缺氧诱导因子1α对休克血管反应性的调控作用及其机制
发布时间：2018-09-09 18:16
【摘要】： 严重创伤、休克、脓毒症病人在经历缺血缺氧、再灌注损伤以及肠道菌群移位、内毒素释放等的“多重打击”后,常常在失代偿期出现不可逆的组织细胞损伤,出现全身炎症反应综合症(SIRS)、急性呼吸窘迫综合症(ARDS)乃至多器官功能衰竭(MOF)。究其原因,除了全身炎症失控外,休克后血管反应性降低是另一重要原因。血管低反应性表现为全身血管对缩血管物质和舒血管物质的反应降低或反应麻痹,导致血压不能有效提升、组织灌注难以改善,细胞缺氧和损伤进行性加重。因此,血管低反应性的发生一方面影响休克的发生和发展,另一方面严重地影响着创伤/休克的治疗和转归。研究发现血管低反应性的发生与肾上腺素能受体失敏、血管平滑肌细胞(VSMC)钾、钙通道功能失常及细胞膜超极化有关。此外,本实验室前期研究也发现Rho激酶可通过调节肌球蛋白轻链磷酸酶(MLCP)的活性和肌球蛋白轻链(MLC20)磷酸化水平及钙敏感性变化参与休克后血管反应性的调节。 HIF-1α通过调节多种基因的表达来调节细胞对低氧的适应性反应,是迄今为止发现的唯一的一个在缺氧状态下发挥特异性活性的调节分子,被认为是调节缺氧相关基因表达的关键分子,它同激活蛋白(activated protein 1, AP-1),核转录因子(nuclear factorκB, NF-κB)和p53等协同作用调节机体对缺氧的反应,其功能涉及能量代谢、细胞增殖、造血作用、血管形成、重塑与收缩等诸多方面。 缺血缺氧是各种类型休克的最基本的病理生理变化,故HIF-1α应该是休克后表达和活性变化最显著的分子之一。大量研究表明:失血性休克后期可激发明显的失控性系统炎症和缺血再灌注损伤, HIF-1α通过多种途径参与了上述两种损伤效应的形成和发展。而有关HIF-1α与血管舒缩活性及反应性的相关研究目前鲜有文献报道。由此,本实验选择缺氧诱导因子1α(HIF-1α)及其一系列下游分子作为研究靶点,以HIF-1α特异性阻断剂寡霉素为工具药,探讨HIF-1α对休克血管反应性的调控作用。具体内容包括两大部分:⑴HIF-1α在失血性休克后血管反应性变化中的调节作用;⑵失血性休克后HIF-1α调节血管反应性的机制。 主要实验方法: 第一部分观察HIF-1α在失血性休克后血管反应性变化中的调节作用,包括:建立大鼠重症失血性休克模型,制备肠系膜上动脉(SMA)血管环,利用离体血管环张力测定技术,观察休克后不同时相点(休克0.5h,休克1.0h,休克2.0h,休克3.0h,休克4.0h,休克6.0h)SMA对梯度浓度去甲肾上腺素(NE)的收缩反应性。同时取肠系膜动脉,利用RT-PCR技术分析测定休克后各时相点HIF-1αmRNA表达变化。同时利用以HIF-1α特异性阻断剂寡霉素为工具药,观察给药后休克各时相点血管环张力和HIF-1αmRNA表达变化,进而分析HIF-1α基因转录水平对休克血管反应性的影响。第二部分,通过在体和离体实验,探讨失血性休克后HIF-1α调节血管反应性的机制。在体实验:取大鼠失血性休克SMA组织,RT-PCR观察休克后eNOS、iNOS、HO-1、COX-2 mRNA时相表达变化,同时分别采用连二亚硫酸钠(Na2S2O4)还原法、硝酸还原酶法和放射免疫技术(RIA)测定休克后各时相血NO、CO、PGI含量变化,进而分析失血性休克后HIF-1α对eNOS / iNOS—NO、HO-1—CO和COX-2—PGI通路的影响。离体实验:利用Transwell培养小室缺氧共培养血管平滑肌细胞(VSMC)和内皮细胞(VEC),测定Transwell下腔荧光渗透率反映VSMC对去甲肾上腺素(NE)的收缩反应性;同时利用RT-PCR半定量分析HIF-1α及其相关分子的mRNA表达变化规律:内皮型一氧化氮合酶(eNOS)、诱生型一氧化氮合酶(iNOS)、环氧合酶-2(COX-2)、血红素氧合酶-1(HO-1),进一步分析缺氧后VSMC收缩反应的影响与上述分子的影响的关系。 主要研究结果: 1.失血性休克后HIF-1αmRNA表达逐渐增强,并于4h出现表达峰值(P 0.01)。血管反应性呈现双相变化,即早期(0.0h-1.0h)血管反应性增高,量-效曲线左移、最大收缩力(Emax)显著性增大和pD2减小(P 0.01)。至休克中、后期,血管反应性进行性下降,表现为量-效曲线右移、Emax降低和pD2增大,至休克后4h血管反应性即低于正常水平(P 0.01)。休克后给药组血管反应性亦呈现双相变化,但其幅度明显降低。表现为在早期(0.5-1.0h)血管反应性的抬高趋势被部分抑制(P 0.01),至休克晚期(4.0-6.0h)可使血管反应性得以轻度回升(P 0.05或P 0.01)。 2.失血性休克后eNOS、iNOS、HO-1、COX-2 mRNA表达均随时相的延长而逐渐增强,分别于1.0h、2.0h、3.0h和4.0h到达高峰(P 0.05或P 0.01)。给药组eNOS、HO-1、COX-2 mRNA表达量基本波动于正常范围。而iNOS则表现为休克早、中期(1.0h-3.0h)表达受抑制,而在晚期(4.0h-6.0h)较休克同时相有显著增加(P 0.01)。 3.血浆NO、PGI和全血CO浓度均随着休克时相进展而显著升高(P 0.05或P0.01)。HIF-1α特异性阻断剂寡霉素可使CO则稳定于正常水平,而NO和PGI表达被部分抑制,随着休克时相的延长有增高趋势,但其幅度显著低于休克同时相组(P 0.01)。 4.缺氧后VSMC收缩反应性呈现双相变化,即缺氧早期(0.0-1.0h) VSMC收缩反应性显著性增高且于0.5h达到峰值(P 0.01)。至缺氧后期(4.0-6.0h)VSMC收缩反应性进行性下降,至4h血管反应性即低于正常水平,至6h仅为正常对照的70% (P0.05)。给药组则表现为缺氧后早期反应性的增高趋势被完全抑制(P 0.05或P 0.01),而4.0h-6.0h VSMC的收缩反应性可有部分提高(P 0.05)。 5.VSMC+VEC混合培养后,随着缺氧时相的延长, HIF-1α、iNOS、HO-1、COX-2 mRNA表达均逐渐增强,分别于4.0h、2.0h、3.0h和4.0h到达高峰(P 0.01或P 0.05)。