D-半乳糖预处理鼠肺感染时心功能的改变及机制
摘要
1．背景：
随着自然老化的进展，老年人各器官结构和功能都发生了明显变化、功能储备降低。老化肺的改变使老年人易于发生肺部感染。老年人肺炎具有发病率高、并发症多、易发生老年多器官功能不全和衰竭等特点，是导致老年人死亡的重要原因。但肺炎诱发老年人肺外器官功能障碍的机制还不完全清楚，这为预防和治疗老年人多器官功能不全造成很大障碍。有研究认为老年人肺炎时心脏病事件发生率增高、致死率增高，但具体机制也不明了。
2．目的：
建立人工老化动物模型和肺部感染模型，观察人工诱发老化动物肺部感染后心脏功能相关参数的改变与普通成年鼠的区别，了解人工老化动物心功能改变的机制，为老年人肺部感染后心脏功能改变机制的研究提供初步实验参考。
3．研究材料和方法：
3．1 在肺部感染时普通成年(NS)与D-半乳糖(D-gal)处理大鼠心脏功能改变的差异
选健康成年雄性SD大鼠52只分别以D-gal经皮注射制作人工老化动物模型，另一组注射等量生理盐水作对照。其后每组随机选取24只大鼠进行肺部感染实验。大鼠麻醉后经气管内注入绿脓杆菌生理盐水悬液制作大鼠肺部感染模型，以注入生理盐水为对照。制作心脏血流动力学观测模型记录左心室内血流动力学参数：心率(HR)、左心室最高收缩压(LVSP)、左室舒张末期压(LVEDP)、等容收缩期左室内压力最大上升速率(+dp/dt_(max))、等容舒张期左室内压力最大下降速率(-dp／dt_(max))等。实验末查动脉血气分析、血浆肿瘤坏死因子-a(TNF-a)；留取心标本制作光镜和电镜病理片。
3．2 肺部感染时D-gal处理小鼠心肌组织中部分物质含量的改变
中文摘要 博士论文
健康雄性NIH小鼠随机分为2组，一组制作老化动物模型、另一组作为对照。
每组再随机选取36只小鼠进行肺部感染实验，分别分为3组：对照组、肺部感染
后 1天组和3天组。取血检测血浆TNF－a；留取心肌组织制作电镜、光镜和免疫
组化标本；留取心肌组织检测三磷酸腺昔（ATP）含量、铜锌－超氧化物歧化酶
（Gu，Zn－SOD）mRNA和肿瘤坏死因子－a（TNF a）mRNA表达量的改变；检测心肌
组织中丙H醛（MDA）含量、总超氧化物歧化酶（T－SOD）活性、铜锌－超氧化物歧
化酶（Gu，Zn－SOD）活性、一氧化氮合酶（NO）活性、TNF－a含量等。
3．3 褪黑素（MT）干预对D－gal处理小鼠心肌中部分物质含量的影响
健康雄性叮H小鼠175只随机分为2组，一组制作老化动物模型、另一组作
为对照。每组随机选取 48只小鼠进行肺部感染和 MT干预实验，分别分为 4组：
对照组、肺部感染后3天组、MT干预组、MT溶媒对照组。标本的留取和检测项目
同3．2部分。
4．结果：
4．1 在肺部感染时NS与D－gal处理大鼠心脏功能改变的差异
在人工诱发肺部感染试验中，NS组与D－gal组大鼠死亡例数无明显差别
（n0．05）。在肺部感染后不同时间点皿、＋巾／上。x、－巾／以＿各值降低：w皿P、
T值升高。其中仅有LVEDP在有／无肺部感染、NS组／D了 组的比较中均有显
著性差异。肺部感染大鼠的动脉血氧分压（Pa02）、血氧饱和度（Sa02）明显降低，
血浆 TNF－口明显增高（P＜0．05）；上述指标在 NS与 D－gal组间比较中均无明显差
别叩川．05人心肌组织电镜检查显示肺部感染后心肌线粒体发生变性，感染后期
出现空泡变性和固缩表现，D－gal处理大鼠心肌组织线粒体损伤趋于加重。
4．2肺部感染时D下al处理小鼠心肌中部分物质含量的改变
肺部感染后小鼠的死亡率增加（P＜0．05）。肺部感染小鼠心肌组织中MDA、TNF－
a含量增加，T－SOD、Gu，Zn－SOD活性及ATP含量降低；在D－gal组小鼠心肌
中MDA增加更明显、T－SOD、Gu，Zn－SOD活性及ATP含量降低显著（P＜0．05）；相
关分析的结果表明，心肌组织ATP含量与T七 活性呈正相关k司．51，P州．05人
3
中文摘要 博士论文
与MDA含量呈负相关（r＝一0．43，P＜0．05）；心肌组织中TNF－口含量在D－gal组
与屹 组之间无显著性差异（P＞0．05）。应用半定量盯－PCR技术观察了h，Zn－SOD
InRNA和TNF－a InRNA表达量的变化，组间比较结果显示SOD－InRNA表达量在肺部
感染后三天有明显增加（P＜0．05）；TNF－InRN表达量在肺部感染后的第一天和第
三天均有明显增加（P＜0．05）；D－gal组与 NS组比较，各组间无显著性差异
（P＞0．05）。小鼠肺部感染后血浆中TNF－口含量增高；不同时间点相比无显著性
差异叩川．05）；NS组血浆川F－口含量
1. Backgrounds
The structure and function of most organs change obviously in the process of aging, and the function reserve of most senile organs become decreased. In this process, the senile lungs become to be vulnerable. In the elderly, pneumonia is very prevalent and often complicated with other organs dysfunction or even failure. It is also one of the common causes of death in the elderly. But the mechanism of multiple organ dysfunction (or failure) induced by pneumonia in the elderly is still not very clear. In previous reports, heart events get frequent and the death rate caused by heart events is much higher when pneumonia occurs in the elderly, however the mechanism remains unclear.
2. Objectives
