100%氧气吸入对脓毒血症动物脏器损伤的保护作用及其机制研究
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摘要
脓毒血症是指由侵袭性感染引起的全身性炎症反应综合征(Systemic inflammatory response syndrome,SIRS),是ICU患者死亡的主要原因之一。尽管近年来对脓毒血症发病机制及救治策略的研究已取得了一定的进展,但仍未获根本性突破,其死亡率依然高达20%-50%[1],且缺乏方便、有效的诊断与治疗手段。吸氧是临床上常用的辅助治疗手段。在人体缺氧或将要出现缺氧的时候,通过给氧以增加吸入气体氧浓度,从而提高肺泡内气体氧浓度,进而提高肺泡血氧含量,改善组织供氧状况,称为氧气疗法(简称氧疗)。在氧疗中,吸入氧浓度大于21%时称为高氧治疗,这是临床上常用的治疗手段。一般认为,高氧治疗存在氧毒性的顾虑。但是近年来有研究发现,100%氧气早期应用可有效保护各种休克动物器官功能,显著提高休克动物存活率[2-4]。同时发现合理高氧治疗具有降低全身炎症反应程度、抗感染等作用[5, 6]。我们的前期研究也发现100%氧气合理吸入可明显提高酵母多糖所致MODS动物的生存率。高迁移率族蛋白-1(HMGB1)是一种晚期炎症因子,且与脓毒血症密切相关。关于HMGB1与脓毒血症的相关性研究是当前的热点之一。然而,目前关于HMGB1与脓毒血症病情严重程度的相关性研究尚未得出统一的结论。因此,本研究拟利用鼠脓毒血症模型观察早期纯氧干预能否减轻脓毒血症脏器损伤、降低死亡率,以及HMGB1与脓毒血症中脏器损伤程度的相关性,HMGB1是否参与了早期纯氧干预脓毒血症的机制过程。
实验一100%氧气吸入能减轻脓毒血症鼠脏器损伤并降低其死亡率
目的:观察100%O2吸入能否降低脓毒血症小鼠的死亡率,减轻其脏器损伤。方法:50只雄性昆明小鼠,被随机分为2组(每组25只):对照组和纯氧治疗(100%O2)组。两组动物均给予LPS(生理盐水溶解,50mg·kg-1,腹腔注射)。高氧治疗(100%O2)组在腹腔注射LPS后,分别于第4h和12h给予100%O2吸入,每次持续2h。各组动物在24h时观察死亡率,并从存活动物中随机处死5只,取心、肺、肝、肾组织,经4%多聚甲醛固定后,切片,HE染色,进行病理学观察和评分。
结果:对照组动物24小时死亡率(52%)显著高于100%O2干预组(其24小时死亡率为24%)(P<0.05);100%O2干预组动物心、肺、肝、肾病理损伤评分明显低于对照组(P<0.05)。表明100%O2吸入能够明显减轻脓毒血症动物脏器损伤并可显著降低其死亡率。
实验二血清HMGB1水平与脓毒血症鼠脏器损伤程度的相关性分析
目的:证实血浆HMGB1水平与脓毒血症鼠脏器损伤程度存在相关性。
方法:240只雄性SD大鼠随机分为4组(每组60只):脓毒血症一(LPS-4)组经腹腔注射LPS(生理盐水溶解,4mg·kg-1);脓毒血症二(LPS-8)组经腹腔注射LPS(8mg·kg-1);脓毒血症三(LPS-16)组经腹腔注射LPS(16mg·kg-1);盐水对照(control)组经腹腔注射相同容积的生理盐水。四组动物分别于注射后2h、4h、8h、16h、24h、32h和48h随机取5只,戊巴比妥钠(2%,50mg·kg-1)腹腔注射麻醉后,经心脏取血5ml,分离血清,并取心、肺、肝、肾脏器组织,-20℃保存。另外5只雄性SD大鼠不做任何处理,处理同上,作为注射前的对照(结果中的0h)。血清采用ELASA和全自动生化分析仪检测HMGB1的血清水平和cTnI、ALT、AST、CRE、BUN的水平,脏器标本经4%多聚甲醛固定后,切片,HE染色,进行病理学观察和评分。合并三个脓毒血症组数据,分析其HMGB1血清水平与脏器病理损伤和血清生化指标之间的相关性。
结果:血清HMGB1水平与大鼠脓毒血症脏器病理损伤评分及血清生化指标之间存在明显相关性:心(rs=0.755, P<0.05),肺(rs=0.758, P<0.05),肝(rs=0.789, P<0.05),肾(rs=0.796, P<0.05);ALT(r=0.374, P<0.05), AST (r=0.447, P<0.05), CRE (r=0.503, P<0.05), BUN (r=0.512, P<0.05), cTnI (r=0.693, P<0.05)。
实验三HMGB1参与100%氧气吸入对脓毒血症动物脏器的保护作用机制
目的:研究HMGB1是否参与了100%O2吸入对脓毒血症小鼠脏器的保护作用机制。
方法:50只雄性昆明小鼠,被随机分为2组(每组25只):对照组和治疗(100%O2)组。两组动物均给予LPS(生理盐水溶解,50mg·kg-1,腹腔注射)。治疗(100%O2)组在腹腔注射LPS后,分别于第4h和12h给予100% O2吸入,每次持续2h。各组动物在24h时从存活动物中随机处死5只,心脏取血1ml,分离血清,保存于-80℃,采用ELASA检测HMGB1血清浓度。
结果:两组组动物24h时HMGB1血清浓度存在明显差异(P<0.05),表明HMGB1可能参与了100%O2吸入对脓毒血症小鼠脏器的保护作用机制。
结论
1、100%O2吸入能明显减轻脓毒血症动物脏器损伤,降低其死亡率。
2、血清HMGB1水平与脓毒血症动物脏器损伤程度存在相关性,有可能作为脓毒血症脏器损伤程度的判断指标之一。