给药组各时相表现为上述mRNA表达增强趋势被完全抑制,基本均波动于正常范围内。eNOS mRNA表达受缺氧和给药处理方式的影响轻微,缺氧组和给药组各时相表达量与正常对照相比均无显著变化。 结论: 1.失血性休克后大鼠SMA收缩反应呈双相变化,即休克早期血管反应性增高,晚期血管反应性降低。HIF-1αmRNA表达随休克时相进展逐渐上调,至晚期进行性下降。HIF-1α阻断剂寡霉素处理可对休克后血管反应性的双相变化产生双相调节作用:在早期0.5-1h可部分抑制血管反应性的抬高趋势,至休克晚期可使血管反应性得以轻度回升。HIF-1α在失血性休克大鼠血管收缩反应性的双相变化的形成中发挥了重要的调节作用:其转录水平在休克早期的轻度上调与血管收缩反应性呈正相关,至休克晚期则呈负相关。 2.休克后eNOS、iNOS、HO-1和COX-2 mRNA表达依次激活、上调并达峰值,在阻断HIF-1α表达后其转录水平亦不同程度地受到明显抑制。HIF-1α调节血管反应性的途径包括eNOS/iNOS—NO、HO-1—CO、COX-2—PGI等通路,通过影响具有血管舒缩功能调节作用分子的基因表达,从而引起血管舒缩活性物质的生成和释放的相应变化:HS早期HIF-1α及其下游分子代偿性增加,其轻度表达有利于血管反应性的适应性保护,为正相关因素。至休克失代偿期转化为负相关:即HIF-1α过度激活、表达并蓄积,引起NO、CO、PGI等血管活性物质的产生失调、释放失控和作用过度,造成组织损伤。 3.缺氧刺激可引起VSMC对NE收缩反应性类似在体实验的双相变化,阻断HIF-1α表达可明显削弱该双相变化的幅度。HIF-1α参与了VSMC收缩反应性的调节,其机制主要与iNOS—NO、HO-1—CO、COX-2—PGI通路有关。
[Abstract]:Severe trauma, shock, sepsis patients often suffer from irreversible cell injury, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS) and even multiple organ failure (MOF) during decompensation after multiple blows such as ischemia and hypoxia, reperfusion injury, intestinal flora translocation, and endotoxin release. In addition to systemic inflammatory disorders, the decrease in vascular responsiveness after shock is another important cause. Vascular hyporesponsiveness is manifested by decreased or paralyzed responses of systemic vessels to vasoconstrictor and vasodilator substances, resulting in an ineffective increase in blood pressure, difficulty in improving tissue perfusion, and progressive increase in cellular hypoxia and injury. It has been found that the occurrence of vascular hyporeactivity is related to adrenergic receptor desensitization, vascular smooth muscle cell (VSMC) potassium, calcium channel dysfunction and membrane hyperpolarization. Pre-laboratory studies have also shown that Rho kinase can regulate vascular responsiveness after shock by regulating myosin light chain phosphatase (MLCP) activity, myosin light chain (MLC20) phosphorylation and calcium sensitivity.
HIF-1a regulates the adaptive response of cells to hypoxia by regulating the expression of a variety of genes. It is the only regulatory molecule that has been found to play a specific role in hypoxia. It is considered to be the key molecule to regulate the expression of hypoxia-related genes. It is associated with activated protein 1 (AP-1), nuclear transcription factor (nu). Clear factor kappa B, NF-kappa B) and p53 regulate the body's response to hypoxia. Their functions involve energy metabolism, cell proliferation, hematopoiesis, angiogenesis, remodeling and contraction.