To build up some methods to make artificial accelerated aging animal models and artificial lung infection animal models, to observe the changes in cardiac function related parameters induced by pneumonia in aging rodent models, and to compare these changes with those of normal rodent pneumonia models. To study the mechanism of cardiac function changes in the artificial aging animal models with pneumonia and to provide some references to the study of the mechanism of the cardiac function changes in the elderly when pneumonia occurs.
3. Methods
3.1 The difference of cardiac function changes induced by pneumonia between normal
and D-galactose pretreated rats
Fifty-two normal male SD rats were divided into two groups randomly. One group was treated with D-galactose by subcutaneous injection (D-gal group), and the other group was treated with normal saline by subcutaneous injection (NS group). Then, 16 rats of each groups were injected pseudomonas aeruginosa saline suspension directly through trachea to induce pneumonia. The other rats were injected with normal saline to be used as control. Then, murine hemodynamics including heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximal pressure increasing rate during isovolumetric contraction phase (+dp/dtmax), the maximal pressure decreasing rate during isovolumetric relaxation phase (-dp/dtmax), and T value were observed respectively in 24 hours and 72 hours after pneumonia was induced. At the end of the experiment, blood gas analysis and tumor necrosis factor- a (TNF- a) measurement were performed. Some cardiac tissues were also observed by microscope and electron microscope.
3.2 The changes of some materials in the heart of artificially accelerated aging mouse models with pneumonia
Some normal male NIH mice were divided into two groups randomly. One group was pretreated with D-galactose by subcutaneous injection (D-gal group), and the other group was pretreated with normal saline by subcutaneous injection (NS group). Then, some mice of each group were injected pseudomonas aeruginosa saline suspension directly through trachea to induce pneumonia. The other rats were injected with normal saline to be used as control. Then mice were killed in 24 hours and 72 hours after pneumonia was induced, and some measurements were performed, and the measured parameters included plasma level of TNF- a , the heart tissue content of Adenosine Triphosphate (ATP), TNF- a and malondialdehyde (MDA), the activity of total Superoxide Dismutase (T-SOD), Gu,Zn-SOD, Nitric Oxide Synthase (NOS), the
expression changes of Gu^n-SOD mRNA and TNF- a rnRNA in the heart tissue. Some cardiac tissues were also observed by immunohistochemical analysis, microscope and electron microscope.