3、HMGB1可能参与了100%O2吸入对脓毒血症小鼠脏器的保护作用机制。
Sepsis, the SIRS (systemic inflammatory response syndrome) induced by severe infection, is a major cause of death in the ICU patients. Despite great advances have been made in the mechanism and developing the measures for improving the treatment outcome, the mortality for sepsis remains approximately 20-50% [1]. Because its mechanism is not clear, there is lack of accurate or available method for assessing the patients with sepsis and there is no effective treating measures up to now. When the body has hypoxia or will have hypoxia, oxygen inhalation can increase the oxygen concentration of inspired gas, and then raise the partial pressure of oxygen in the alveolus, elevate the blood oxygen level of the arterial blood by facilitating diffusion as well as improve the oxygen supply in the tissues. We call it oxygen therapy. Hyperoxia therapy is the oxygen therapy in which the inspired concentration of oxygen is higher than 21%, and it is widely used clinically. As is known, hyperoxia therapy may induce oxygen toxicity. However, recent studies found that early 100% oxygen therapy can significantly protect the organ function and increase the survival rate in various kinds of animal model with shock [2-4]. It is reported that hyperoxia therapy with proper conditions can decrease the inflammation and infection[5, 6]. Our team also find that reasonable 100% oxygen inhalation can significantly improve the survival rate of the mice with zymosan-induced MODS. High mobility group box 1 (HMGB1) is liberated from the immune cells and acts as a late pro-inflammatory cytokine. It plays an important role in sepsis. More recently, attention has been paid to the relation of HMGB1 with sepsis. However, there is controversy over the relationship between HMGB1 and the severity of sepsis. We here constructed the animal model with lipopolysaccharide (LPS)-induced sepsis to observe the effect of 100% oxygen inhalation on the organs injury and mortality in septic animals, to analyze its relationship with serum HMGB1, and to clarify the role of HMGB1 in the effect of 100% oxygen inhalation on sepsis.
PartⅠThe effect of 100% oxygen inhalation on organ injury and mortality in septic mouse
Objective: To prove the protection of 100% oxygen inhalation on LPS-induced sepsis in mouse.