Ischemia and hypoxia are the most basic pathophysiological changes in various types of shock, so HIF-1a should be one of the most significant changes in expression and activity after shock. A large number of studies have shown that late hemorrhagic shock can trigger obvious uncontrolled systemic inflammation and ischemia-reperfusion injury, and HIF-1a participates in the above two kinds of injury through a variety of pathways. In this study, hypoxia-inducible factor-1a (HIF-1a) and a series of its downstream molecules were selected as research targets, and the specific blocker of HIF-1a, oligomycin, was used as a tool drug to explore the vascular responsiveness of HIF-1a to shock. Specific contents include two major parts: _HIF-1a in the regulation of vascular reactivity after hemorrhagic shock; _after hemorrhagic shock HIF-1a regulation of vascular reactivity mechanism.
Main experimental methods:
In the first part, we observed the role of HIF-1 alpha in the regulation of vascular reactivity after hemorrhagic shock, including the establishment of severe hemorrhagic shock model in rats, the preparation of superior mesenteric artery (SMA) vascular ring, and the use of in vitro vascular ring tension measurement technique to observe the different phases of shock (shock 0.5 h, shock 1.0 h, shock 2.0 h, shock 3.0 h, shock 4.0 h, shock). Meanwhile, the mesenteric artery was harvested and the expression of HIF-1 alpha mRNA was detected by RT-PCR. Meanwhile, the tension of vascular rings and HIF-1 alpha mRNA expression were observed by using oligomycin, a specific blocker of HIF-1 alpha, as a tool drug. In the second part, the mechanism of HIF-1a regulating vascular reactivity after hemorrhagic shock was studied by in vitro and in vivo experiments. In vivo, SMA tissues from rats with hemorrhagic shock were harvested and the expression of eNOS, iNOS, HO-1, COX-2 mRNA was observed by RT-PCR. Sodium dithionite (Na2S2O4) reduction method, nitrate reductase method and radioimmunoassay (RIA) were used to determine the changes of NO, CO and PGI in blood at different stages after shock. The effects of HIF-1a on eNOS/iNOS-NO, HO-1-CO and COX-2-PGI pathway after hemorrhagic shock were analyzed. Vascular smooth muscle cells (VSMC) and endothelial cells (VEC) were used to measure the fluorescence permeability of the Transwell inferior cavity to reflect the contractile response of VSMC to norepinephrine (NE), and the mRNA expression of HIV-1 alpha and its related molecules was semi-quantitatively analyzed by RT-PCR: endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX). - 2 (COX-2), heme oxygenase-1 (HO-1), further analyzed the relationship between the effects of hypoxia on the contractile response of VSMC and the effects of these molecules.
