高渗氯化钠溶液复苏对失血性休克大鼠各器官细胞HO-1 mRNA表达及凋亡的干预研究
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摘要
研究背景：
失血性休克是创伤早期最常见的死亡原因，以全身微循环灌流量急剧锐减、细胞普遍缺氧和重要器官遭受损害为特征的病理过程，即微循环障碍导致细胞线粒体氧供受损，也是细胞水平的一种急性营养代谢障碍。失血性休克的病理生理变化和救治方法的研究一直是创伤学研究中的热点问题。
目前，使用高渗氯化钠溶液(7.5％)作为复苏液的概念已被公认并获得进一步阐述。近年来，不少研究表明，高渗氯化钠溶液复苏失血性休克过程中尚具有一些独特的作用机制，如具有良好的免疫调理功能、能减轻缺血／再灌注引起的组织器官损伤、有效地改善微循环等，十分值得关注。
血红素氧合酶-1(HO-1)，是诱导型酶，在抗氧化应激损伤、减轻缺血／再灌注损伤等方面具有重要的作用。
本研究将通过定量检测和比较假手术组(Sham组)、等渗盐水复苏组(NS组)和高渗氯化钠溶液复苏组(HTS组)大鼠的心、肝、肺、肾和小肠黏膜等器官细胞HO-1 mRNA表达及细胞凋亡发生情况，从而在分子生物学水平探讨高渗氯化钠溶液复苏失血性休克的救治疗效和作用机制。
方法：
本研究将21只SD大鼠制作成重度失血性休克模型，根据院前期不同的复苏液体随机分为假手术组(Sham组)、高渗氯化钠溶液复苏组(HTS组)和等渗盐水复苏组(NS组)，每组7只，采用SYBR GreenⅠ实时荧光定量逆转录-聚合酶链反应技术和流式细胞仪FITC-Annexin V／PI荧光染色法，定量检测各组大鼠心、肝、肺、肾和小肠黏膜等器官细胞的HO-1 mRNA表达及细胞凋亡发生情况，并加以统计学比较和分析。
结果：
1、在该重度失血性休克大鼠模型中，等渗盐水和高渗氯化钠溶液复苏均可立即产生有效的复苏作用，迅速改善大鼠的血流动力学状态，且维持平稳。
2、NS组和HTS组大鼠经失血性休克／复苏后，各器官的细胞凋亡发生率均明显增高，其中以小肠黏膜和肺尤为明显。与Sham比较，NS组大鼠的心、肝、肺、肾、小肠黏膜等器官细胞凋亡率均明显增高，差异均具有统计学意义(P＜0.01或P＜0.05)。HTS组大鼠的肺和小肠黏膜的细胞凋亡率也明显增高，与Sham组比较，差异具有统计学意义(P＜0.01)。此外，NS组大鼠的心、肺和小肠黏膜等器官的细胞凋亡发生率均较明显高于HTS组大鼠，差异具有统计学意义(P均＜0.01)。
3、失血性休克／复苏能诱导大鼠各器官细胞增加HO-1 mRNA的表达。但与Sham组比较，仅HTS组大鼠肝、肾等器官细胞HO-1 mRNA表达显著增加，差异具有统计学意义(P均=0.013)。
4、经过失血性休克和复苏后，NS组和HTS组大鼠肺细胞和小肠黏膜细胞的HO-1 mRNA表达和细胞凋亡之间存在着明显的负相关关系。
结论：
在该重度失血性休克大鼠模型，与等渗盐水复苏比较，高渗氯化钠溶液复苏能更有效地减少失血性休克／复苏后各器官细胞凋亡的发生率和诱导细胞HO-1mRNA的表达增加，可能有助于更好地保护机体细胞和维持器官功能状态。从而改善预后。诱导HO-1基因的过表达和减少细胞凋亡的发生率可能是高渗氯化钠溶液复苏救治失血性休克的分子生物学机制之一。
Background:
Hemorrhagic shock accounts for a large portion of civilian and military traumadeaths. It's physiopathologic characteristic is failure of the microcirculatory system thatresults in inadequate tissue perfusion with subsequent ischemia, cellular hypoxia, andorgan dysfunction. Consequently, the study of hemorrhagic shock remains a focal issuein traumatology.
At present, hypertonic saline (HTS) has been applied as alternative resuscitationstrategies in patients of hemorrhagic shock. HTS solutions usually consist of 7.5%NaCl. A number of recent studies disclosed previously unsuspected properties of HTSresuscitation, amongst them the correction of endothelial and red cell edemaaccompanying significant consequences in capillary blood flow. Furthermore, HTSresuscitation may have favorable immunomodulatory effects and alleviateischemia-reperfusion injury of organs.
