metabolism, which occupied 8.33% of genes whose biological function were known.
5. FE intervention on HS rats prolonged survival time and elevated survival rate, decreased bacterial translocation and TNF-a, increased FFA and TG after hemorrhage.
6. Our study indicated that lipid metabolism maybe is an important item monitoring the course of HS, and to interfere lipid metabolism may effect on HS.
无论是战时还是平时,失血性休克(hemorrhagic shock,HS)均是引起急诊创伤病例死亡的首要因素。随着人们对HS发生、发展病理生理机制认识的日渐深入以及多种救治措施的综合应用,使得HS的救治效果大为改善,救治成功率不断提高。但临床急诊中仍有部分患者,即使救治及时、控制出血、联合应用多种救治措施,却仍然难以摆脱死亡的威胁。原因之一在于HS是一种全身性、多系统、多器官参与的严重综合征,其有效救治的“黄金时间”非常短暂,另外其病程进展的病理生理机制尚未彻底阐明,救治措施尚需进一步完善。
HS发生后,“炎性瀑布”及多器官功能衰竭是导致病人死亡的主要因素之一,而“炎性瀑布”及多器官功能衰竭与物质及能量代谢的变化密切相关。HS状态下机体的代谢异常,包括糖类、脂类、氨基酸、维生素及核酸等物质,而每种物质的代谢不是彼此孤立的,而是相互联系,或相互转换,或相互依存,构成统一的整体。系统生物学的研究方法—代谢组学可以高通量检测复杂代谢产物并能筛选出变化最为显著的一种或几种代谢物的变化,为系统分析HS中的物质及能量代谢变化提供了可能。目前在HS研究领域,尚未见有关血浆代谢组学的研究报道。
物质及能量的代谢变化与器官及组织的病理生理变化息息相关,密不可分。而肝脏被誉为“物质代谢中枢”,同时也是HS发生后受累最为严重的器官之一。因此,HS状态肝脏基因组的差异表达,可能是血浆代谢组变化的分子基础之一,将为探讨血浆代谢组变化的可能机制提供佐证。研究目的及方法:
本研究以HS大鼠为研究模型,应用1H-NMR分析方法,观测HS大鼠血浆代谢组的变化,并用主成分分析(PCA)的方法筛选代谢组主成分(PC);根据筛选出的PC,深入分析PC的变化规律,以期为HS病程进展的监测提供新的靶标;利用大鼠全基因组芯片对HS大鼠肝脏基因表达谱进行分析,以期从基因水平探讨HS代谢变化的分子基础,希望发现新的HS损伤因素,为阐明HS的病理生理机制提供参考依据;并根据代谢组主成分对HS大鼠施行相应的干预措施,观察其对大鼠HS损伤的改善及代谢异常的纠正效果,以期为HS损伤的防治提供新的线索。
研究内容及结果分析
1. HS大鼠模型的建立手术后从股动脉放血,以控压模式分别制作重度HS(SHS)及中度HS(MHS)大鼠模型。记录失血量,并在SHS模型制成后60min内,每10min记录一次平均动脉压(MAP);MHS模型制成后120min内,每10min记录一次平均动脉压(MAP)。结果显示SHS模型60min内MAP为51.25±10.77mmHg,失血量占总血量的百分比为45.31±5.34%;MHS模型120min内MAP为80.87±7.42mmHg,失血量占总血量的百分比为32.37±3.36%。建立的HS模型稳定性好,符合HS模型的要求。
2.基于1H-NMR的HS大鼠血浆代谢组学分析应用核磁共振仪(1H-NMR)对HS及对照(Control, C)组大鼠血浆代谢组进行检测;用PCA的方法,筛选出代谢组的PC。结果显示两组间血浆代谢物含量差异明显。对PC相对应的代谢物谱峰进一步分析表明,与对照组比较,休克组血浆中乳酸、VLDL、LDL、以及不饱和脂肪酸等代谢物发生了明显变化。
3. HS大鼠血浆脂类代谢分析根据主成分分析的结果提示,分别对重度HS、中度HS及中度HS不同时相大鼠血浆脂类水平进行了进一步分析,包括游离脂肪酸(FFA)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、脂类介质—血栓素B2(TXB2)、6-酮-前列腺素F1a(6-Keto-PGF1a)及8-异前列腺素F2a(8-iso-PGF2a)。实验结果显示:①HS大鼠与C组大鼠比较:血浆FFA、TC、HDL-C及HDL-C/LDL-C(H/L)比值均显著降低,TG、LDL-C明显上升;随着HS程度的加重FFA、TG、TC水平及H/L比值呈下降趋势;随着HS时间的延长,FFA水平及H /L比值呈进行性下降,TG呈先上升后下降的趋势。②HS大鼠与C组大鼠比较:血浆TXB2及8-iso-PGF2a水平及TXB2/6-keto-PGF1a(T/K)比值明显上升,且随着HS程度的加重三指标的升高幅度愈加显著;6-Keto-PGF1a水平明显下降,且随着HS程度的加重下降幅度愈加显著。随着HS时间的延长, TXB2、8-iso-PGF2a及T/K比值呈先下降再上升的趋势;而6-Keto-PGF1a呈先上升再下降的趋势。