Main findings:
1. After hemorrhagic shock, the expression of HIF-1 alpha mRNA increased gradually and reached its peak at 4 h (P 0.01). Vascular responsiveness showed two-phase change, i.e. early (0.0h-1.0h) vascular responsiveness increased, dose-response curve shifted to the left, maximum contractility (Emax) increased significantly and pD2 decreased (P 0.01). Vascular responsiveness decreased progressively in the middle and late stages of the shock. The dose-response curve shifted to the right, Emax decreased and pD2 increased. Vascular responsiveness was lower than the normal level at 4 hours after shock (P 0.01). Vascular responsiveness also showed biphasic changes, but the amplitude was significantly decreased in the treatment group after shock. The reactivity of the tube was slightly increased (P 0.05 or P 0.01).
2. After hemorrhagic shock, the expression of eNOS, iNOS, HO-1, COX-2 mRNA increased gradually with the prolongation of the phase, reaching the peak at 1.0 h, 2.0 h, 3.0 h and 4.0 h respectively (P Compared with shock, there was a significant increase in phase (P 0.01).
3. Plasma NO, PGI and whole blood CO concentrations increased significantly with the progression of shock phase (P 0.05 or P 0.01). HIF-1a specific blocker oligomycin could stabilize CO at normal level, while NO and PGI expression were partially inhibited. With the prolongation of shock phase, NO and PGI expression increased, but the amplitude was significantly lower than that of shock phase group (P 0.01).
4. After hypoxia, the contractile reactivity of VSMC showed a biphasic change, that is, the contractile reactivity of VSMC increased significantly in the early stage of hypoxia (0.0-1.0 h) and reached a peak at 0.5 h (P The increase trend of early reactivity after hypoxia was completely inhibited (P 0.05 or P 0.01), while the contractile reactivity of VSMC at 4.0h-6.0h was partly increased (P 0.05).
5. After mixed culture of VSMC and VEC, the expression of HIF-1a, iNOS, HO-1, COX-2 mRNA increased gradually with the prolongation of hypoxia, reaching the peak at 4.0 h, 2.0 h, 3.0 h and 4.0 h respectively (P 0.01 or P 0.05). The enhanced expression of eNOS mRNA was completely inhibited and fluctuated within the normal range in the administration group. There was no significant difference between hypoxia group and administration group.
Conclusion:
1. After hemorrhagic shock, the contractile response of SMA in rats showed a biphasic change, that is, the vascular reactivity increased in the early stage of shock and decreased in the late stage of shock. HIF-1a partially inhibits the elevation of vasoconstrictive responsiveness at early 0.5-1 h and slightly increases vasoconstrictive responsiveness at late stage of shock. HIF-1a plays an important regulatory role in the formation of biphasic changes in vasoconstrictive responsiveness in hemorrhagic shock rats: its transcriptional level is slightly up-regulated at early stage of shock and exhibits vasoconstrictive responsiveness. Positive correlation was negative in late shock stage.
2. After shock, the expression of eNOS, iNOS, HO-1 and COX-2 mRNA was activated in turn, up-regulated and peaked. The transcriptional level of HIF-1 alpha was also significantly inhibited after blocking the expression of HIF-1 alpha. The expression of HIF-1a and its downstream molecules increased compensatively in the early stage of HS. The slight expression of HIF-1a was beneficial to the adaptive protection of vascular reactivity and was a positive correlation factor. The production of vasoactive substances such as PGI is out of control, releasing out of control and overacting, resulting in tissue damage.