Heme oxygenase-1 (HO-1), a stress-inducible protein, is an important cytoprotective agent against oxidative stress and ischemia/reperfusion (I/R) injury.
Our study used a model of rat with severe hemorrhagic shock to test the effects ofdifferent crystalloid solutions on HO-1 mRNA expression and apoptosis of visceralorgans, and evaluated the resuscitative value and mechanism of action of hypertonicsaline resuscitation on the molecular biologic level.
Methods:
A model of rat with severe hemorrhagic shock was established in 21 SDrats. According to different crystalloid solutions administered in the "pre-hospitalphase", the rats were randomly divided into Sham group (only underwent anesthesiaand cannulation without shock or resuscitation), normal saline resuscitation group (NSgroup), and hypertonic saline resuscitation group (HTS group). Each group contained7 rats. The HO-1 mRNA expression and apoptosis in heart, liver, lung, kidney andsmall intestinal mucosa of rats after hemorrhage and resuscitation were detected bySYBR Green I fluorescence quantitative reverse transcriptase-polymerase chainreaction, FITC-Annexin V/PI double staining method and flow cytometry. The curativeeffects were compared and analysed statistically.
Results:
1、In this model of rat with severe hemorrhagic shock, after receiving a solution ofeither normal saline or hypertonic saline, rats of NS and HTS groups rapidly showedsimilar trends toward restoration of hemodynamic parameters and stably sustained meanarterial pressure (MAP) thereafter.
2、There was increased apoptosis of visceral organs in rats of NS and HS groupsafter hemorrhagic shock and resuscitation, especially in the lung and small intestinalmucosa. The apoptotic rates of heart, liver, lung, kidney and small intestinal mucosa were obviously higher in NS group than those in Sham group, and the comparisonshowed statistically significant difference (P＜0.01 or P＜0.05). Compared with Shamgroup, the higher apoptotic rates of lung and small intestinal mucosa of HTS groupshowed statistically significant difference (P＜0.01). In addition, the apoptotic ratesof heart, lung, and small intestinal mucosa were obviously higher in NS group thanthose in HTS group (P all＜0.01).
3、The HO-1 mRNA expressions of visceral organ cells were induced byhemorrhagic shock and resuscitation, but were further increased with HTS. The HO-1mRNA expressions of liver and kidney cells were higher in HTS group than those inSham group, and the comparison showed statistically significant difference (P all=0.013).
4、There was significant negative correlation between HO-1 mRNA expression andapoptosis of lung and small intestinal mucosa in rats of NS and HS groups afterhemorrhagic shock and resuscitation.
Conclusion:
In this model of rat with severe hemorrhagic shock, small volume resuscitation withHTS is more effective than NS in reducing the apoptosis and increasing the HO-1mRNA expression of visceral organs of rats with severe hemorrhagic shock, and mayrepresent a novel mechanism, by which HTS resuscitation imparts protection to theorgans and benefits improvement of prognosis.
失血性休克是创伤早期最常见的死亡原因，以全身微循环灌流量急剧锐减、细胞普遍缺氧和重要器官遭受损害为特征的病理过程，即微循环障碍导致细胞线粒体氧供受损，也是细胞水平的一种急性营养代谢障碍。失血性休克的病理生理变化和救治方法的研究一直是创伤学研究中的热点问题。
目前，使用高渗氯化钠溶液(7.5％)作为复苏液的概念已被公认并获得进一步阐述。近年来，不少研究表明，高渗氯化钠溶液复苏失血性休克过程中尚具有一些独特的作用机制，如具有良好的免疫调理功能、能减轻缺血／再灌注引起的组织器官损伤、有效地改善微循环等，十分值得关注。
血红素氧合酶-1(HO-1)，是诱导型酶，在抗氧化应激损伤、减轻缺血／再灌注损伤等方面具有重要的作用。
本研究将通过定量检测和比较假手术组(Sham组)、等渗盐水复苏组(NS组)和高渗氯化钠溶液复苏组(HTS组)大鼠的心、肝、肺、肾和小肠黏膜等器官细胞HO-1 mRNA表达及细胞凋亡发生情况，从而在分子生物学水平探讨高渗氯化钠溶液复苏失血性休克的救治疗效和作用机制。
方法：
本研究将21只SD大鼠制作成重度失血性休克模型，根据院前期不同的复苏液体随机分为假手术组(Sham组)、高渗氯化钠溶液复苏组(HTS组)和等渗盐水复苏组(NS组)，每组7只，采用SYBR GreenⅠ实时荧光定量逆转录-聚合酶链反应技术和流式细胞仪FITC-Annexin V／PI荧光染色法，定量检测各组大鼠心、肝、肺、肾和小肠黏膜等器官细胞的HO-1 mRNA表达及细胞凋亡发生情况，并加以统计学比较和分析。