Methods: Fifty male Kunming mouse were randomly divided into Control and Hyperoxygen groups with n=25 in each group. The animals in Control group were treated with LPS intraperitoneally (dissolved by saline, 50mg·kg-1). The animals in Hyperoxygen group were treated with LPS intraperitoneally (dissolved by saline, 50mg·kg-1), then 2 hours of 100% oxygen inhalation was given at 4 hours and 12 hours after LPS administration respectively. Mortality at 24 hours after LPS injecton was detected in two groups, and five survival animals were killed, the heart, lung, liver and kidney were immediately removed. The specimens were fixed in 4% formaldehyde for 12-24 hours, embedded in paraffin, sectioned for 5μm in thickness, and stained with hematoxylin and eosin (H&E). Histological changes were examined and scored according to the pathologic scoring system.
Results: Mortality rate in Hyperoxygen group was 24%, lower than that in Control group with the mortality of 52%(P < 0.05). The pathologic scores of heart, lung, liver and kidney were lower in Hyperoxygen group than in Control group (P < 0.05). The results above mentioned suggest that reasonable 100% oxygen inhalation can protect the organs injury and decrease the mortality of LPS-induced sepsis in mouse.
PartⅡThe correlation of serum HMGB1 to the severity of sepsis in rat
Objective: To prove that serum HMGB1 levels is correlated to the severity of sepsis in rats.
Methods: Two hundred and fourty male SD rats were randomly divided into 4 groups with n=60 in each group: LPS-4 group: the animals were treated with LPS 4 mg/kg (i. p.); LPS-8 group: the animals were treated with LPS 8 mg/kg (i. p.); LPS-16 group: the animals were treated with LPS 16 mg/kg (i. p.); Control group: the animals were treated with the same volume of the vehicle (saline). Another 5 animals without administration with LPS or normal saline was used as a control for all the above 4 groups. Five ml of blood sample from 5 animals in each group was drawn from heart under anesthesia by intraperitoneally injected pentobarbital sodium (50 mg/kg) at 2, 4, 8, 16, 24, 32 and 48 hours after LPS or vehicle injection, centrifuged, and stored at -20℃. The level of serum HMGB1 was measured at the above time points. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), cardiac troponin I (cTnI), creatinine (CRE) and blood urea nitrogen (BUN) were measured at the above time points. After drawing blood sample at the above time points, the animals were killed, and the heart, lung, liver and kidney were immediately removed. The specimens were fixed in 4% formaldehyde for 12-24 hours, embedded in paraffin, sectioned for 5μm in thickness, and stained with hematoxylin and eosin (H&E). Histological changes were examined and scored according to the pathologic scoring system. The correlation of serum HMGB1 to the levels of biochemical indicators and histopathologic scores were analyzed.
Results:The level of HMGB1 has a positive, high correlation with the abnormal changes of serum cTnI (r = 0.693, P < 0.05), ALT (r = 0.374, P < 0.05), AST (r = 0.447, P <0.05), CRE (r = 0.503, P < 0.05) and BUN (r = 0.512, P < 0.05) as well as the pathologic scores of heart(rs = 0.755, P < 0.05), lung (rs = 0.758, P < 0.05), liver (rs = 0.789, P < 0.05) and kidney (rs = 0.796, P < 0.05).
PartⅢHMGB1 takes part in the mechanism of protection of 100% oxygen inhalation in septic mouse
Objective: To investigate whether HMGB1 takes part in the mechanism of protection of 100% oxygen inhalation against organs injury in septic mouse. Methods: Fifty male Kunming mouse were randomly divided into Control and Hyperoxygen groups with n=25 in each group. The animals in Control group were treated with LPS intraperitoneally (dissolved by saline, 50mg·kg-1). The animals in Hyperoxygen group were treated with LPS intraperitoneally (dissolved by saline, 50mg·kg-1), then 2 hours of 100% oxygen inhalation was given at 4 hours and 12 hours after LPS administration respectively. Five ml of blood sample from 5 animals in each group was drawn from heart under anesthesia by intraperitoneally injected pentobarbital sodium (50 mg/kg) at 24 hours after LPS administration. Serum HMGB1 levels were detected. Results: The level of serum HMGB1 was significantly higher in Control group than in Hyperoxygen group (P<0.05), suggesting that HMGB1 may take part in the mechanism of the protection of 100% oxygen inhalation against organs injury in septic mouse.