3. Hypoxic stimulation can induce a biphasic change in the contractile response of VSMC to NE similar to in vivo experiment. Blocking the expression of HIF-1a can significantly weaken the biphasic change. HIF-1a participates in the regulation of contractile response of VSMC, and its mechanism is mainly related to iNOS-NO, HO-1-CO, COX-2-PGI pathway.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2007
【分类号】：R363
本文编号：2233184
[Abstract]:Severe trauma, shock, sepsis patients often suffer from irreversible cell injury, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS) and even multiple organ failure (MOF) during decompensation after multiple blows such as ischemia and hypoxia, reperfusion injury, intestinal flora translocation, and endotoxin release. In addition to systemic inflammatory disorders, the decrease in vascular responsiveness after shock is another important cause. Vascular hyporesponsiveness is manifested by decreased or paralyzed responses of systemic vessels to vasoconstrictor and vasodilator substances, resulting in an ineffective increase in blood pressure, difficulty in improving tissue perfusion, and progressive increase in cellular hypoxia and injury. It has been found that the occurrence of vascular hyporeactivity is related to adrenergic receptor desensitization, vascular smooth muscle cell (VSMC) potassium, calcium channel dysfunction and membrane hyperpolarization. Pre-laboratory studies have also shown that Rho kinase can regulate vascular responsiveness after shock by regulating myosin light chain phosphatase (MLCP) activity, myosin light chain (MLC20) phosphorylation and calcium sensitivity.
HIF-1a regulates the adaptive response of cells to hypoxia by regulating the expression of a variety of genes. It is the only regulatory molecule that has been found to play a specific role in hypoxia. It is considered to be the key molecule to regulate the expression of hypoxia-related genes. It is associated with activated protein 1 (AP-1), nuclear transcription factor (nu). Clear factor kappa B, NF-kappa B) and p53 regulate the body's response to hypoxia. Their functions involve energy metabolism, cell proliferation, hematopoiesis, angiogenesis, remodeling and contraction.
Ischemia and hypoxia are the most basic pathophysiological changes in various types of shock, so HIF-1a should be one of the most significant changes in expression and activity after shock. A large number of studies have shown that late hemorrhagic shock can trigger obvious uncontrolled systemic inflammation and ischemia-reperfusion injury, and HIF-1a participates in the above two kinds of injury through a variety of pathways. In this study, hypoxia-inducible factor-1a (HIF-1a) and a series of its downstream molecules were selected as research targets, and the specific blocker of HIF-1a, oligomycin, was used as a tool drug to explore the vascular responsiveness of HIF-1a to shock. Specific contents include two major parts: _HIF-1a in the regulation of vascular reactivity after hemorrhagic shock; _after hemorrhagic shock HIF-1a regulation of vascular reactivity mechanism.
Main experimental methods:
In the first part, we observed the role of HIF-1 alpha in the regulation of vascular reactivity after hemorrhagic shock, including the establishment of severe hemorrhagic shock model in rats, the preparation of superior mesenteric artery (SMA) vascular ring, and the use of in vitro vascular ring tension measurement technique to observe the different phases of shock (shock 0.5 h, shock 1.0 h, shock 2.0 h, shock 3.0 h, shock 4.0 h, shock). Meanwhile, the mesenteric artery was harvested and the expression of HIF-1 alpha mRNA was detected by RT-PCR. Meanwhile, the tension of vascular rings and HIF-1 alpha mRNA expression were observed by using oligomycin, a specific blocker of HIF-1 alpha, as a tool drug. In the second part, the mechanism of HIF-1a regulating vascular reactivity after hemorrhagic shock was studied by in vitro and in vivo experiments. In vivo, SMA tissues from rats with hemorrhagic shock were harvested and the expression of eNOS, iNOS, HO-1, COX-2 mRNA was observed by RT-PCR. Sodium dithionite (Na2S2O4) reduction method, nitrate reductase method and radioimmunoassay (RIA) were used to determine the changes of NO, CO and PGI in blood at different stages after shock. The effects of HIF-1a on eNOS/iNOS-NO, HO-1-CO and COX-2-PGI pathway after hemorrhagic shock were analyzed. Vascular smooth muscle cells (VSMC) and endothelial cells (VEC) were used to measure the fluorescence permeability of the Transwell inferior cavity to reflect the contractile response of VSMC to norepinephrine (NE), and the mRNA expression of HIV-1 alpha and its related molecules was semi-quantitatively analyzed by RT-PCR: endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX). - 2 (COX-2), heme oxygenase-1 (HO-1), further analyzed the relationship between the effects of hypoxia on the contractile response of VSMC and the effects of these molecules.