结果：
1、在该重度失血性休克大鼠模型中，等渗盐水和高渗氯化钠溶液复苏均可立即产生有效的复苏作用，迅速改善大鼠的血流动力学状态，且维持平稳。
2、NS组和HTS组大鼠经失血性休克／复苏后，各器官的细胞凋亡发生率均明显增高，其中以小肠黏膜和肺尤为明显。与Sham比较，NS组大鼠的心、肝、肺、肾、小肠黏膜等器官细胞凋亡率均明显增高，差异均具有统计学意义(P＜0.01或P＜0.05)。HTS组大鼠的肺和小肠黏膜的细胞凋亡率也明显增高，与Sham组比较，差异具有统计学意义(P＜0.01)。此外，NS组大鼠的心、肺和小肠黏膜等器官的细胞凋亡发生率均较明显高于HTS组大鼠，差异具有统计学意义(P均＜0.01)。
3、失血性休克／复苏能诱导大鼠各器官细胞增加HO-1 mRNA的表达。但与Sham组比较，仅HTS组大鼠肝、肾等器官细胞HO-1 mRNA表达显著增加，差异具有统计学意义(P均=0.013)。
4、经过失血性休克和复苏后，NS组和HTS组大鼠肺细胞和小肠黏膜细胞的HO-1 mRNA表达和细胞凋亡之间存在着明显的负相关关系。
结论：
在该重度失血性休克大鼠模型，与等渗盐水复苏比较，高渗氯化钠溶液复苏能更有效地减少失血性休克／复苏后各器官细胞凋亡的发生率和诱导细胞HO-1mRNA的表达增加，可能有助于更好地保护机体细胞和维持器官功能状态。从而改善预后。诱导HO-1基因的过表达和减少细胞凋亡的发生率可能是高渗氯化钠溶液复苏救治失血性休克的分子生物学机制之一。
Background:
Hemorrhagic shock accounts for a large portion of civilian and military traumadeaths. It's physiopathologic characteristic is failure of the microcirculatory system thatresults in inadequate tissue perfusion with subsequent ischemia, cellular hypoxia, andorgan dysfunction. Consequently, the study of hemorrhagic shock remains a focal issuein traumatology.
At present, hypertonic saline (HTS) has been applied as alternative resuscitationstrategies in patients of hemorrhagic shock. HTS solutions usually consist of 7.5%NaCl. A number of recent studies disclosed previously unsuspected properties of HTSresuscitation, amongst them the correction of endothelial and red cell edemaaccompanying significant consequences in capillary blood flow. Furthermore, HTSresuscitation may have favorable immunomodulatory effects and alleviateischemia-reperfusion injury of organs.
Heme oxygenase-1 (HO-1), a stress-inducible protein, is an important cytoprotective agent against oxidative stress and ischemia/reperfusion (I/R) injury.
Our study used a model of rat with severe hemorrhagic shock to test the effects ofdifferent crystalloid solutions on HO-1 mRNA expression and apoptosis of visceralorgans, and evaluated the resuscitative value and mechanism of action of hypertonicsaline resuscitation on the molecular biologic level.
Methods:
A model of rat with severe hemorrhagic shock was established in 21 SDrats. According to different crystalloid solutions administered in the "pre-hospitalphase", the rats were randomly divided into Sham group (only underwent anesthesiaand cannulation without shock or resuscitation), normal saline resuscitation group (NSgroup), and hypertonic saline resuscitation group (HTS group). Each group contained7 rats. The HO-1 mRNA expression and apoptosis in heart, liver, lung, kidney andsmall intestinal mucosa of rats after hemorrhage and resuscitation were detected bySYBR Green I fluorescence quantitative reverse transcriptase-polymerase chainreaction, FITC-Annexin V/PI double staining method and flow cytometry. The curativeeffects were compared and analysed statistically.
Results:
1、In this model of rat with severe hemorrhagic shock, after receiving a solution ofeither normal saline or hypertonic saline, rats of NS and HTS groups rapidly showedsimilar trends toward restoration of hemodynamic parameters and stably sustained meanarterial pressure (MAP) thereafter.
2、There was increased apoptosis of visceral organs in rats of NS and HS groupsafter hemorrhagic shock and resuscitation, especially in the lung and small intestinalmucosa. The apoptotic rates of heart, liver, lung, kidney and small intestinal mucosa were obviously higher in NS group than those in Sham group, and the comparisonshowed statistically significant difference (P＜0.01 or P＜0.05). Compared with Shamgroup, the higher apoptotic rates of lung and small intestinal mucosa of HTS groupshowed statistically significant difference (P＜0.01). In addition, the apoptotic ratesof heart, lung, and small intestinal mucosa were obviously higher in NS group thanthose in HTS group (P all＜0.01).