4. HS大鼠肝脏基因组学分析利用Affymetrix Rat 230A芯片对大鼠肝脏基因表达进行分析。结果显示HS组与C组比较,共出现差异表达上调基因256条,其中具有明确生物学功能的基因107条;下调基因47条,其中具有明确生物学功能的基因13条。根据基因的生物学功能,差异表达基因主要为:物质转运相关基因、转录调节相关基因、信号转导相关基因、应激反应相关基因、代谢相关基因、发育相关基因、细胞粘附相关基因、细胞增殖、分化及周期调控相关基因、细胞凋亡等。其中与脂类代谢相关的基因有10条,包括SCD1、FASN、ACLY、ELOVL6、HMGCR、CYP7A1、CYP4A12、EGR1、NR1i3及LCN2等,占已知功能差异表达基因的8.33%(10/120)。
5.脂肪乳干预对HS大鼠的影响根据前面实验结果提示,设对照组、重度HS组及重度HS脂肪乳干预组。分别对各组大鼠存活时间及存活率及平均动脉压(MAP)进行比较;对各组大鼠肝、脾、肾及肠系膜淋巴结细菌培养及菌落计数,比较肠道细菌移位情况;分别对各组血浆肿瘤坏死因子(TNF-a)进行检测,以了解干预措施对炎症反应的影响;对各组血浆TG、TC、HDL-C、LDL-C及FFA进行测定,以了解干预措施对脂类代谢水平的影响。结果显示重度HS脂肪乳干预组与HS组比较,大鼠存活时间明显延长,120min及180min存活率显著提高;在观察期MAP明显升高;大鼠肝、脾、肾及肠系膜淋巴结四部位的细菌移位量明显降低;血浆TNF-a的水平显著降低;血浆TG及FFA水平明显提高,而HDL-C、LDL-C水平及H /L比值无显著变化。
综上说明HS状态,脂类代谢明显异常,尤其是作为能量底物的FFA随HS程度加重或/和时间的延长而显著降低,而TG随HS时间的延长呈先上升后下降的趋势,提示机体的代偿机制难以纠正能量供应的相对不足;肝脏差异表达基因中,有10条与脂类代谢相关,可能是脂类代谢变化的分子基础;脂肪乳干预能显著提高HS大鼠血浆FFA及TG水平,明显延长HS大鼠的存活时间,显著降低炎症反应,提示脂肪乳干预可能是纠正或缓解HS的有效措施之一。
结论:
1. HS大鼠血浆代谢组与对照组比较存在显著性差异,其PC为脂类及乳酸;
2. HS大鼠与对照组大鼠比较:血浆FFA、TC、HDL-C及H/L比值均显著降低,TG、LDL-C明显上升;随着HS程度的加重FFA、TG、TC水平及H/L比值呈下降趋势;随着HS时间的延长,FFA水平及H/L比值呈进行性下降,TG呈先上升后下降的趋势。
3. HS大鼠与对照组比较:血浆TXB2及8-iso-PGF2a水平及T/K比值明显上升,且随着HS程度的加重三指标的升高幅度愈加显著;6-Keto-PGF1a水平明显下降,且随着HS程度的加重下降幅度愈加显著。随着HS时间的延长, TXB2、8-iso-PGF2a及T/K比值呈先下降再上升的趋势;而6-Keto-PGF1a呈先上升再下降的趋势。
4. HS大鼠肝脏基因组呈现多基因差异表达,与脂类代谢相关基因有10条,占已知功能差异表达基因的8.33%(10/120)。
5.脂肪乳干预大鼠抗HS能力提高,其存活时间明显延长,120min及180min存活率显著提高,肠道细菌移位量降低,血浆FFA及TG水平显著升高,TNF-a水平显著降低。
6.本研究结果提示血浆脂类水平异常可能是失血性休克病程进展的重要标志之一,对脂类代谢进行干预可能是纠正或缓解HS的有效措施之一。
Background:
Hemorrhagic shock(HS) is generally precipitated by traumatic event that results in an acute loss of blood from the intravascular space. It remains a major cause of death and disability in battlefield injuries, as well as in civilian trauma. With the deeper recognition of mechanism and development of treatment for HS, treatment success rate tend to ascend in recent years. But many of these people with severe HS will reach hospitals in salvageable condition but will still die. One of the reasons is that the syndrome of hemorrhagic shock in humans leads to cardiovascular failure and death by impairing the several important organs including heart, liver, spleen, lung, kidney and brain. Another reason for the continued deaths from injury is an incomplete understanding of the human response to hemorrhagic shock, and new therapeutic approaches need to be explored.