Conclusion
1. 100% oxygen inhalation can protect the organs injury and decrease the mortality in LPS-induced septic mouse.
2. The level of serum HMGB1 is highly correlated with the severity of sepsis in a rat model, and therefore could be a potential indicator for judging the severity of sepsis in patients.
3. HMGB1 may take part in the mechanism of the protection of 100% oxygen inhalation against organs injury in septic mouse.
实验一100%氧气吸入能减轻脓毒血症鼠脏器损伤并降低其死亡率
目的:观察100%O2吸入能否降低脓毒血症小鼠的死亡率,减轻其脏器损伤。方法:50只雄性昆明小鼠,被随机分为2组(每组25只):对照组和纯氧治疗(100%O2)组。两组动物均给予LPS(生理盐水溶解,50mg·kg-1,腹腔注射)。高氧治疗(100%O2)组在腹腔注射LPS后,分别于第4h和12h给予100%O2吸入,每次持续2h。各组动物在24h时观察死亡率,并从存活动物中随机处死5只,取心、肺、肝、肾组织,经4%多聚甲醛固定后,切片,HE染色,进行病理学观察和评分。
结果:对照组动物24小时死亡率(52%)显著高于100%O2干预组(其24小时死亡率为24%)(P<0.05);100%O2干预组动物心、肺、肝、肾病理损伤评分明显低于对照组(P<0.05)。表明100%O2吸入能够明显减轻脓毒血症动物脏器损伤并可显著降低其死亡率。
实验二血清HMGB1水平与脓毒血症鼠脏器损伤程度的相关性分析
目的:证实血浆HMGB1水平与脓毒血症鼠脏器损伤程度存在相关性。
方法:240只雄性SD大鼠随机分为4组(每组60只):脓毒血症一(LPS-4)组经腹腔注射LPS(生理盐水溶解,4mg·kg-1);脓毒血症二(LPS-8)组经腹腔注射LPS(8mg·kg-1);脓毒血症三(LPS-16)组经腹腔注射LPS(16mg·kg-1);盐水对照(control)组经腹腔注射相同容积的生理盐水。四组动物分别于注射后2h、4h、8h、16h、24h、32h和48h随机取5只,戊巴比妥钠(2%,50mg·kg-1)腹腔注射麻醉后,经心脏取血5ml,分离血清,并取心、肺、肝、肾脏器组织,-20℃保存。另外5只雄性SD大鼠不做任何处理,处理同上,作为注射前的对照(结果中的0h)。血清采用ELASA和全自动生化分析仪检测HMGB1的血清水平和cTnI、ALT、AST、CRE、BUN的水平,脏器标本经4%多聚甲醛固定后,切片,HE染色,进行病理学观察和评分。合并三个脓毒血症组数据,分析其HMGB1血清水平与脏器病理损伤和血清生化指标之间的相关性。
结果:血清HMGB1水平与大鼠脓毒血症脏器病理损伤评分及血清生化指标之间存在明显相关性:心(rs=0.755, P<0.05),肺(rs=0.758, P<0.05),肝(rs=0.789, P<0.05),肾(rs=0.796, P<0.05);ALT(r=0.374, P<0.05), AST (r=0.447, P<0.05), CRE (r=0.503, P<0.05), BUN (r=0.512, P<0.05), cTnI (r=0.693, P<0.05)。
实验三HMGB1参与100%氧气吸入对脓毒血症动物脏器的保护作用机制
目的:研究HMGB1是否参与了100%O2吸入对脓毒血症小鼠脏器的保护作用机制。
方法:50只雄性昆明小鼠,被随机分为2组(每组25只):对照组和治疗(100%O2)组。两组动物均给予LPS(生理盐水溶解,50mg·kg-1,腹腔注射)。治疗(100%O2)组在腹腔注射LPS后,分别于第4h和12h给予100% O2吸入,每次持续2h。各组动物在24h时从存活动物中随机处死5只,心脏取血1ml,分离血清,保存于-80℃,采用ELASA检测HMGB1血清浓度。
结果:两组组动物24h时HMGB1血清浓度存在明显差异(P<0.05),表明HMGB1可能参与了100%O2吸入对脓毒血症小鼠脏器的保护作用机制。
结论
1、100%O2吸入能明显减轻脓毒血症动物脏器损伤,降低其死亡率。
2、血清HMGB1水平与脓毒血症动物脏器损伤程度存在相关性,有可能作为脓毒血症脏器损伤程度的判断指标之一。
3、HMGB1可能参与了100%O2吸入对脓毒血症小鼠脏器的保护作用机制。
Sepsis, the SIRS (systemic inflammatory response syndrome) induced by severe infection, is a major cause of death in the ICU patients. Despite great advances have been made in the mechanism and developing the measures for improving the treatment outcome, the mortality for sepsis remains approximately 20-50% [1]. Because its mechanism is not clear, there is lack of accurate or available method for assessing the patients with sepsis and there is no effective treating measures up to now. When the body has hypoxia or will have hypoxia, oxygen inhalation can increase the oxygen concentration of inspired gas, and then raise the partial pressure of oxygen in the alveolus, elevate the blood oxygen level of the arterial blood by facilitating diffusion as