3、The HO-1 mRNA expressions of visceral organ cells were induced byhemorrhagic shock and resuscitation, but were further increased with HTS. The HO-1mRNA expressions of liver and kidney cells were higher in HTS group than those inSham group, and the comparison showed statistically significant difference (P all=0.013).
4、There was significant negative correlation between HO-1 mRNA expression andapoptosis of lung and small intestinal mucosa in rats of NS and HS groups afterhemorrhagic shock and resuscitation.
Conclusion:
In this model of rat with severe hemorrhagic shock, small volume resuscitation withHTS is more effective than NS in reducing the apoptosis and increasing the HO-1mRNA expression of visceral organs of rats with severe hemorrhagic shock, and mayrepresent a novel mechanism, by which HTS resuscitation imparts protection to theorgans and benefits improvement of prognosis.
引文
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34、Shields CJ, O'Sullivan AW, Wang JH, et al. Hypertonic saline enhances host response to bacterial challenge by augmenting receptor-independent neutrophil intracellular superoxide formation[J]. Ann Surg, 2003, 238 (2): 249-257.
35、Deree J, Martins JO, Leedom A, et al. Hypertonic saline and pentoxifylline reduces hemorrhagic shock resuscitation-induced pulmonary inflammation through attenuation of neutrophil degranulation and proinflammatory mediator synthesis[J]. J Trauma, 2007, 62 (1): 104-111.
36、Coimbra R, Loomis W, Melbostad H, et al. Role of hypertonic saline and pentoxifylline on neutrophil activation arid tumor necrosis factor-alpha synthesis: a novel resuscitation strategy[J]. J Trauma, 2005, 59(2):257-264.
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38、Coimbra R,Porcides R, Loomis W, et al. HSPTX protects against hemorrhagic shock resuscitation-induced tissue injury: an attractive alternative to Ringer's lactate[J]. J Trauma, 2006,60(1):41-51.
39,Fujiyoshi N, Deitch EA, Feketeova E, et al. Amiloride combined with small-volume resuscitation with hypertonic saline is superior in ameliorating trauma-hemorrhagic shock-induced lung injury in rats to the administration of either agent alone[J]. Crit Care Med, 2005, 3(11):2592-2598.
40、Loomis WH, Namiki S, Hoyt DB, et al. Hypertonicity rescues T cells from suppression by trauma-induced anti-inflammatory mediators[J]. Am J Physiol Cell Physiol, 2001, 281 (3): C840-848.
41, Loomis WH, Namiki S, Ostrom RS, et al. Hypertonic stress increases T cell interleukin-2 expression through a mechanism that involves ATP release, P2 receptor, and p38 MAPK activation[J]. J Biol Chem, 2003, 278(7): 4590-4596.
42、Junger WG, Hoyt DB, Hamreus M, et al. Hypertonic saline activates protein tyrosine kinases and mitogen-activated protein kinase p38 in T-cells[J]. J Trauma, 1997,42 (3):437-445.
43、Lu YQ, Cai XJ, Gu LH, et al. Hypertonic saline resuscitation maintains a more balanced profile of T-lymphocyte subpopulations in a rat model of hemorrhagic shock[J]. Journal of Zhejiang University SCIENCE, 2007, 8B (1): 70-75.
44, Rizoli SB, Rhind SG, Shek PN, et al. The immunomodulatory effects of hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic shock: a randomized,controlled, double-blinded trial[J]. Ann Surg, 2006, 243.(1):47-57.
45、Bulger EM, Cuschieri J, Warner K, et al. Hypertonic resuscitation modulates the inflammatory response in patients with traumatic hemorrhagic shock[J]. Ann Surg,2007,245 (4):635-641.
46、Bulger EM, Jurkovich GJ, Nathens AB, et al. Hypertonic resuscitation of hypovolemic shock after blunt trauma: a randomized controlled trial[J]. Arch Surg, 2008, 143 (2):139-148.
47 、Gonzalez EA, Kozar RA, Suliburk JW, et al. Conventional dose hypertonic saline provides optimal gut protection and limits remote organ injury after gut ischemia reperfusion[J]. J Trauma, 2006, 61 (1): 66-73.
48、Ozguc H, Tokyay R, Kahveci N, et al. Hypertonic saline dextran alleviates hepatic injury in hypovolemic rats undergoing porta hepatis occlusion[J]. Shock, 2003,19(4):383-387.
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50、Sass G, Soares MC, Yamashita K, et al. Heme oxygenase-1 and its reaction product, carbon monoxide , prevent inflammation-related apoptotic liver damage in mice[J]. Hepatology, 2003, 38 (4): 909-918.
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