3.3 The influence of melatonin on the changes of some materials in the heart of artificially accelerated aging mouse models with pneumonia
In this part, D-galactose pretreated and normal mice were randomly divided into 2 groups respectively. They were injected with normal saline (the normal group) or pseudomonas aeruginosa saline suspension directly through trachea (the others group) to induce pneumonia. Then each group was divided into four subgroups, i.e. the control group, 3-day pneumonia group, MT-pneumonia grou
随着自然老化的进展，老年人各器官结构和功能都发生了明显变化、功能储备降低。老化肺的改变使老年人易于发生肺部感染。老年人肺炎具有发病率高、并发症多、易发生老年多器官功能不全和衰竭等特点，是导致老年人死亡的重要原因。但肺炎诱发老年人肺外器官功能障碍的机制还不完全清楚，这为预防和治疗老年人多器官功能不全造成很大障碍。有研究认为老年人肺炎时心脏病事件发生率增高、致死率增高，但具体机制也不明了。
2．目的：
建立人工老化动物模型和肺部感染模型，观察人工诱发老化动物肺部感染后心脏功能相关参数的改变与普通成年鼠的区别，了解人工老化动物心功能改变的机制，为老年人肺部感染后心脏功能改变机制的研究提供初步实验参考。
3．研究材料和方法：
3．1 在肺部感染时普通成年(NS)与D-半乳糖(D-gal)处理大鼠心脏功能改变的差异
选健康成年雄性SD大鼠52只分别以D-gal经皮注射制作人工老化动物模型，另一组注射等量生理盐水作对照。其后每组随机选取24只大鼠进行肺部感染实验。大鼠麻醉后经气管内注入绿脓杆菌生理盐水悬液制作大鼠肺部感染模型，以注入生理盐水为对照。制作心脏血流动力学观测模型记录左心室内血流动力学参数：心率(HR)、左心室最高收缩压(LVSP)、左室舒张末期压(LVEDP)、等容收缩期左室内压力最大上升速率(+dp/dt_(max))、等容舒张期左室内压力最大下降速率(-dp／dt_(max))等。实验末查动脉血气分析、血浆肿瘤坏死因子-a(TNF-a)；留取心标本制作光镜和电镜病理片。
3．2 肺部感染时D-gal处理小鼠心肌组织中部分物质含量的改变
中文摘要 博士论文
健康雄性NIH小鼠随机分为2组，一组制作老化动物模型、另一组作为对照。
每组再随机选取36只小鼠进行肺部感染实验，分别分为3组：对照组、肺部感染
后 1天组和3天组。取血检测血浆TNF－a；留取心肌组织制作电镜、光镜和免疫
组化标本；留取心肌组织检测三磷酸腺昔（ATP）含量、铜锌－超氧化物歧化酶
（Gu，Zn－SOD）mRNA和肿瘤坏死因子－a（TNF a）mRNA表达量的改变；检测心肌
组织中丙H醛（MDA）含量、总超氧化物歧化酶（T－SOD）活性、铜锌－超氧化物歧
化酶（Gu，Zn－SOD）活性、一氧化氮合酶（NO）活性、TNF－a含量等。
3．3 褪黑素（MT）干预对D－gal处理小鼠心肌中部分物质含量的影响
健康雄性叮H小鼠175只随机分为2组，一组制作老化动物模型、另一组作
为对照。每组随机选取 48只小鼠进行肺部感染和 MT干预实验，分别分为 4组：
对照组、肺部感染后3天组、MT干预组、MT溶媒对照组。标本的留取和检测项目
同3．2部分。
4．结果：
4．1 在肺部感染时NS与D－gal处理大鼠心脏功能改变的差异
在人工诱发肺部感染试验中，NS组与D－gal组大鼠死亡例数无明显差别
（n0．05）。在肺部感染后不同时间点皿、＋巾／上。x、－巾／以＿各值降低：w皿P、
T值升高。其中仅有LVEDP在有／无肺部感染、NS组／D了 组的比较中均有显
著性差异。肺部感染大鼠的动脉血氧分压（Pa02）、血氧饱和度（Sa02）明显降低，
血浆 TNF－口明显增高（P＜0．05）；上述指标在 NS与 D－gal组间比较中均无明显差
别叩川．05人心肌组织电镜检查显示肺部感染后心肌线粒体发生变性，感染后期
出现空泡变性和固缩表现，D－gal处理大鼠心肌组织线粒体损伤趋于加重。
4．2肺部感染时D下al处理小鼠心肌中部分物质含量的改变
肺部感染后小鼠的死亡率增加（P＜0．05）。肺部感染小鼠心肌组织中MDA、TNF－
a含量增加，T－SOD、Gu，Zn－SOD活性及ATP含量降低；在D－gal组小鼠心肌
中MDA增加更明显、T－SOD、Gu，Zn－SOD活性及ATP含量降低显著（P＜0．05）；相
关分析的结果表明，心肌组织ATP含量与T七 活性呈正相关k司．51，P州．05人
3
中文摘要 博士论文
与MDA含量呈负相关（r＝一0．43，P＜0．05）；心肌组织中TNF－口含量在D－gal组
与屹 组之间无显著性差异（P＞0．05）。应用半定量盯－PCR技术观察了h，Zn－SOD
InRNA和TNF－a InRNA表达量的变化，组间比较结果显示SOD－InRNA表达量在肺部
感染后三天有明显增加（P＜0．05）；TNF－InRN表达量在肺部感染后的第一天和第
三天均有明显增加（P＜0．05）；D－gal组与 NS组比较，各组间无显著性差异
（P＞0．05）。小鼠肺部感染后血浆中TNF－口含量增高；不同时间点相比无显著性
差异叩川．05）；NS组血浆川F－口含量
1. Backgrounds
The structure and function of most organs change obviously in the process of aging, and the function reserve of most senile organs become decreased. In this process, the senile lungs become to be vulnerable. In the elderly, pneumonia is very prevalent and often complicated with other organs dysfunction or even failure. It is also one of the common causes of death in the elderly. But the mechanism of multiple organ dysfunction (or failure) induced by pneumonia in the elderly is still not very clear. In previous reports, heart events get frequent and the death rate caused by heart events is much higher when pneumonia occurs in the elderly, however the mechanism remains unclear.
2. Objectives