The main factors leading HS to refractory are cascade effects and multiple organ dysfunction syndrome, and they are correlated with variations of substance and energy metabolism. The rapid development of HS is accompanied by a series of abnormal metabolism implicated in many different pathways, such as sugar, lipid, amino acid, vitamin, nucleotide and other metabolism. 1H-nuclear magnetic resonance (1H-NMR)-based metabonomic approach is a newly developed technology that can be exploited to be a useful tool for disease diagnosis. And it has been widely used in many fields, but no report is found in HS so far.
The liver is responsible for maintaining homeostasis in the body and is the main source of energy to peripheral organs. Hence, it is readily susceptible to the ischemic injury associated with hemorrhagic shock. Disturbances in liver function profoundly affect other body systems leading to multiple organ failure and death. Therefore, the elucidation of hepatic responses to shock is of great importance in the pathogenesis and treatment of HS.
Objective and methods:
First, to detect the plasma metabonomic profile of rats subjected to HS and Control group by 1H-NMR analyzer. The 1H-NMR spectra of two groups is analyzed and the principal components(PC) are recognized by principal components analysis(PCA). Second, to analysis the PC detailed. Third, to detect differential gene expressions in mouse liver of HS and Control group used Affymetrix Gene Chip Rat 230 2.0 Array. Finally, to evaluate the effect of fat emulsion(FE) on rats subjected to HS.
Contents and results:
1. Establish rat model in HS
After rat model being operated and lying quietly for 10 minutes, Hemorrhage was performed through the femoral arterial catheter. The total amount of blood withdrawn and the mean artery blood pressure(MAP) was recorded. The amount of blood withdrawn were 45.31±5.34% and 32.37±3.36% of total blood respectively in model of severe HS(SHS) and moderate HS(MHS); the MAP were 51.25±10.77mmHg and 80.87±7.42mmHg respectively in SHS and MHS.
2. Analysis of plasma metabonomics of Rats Subjected to HS based on 1H-NMR.
Plasma was collected and its 1H-NMR spectra were acquired. The metabonomic profile of two groups were able to be distinguished after the data being processed by principal components analysis(PCA). The remarkable differenceso?f plasma metabonomic profile between two groups were lactate and lipids,such as very low density lipoprotein(VLDL), low density lipoprotein(LDL) and unsaturated fatty acid.