Main findings:
1. After hemorrhagic shock, the expression of HIF-1 alpha mRNA increased gradually and reached its peak at 4 h (P 0.01). Vascular responsiveness showed two-phase change, i.e. early (0.0h-1.0h) vascular responsiveness increased, dose-response curve shifted to the left, maximum contractility (Emax) increased significantly and pD2 decreased (P 0.01). Vascular responsiveness decreased progressively in the middle and late stages of the shock. The dose-response curve shifted to the right, Emax decreased and pD2 increased. Vascular responsiveness was lower than the normal level at 4 hours after shock (P 0.01). Vascular responsiveness also showed biphasic changes, but the amplitude was significantly decreased in the treatment group after shock. The reactivity of the tube was slightly increased (P 0.05 or P 0.01).
2. After hemorrhagic shock, the expression of eNOS, iNOS, HO-1, COX-2 mRNA increased gradually with the prolongation of the phase, reaching the peak at 1.0 h, 2.0 h, 3.0 h and 4.0 h respectively (P Compared with shock, there was a significant increase in phase (P 0.01).
3. Plasma NO, PGI and whole blood CO concentrations increased significantly with the progression of shock phase (P 0.05 or P 0.01). HIF-1a specific blocker oligomycin could stabilize CO at normal level, while NO and PGI expression were partially inhibited. With the prolongation of shock phase, NO and PGI expression increased, but the amplitude was significantly lower than that of shock phase group (P 0.01).
4. After hypoxia, the contractile reactivity of VSMC showed a biphasic change, that is, the contractile reactivity of VSMC increased significantly in the early stage of hypoxia (0.0-1.0 h) and reached a peak at 0.5 h (P The increase trend of early reactivity after hypoxia was completely inhibited (P 0.05 or P 0.01), while the contractile reactivity of VSMC at 4.0h-6.0h was partly increased (P 0.05).
5. After mixed culture of VSMC and VEC, the expression of HIF-1a, iNOS, HO-1, COX-2 mRNA increased gradually with the prolongation of hypoxia, reaching the peak at 4.0 h, 2.0 h, 3.0 h and 4.0 h respectively (P 0.01 or P 0.05). The enhanced expression of eNOS mRNA was completely inhibited and fluctuated within the normal range in the administration group. There was no significant difference between hypoxia group and administration group.
Conclusion:
1. After hemorrhagic shock, the contractile response of SMA in rats showed a biphasic change, that is, the vascular reactivity increased in the early stage of shock and decreased in the late stage of shock. HIF-1a partially inhibits the elevation of vasoconstrictive responsiveness at early 0.5-1 h and slightly increases vasoconstrictive responsiveness at late stage of shock. HIF-1a plays an important regulatory role in the formation of biphasic changes in vasoconstrictive responsiveness in hemorrhagic shock rats: its transcriptional level is slightly up-regulated at early stage of shock and exhibits vasoconstrictive responsiveness. Positive correlation was negative in late shock stage.
2. After shock, the expression of eNOS, iNOS, HO-1 and COX-2 mRNA was activated in turn, up-regulated and peaked. The transcriptional level of HIF-1 alpha was also significantly inhibited after blocking the expression of HIF-1 alpha. The expression of HIF-1a and its downstream molecules increased compensatively in the early stage of HS. The slight expression of HIF-1a was beneficial to the adaptive protection of vascular reactivity and was a positive correlation factor. The production of vasoactive substances such as PGI is out of control, releasing out of control and overacting, resulting in tissue damage.
3. Hypoxic stimulation can induce a biphasic change in the contractile response of VSMC to NE similar to in vivo experiment. Blocking the expression of HIF-1a can significantly weaken the biphasic change. HIF-1a participates in the regulation of contractile response of VSMC, and its mechanism is mainly related to iNOS-NO, HO-1-CO, COX-2-PGI pathway.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2007
【分类号】：R363
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