To build up some methods to make artificial accelerated aging animal models and artificial lung infection animal models, to observe the changes in cardiac function related parameters induced by pneumonia in aging rodent models, and to compare these changes with those of normal rodent pneumonia models. To study the mechanism of cardiac function changes in the artificial aging animal models with pneumonia and to provide some references to the study of the mechanism of the cardiac function changes in the elderly when pneumonia occurs.
3. Methods
3.1 The difference of cardiac function changes induced by pneumonia between normal
and D-galactose pretreated rats
Fifty-two normal male SD rats were divided into two groups randomly. One group was treated with D-galactose by subcutaneous injection (D-gal group), and the other group was treated with normal saline by subcutaneous injection (NS group). Then, 16 rats of each groups were injected pseudomonas aeruginosa saline suspension directly through trachea to induce pneumonia. The other rats were injected with normal saline to be used as control. Then, murine hemodynamics including heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximal pressure increasing rate during isovolumetric contraction phase (+dp/dtmax), the maximal pressure decreasing rate during isovolumetric relaxation phase (-dp/dtmax), and T value were observed respectively in 24 hours and 72 hours after pneumonia was induced. At the end of the experiment, blood gas analysis and tumor necrosis factor- a (TNF- a) measurement were performed. Some cardiac tissues were also observed by microscope and electron microscope.
3.2 The changes of some materials in the heart of artificially accelerated aging mouse models with pneumonia
Some normal male NIH mice were divided into two groups randomly. One group was pretreated with D-galactose by subcutaneous injection (D-gal group), and the other group was pretreated with normal saline by subcutaneous injection (NS group). Then, some mice of each group were injected pseudomonas aeruginosa saline suspension directly through trachea to induce pneumonia. The other rats were injected with normal saline to be used as control. Then mice were killed in 24 hours and 72 hours after pneumonia was induced, and some measurements were performed, and the measured parameters included plasma level of TNF- a , the heart tissue content of Adenosine Triphosphate (ATP), TNF- a and malondialdehyde (MDA), the activity of total Superoxide Dismutase (T-SOD), Gu,Zn-SOD, Nitric Oxide Synthase (NOS), the
expression changes of Gu^n-SOD mRNA and TNF- a rnRNA in the heart tissue. Some cardiac tissues were also observed by immunohistochemical analysis, microscope and electron microscope.
3.3 The influence of melatonin on the changes of some materials in the heart of artificially accelerated aging mouse models with pneumonia
In this part, D-galactose pretreated and normal mice were randomly divided into 2 groups respectively. They were injected with normal saline (the normal group) or pseudomonas aeruginosa saline suspension directly through trachea (the others group) to induce pneumonia. Then each group was divided into four subgroups, i.e. the control group, 3-day pneumonia group, MT-pneumonia grou
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