well as improve the oxygen supply in the tissues. We call it oxygen therapy. Hyperoxia therapy is the oxygen therapy in which the inspired concentration of oxygen is higher than 21%, and it is widely used clinically. As is known, hyperoxia therapy may induce oxygen toxicity. However, recent studies found that early 100% oxygen therapy can significantly protect the organ function and increase the survival rate in various kinds of animal model with shock [2-4]. It is reported that hyperoxia therapy with proper conditions can decrease the inflammation and infection[5, 6]. Our team also find that reasonable 100% oxygen inhalation can significantly improve the survival rate of the mice with zymosan-induced MODS. High mobility group box 1 (HMGB1) is liberated from the immune cells and acts as a late pro-inflammatory cytokine. It plays an important role in sepsis. More recently, attention has been paid to the relation of HMGB1 with sepsis. However, there is controversy over the relationship between HMGB1 and the severity of sepsis. We here constructed the animal model with lipopolysaccharide (LPS)-induced sepsis to observe the effect of 100% oxygen inhalation on the organs injury and mortality in septic animals, to analyze its relationship with serum HMGB1, and to clarify the role of HMGB1 in the effect of 100% oxygen inhalation on sepsis.
PartⅠThe effect of 100% oxygen inhalation on organ injury and mortality in septic mouse
Objective: To prove the protection of 100% oxygen inhalation on LPS-induced sepsis in mouse.
Methods: Fifty male Kunming mouse were randomly divided into Control and Hyperoxygen groups with n=25 in each group. The animals in Control group were treated with LPS intraperitoneally (dissolved by saline, 50mg·kg-1). The animals in Hyperoxygen group were treated with LPS intraperitoneally (dissolved by saline, 50mg·kg-1), then 2 hours of 100% oxygen inhalation was given at 4 hours and 12 hours after LPS administration respectively. Mortality at 24 hours after LPS injecton was detected in two groups, and five survival animals were killed, the heart, lung, liver and kidney were immediately removed. The specimens were fixed in 4% formaldehyde for 12-24 hours, embedded in paraffin, sectioned for 5μm in thickness, and stained with hematoxylin and eosin (H&E). Histological changes were examined and scored according to the pathologic scoring system.
Results: Mortality rate in Hyperoxygen group was 24%, lower than that in Control group with the mortality of 52%(P < 0.05). The pathologic scores of heart, lung, liver and kidney were lower in Hyperoxygen group than in Control group (P < 0.05). The results above mentioned suggest that reasonable 100% oxygen inhalation can protect the organs injury and decrease the mortality of LPS-induced sepsis in mouse.