3. Analysis of plasma lipid profile of rats subjected to HS.
Following the results indicated by PCA, plasma lipid profile of rat subjected to SHS and MHS were measured, such as free fatty acids(FFA), total cholesterol(TC), triglyceride(TG), high density lipoprotein cholesterol(HDL-C), low density lipoprotein cholesterol(LDL-C), thromboxane B2(TXB2), 6-keto-prostaglandin Fla(6-Keto-PGF1a) and 8-iso-prostaglandin F2a (8-iso-PGF2a).
Results of plasma lipid profile:
①Compared with Control, the levels of FFA、TC、HDL-C and the ratio of HDL-C/LDL-C(H/L) decreased, and the levels of TG、LDL-C increased significantly. The severer of the HS was, the more the levels of FFA、TG、TC and H/L decreased. The longer the time of HS lasting, the more the FFA levels and H/L decreased. With the time of HS lasting, the levels of TG increased first, then decreased.
②Compared with Control, the levels of TXB2, 8-iso-PGF2a and the ratio of TXB2/6-keto-PGF1a(T/K) increased, and the severer of HS was, the more the items increased. The levels of 6-Keto-PGF1a decreased, and the severer of HS was, the more the items decreased. Compared among three group of MHS-30, MHS-60 and MHS-120, the levels of TXB2, 8-iso-PGF2a and the ratio of T/K decreased first, then increased in MHS-120. The levels of 6-Keto-PGF1a increased first, then decreased in MHS-120.
4. Hepatic gene expression of rats subjected to hemorrhagic shock.
Hepatic gene expression profiles of each group were detected by Affymetrix Gene Chip Rat 230 2.0 Array and 9 genes were selected to undergo semi-quantitative RT-PCR. The gene chip arrays results showed that 303 genes expression in the HS group was significantly different from the Control group; and of the 303 genes, 256 genes were up-regulated and 47 genes were down-regulated. Their biological function of 107 up-regulated genes and 13 down-regulated genes were known. Differentially expressed genes were categorized based on the best available information regarding their biological functions. Genes with multiple functions were assigned to a single category. These included many genes of transport, transcription, signaling, response to stress, metabolism, biosynthesis, development, cell adhesion, proliferation, differentiation, cell cycle and apoptosis. 10 genes of them were related with lipid metabolism, such as SCD1、FASN、ACLY、ELOVL6、HMGCR、CYP7A1、CYP4A12、EGR1、NR1i3 and LCN2, which occupied 8.33% of genes whose biological function were known.
5. Effect of fat emulsion(FE) on rats subjected to HS.
60 male Wistar rats were randomly divided into a Control group, HS group, and HS-F group, with 20 rats in each group. The survival time, survival rate and mean artery blood pressure(MAP) were recorded. The bacteria translocation of liver, spleen, kidney and mesenteric lymph nodes were detected. The levels of serum TNF-a, FFA, TG, TC, HDL-C and LDL-C were measured. Result: compared with the HS group, survival time prolonged and elevated survival rate in 120min and 180min increased significantly in the HS-F group; the MAP was increased significantly; bacterial translocation was lower in HS-F rats; serum levels of TNF-a were lower in HS-F rats compared with HS rats, and those of FFA and TG were elevated in HS-F rats compared with HS rats, but no difference of HDL-C and LDL-C was shown between them.
Conclusion:
1. The remarkable differences of plasma metabonomic profile between two groups were lactate and lipids.
2. The serum levels of FFA, TC, TG, HDL-C, LDL-C and the ratio of H/L were closely related to the severity and the lasting time of HS.
3. The serum levels of TXB2, 6-Keto-PGF1a, 8-iso-PGF2a and the ratio of T/K were closely related to the severity and the lasting time of HS.
4. Multiple hepatic genes differentially expressed in rats subjected to HS, and 10 genes were related to lipid metabolism, which occupied 8.33% of genes whose biological function were known.
5. FE intervention on HS rats prolonged survival time and elevated survival rate, decreased bacterial translocation and TNF-a, increased FFA and TG after hemorrhage.
6. Our study indicated that lipid metabolism maybe is an important item monitoring the course of HS, and to interfere lipid metabolism may effect on HS.
引文
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