PartⅡThe correlation of serum HMGB1 to the severity of sepsis in rat
Objective: To prove that serum HMGB1 levels is correlated to the severity of sepsis in rats.
Methods: Two hundred and fourty male SD rats were randomly divided into 4 groups with n=60 in each group: LPS-4 group: the animals were treated with LPS 4 mg/kg (i. p.); LPS-8 group: the animals were treated with LPS 8 mg/kg (i. p.); LPS-16 group: the animals were treated with LPS 16 mg/kg (i. p.); Control group: the animals were treated with the same volume of the vehicle (saline). Another 5 animals without administration with LPS or normal saline was used as a control for all the above 4 groups. Five ml of blood sample from 5 animals in each group was drawn from heart under anesthesia by intraperitoneally injected pentobarbital sodium (50 mg/kg) at 2, 4, 8, 16, 24, 32 and 48 hours after LPS or vehicle injection, centrifuged, and stored at -20℃. The level of serum HMGB1 was measured at the above time points. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), cardiac troponin I (cTnI), creatinine (CRE) and blood urea nitrogen (BUN) were measured at the above time points. After drawing blood sample at the above time points, the animals were killed, and the heart, lung, liver and kidney were immediately removed. The specimens were fixed in 4% formaldehyde for 12-24 hours, embedded in paraffin, sectioned for 5μm in thickness, and stained with hematoxylin and eosin (H&E). Histological changes were examined and scored according to the pathologic scoring system. The correlation of serum HMGB1 to the levels of biochemical indicators and histopathologic scores were analyzed.
Results:The level of HMGB1 has a positive, high correlation with the abnormal changes of serum cTnI (r = 0.693, P < 0.05), ALT (r = 0.374, P < 0.05), AST (r = 0.447, P <0.05), CRE (r = 0.503, P < 0.05) and BUN (r = 0.512, P < 0.05) as well as the pathologic scores of heart(rs = 0.755, P < 0.05), lung (rs = 0.758, P < 0.05), liver (rs = 0.789, P < 0.05) and kidney (rs = 0.796, P < 0.05).
PartⅢHMGB1 takes part in the mechanism of protection of 100% oxygen inhalation in septic mouse
Objective: To investigate whether HMGB1 takes part in the mechanism of protection of 100% oxygen inhalation against organs injury in septic mouse. Methods: Fifty male Kunming mouse were randomly divided into Control and Hyperoxygen groups with n=25 in each group. The animals in Control group were treated with LPS intraperitoneally (dissolved by saline, 50mg·kg-1). The animals in Hyperoxygen group were treated with LPS intraperitoneally (dissolved by saline, 50mg·kg-1), then 2 hours of 100% oxygen inhalation was given at 4 hours and 12 hours after LPS administration respectively. Five ml of blood sample from 5 animals in each group was drawn from heart under anesthesia by intraperitoneally injected pentobarbital sodium (50 mg/kg) at 24 hours after LPS administration. Serum HMGB1 levels were detected. Results: The level of serum HMGB1 was significantly higher in Control group than in Hyperoxygen group (P<0.05), suggesting that HMGB1 may take part in the mechanism of the protection of 100% oxygen inhalation against organs injury in septic mouse.
Conclusion
1. 100% oxygen inhalation can protect the organs injury and decrease the mortality in LPS-induced septic mouse.
2. The level of serum HMGB1 is highly correlated with the severity of sepsis in a rat model, and therefore could be a potential indicator for judging the severity of sepsis in patients.
3. HMGB1 may take part in the mechanism of the protection of 100% oxygen inhalation against organs injury in septic mouse.
引文
[1] B. Poulton. Advances in the management of sepsis: the randomised controlled trials behind the Surviving Sepsis Campaign recommendations. International Journal of Antimicrobial Agents, 2006, 27: 97–101
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[3] Meier J, Kemming GI, Kisch-Wedel H, et al. Hyperoxic ventilation reduces six-hour mortality after partial fluid resuscitation from hemorrhagic shock. Shock, 2004, 22(3):240-247
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