摘要
第一部分大鼠肺源性内毒素肺损伤模型的建立
目的观察经气管滴入不同剂量内毒素对大鼠肺炎性改变的影响,探讨肺源性内毒素诱发肺损伤的病理生理变化,为后续研究提供依据。
方法清洁级成年雄性SD大鼠36只,随机分为6组:对照组(C组,n=6)、50μg/kg内毒素组(L1组,n=6)、100μg/kg内毒素组(L2组,n=6)、200μg/kg内毒素组(L3组,n=6)、1000μg/kg内毒素组(L4组,n=6)和5000μg/kg内毒素组(L5组,n=6)。内毒素经由气管滴入,呼吸空气。实验3小时结束,放血处死大鼠。测定大鼠肺损伤评分、肺组织湿/干重比(W/D)、支气管灌洗液(BALF)白细胞计数、血管透性系数。酶联免疫分析法(ELISA法)测灌洗液里肿瘤坏死因子-α(TNF-α)及巨噬细胞炎性蛋白-2(MIP-2)浓度。
结果肺损伤评分、W/D和血管透性系数:与C组比较,L1、L2和L3组变化无统计学意义, L4和L5组各项指标均升高(P<0.05或P<0.01);与L4组比,L5组各项指标升高均有统计学意义(P<0.05或P<0.01)。肺灌洗液里WBC:与C组比较,L1和L2组变化无统计学意义,L3组升高(P<0.05),L4和L5组显著升高(P<0.01)。肺灌洗液里TNF-α浓度:R组没检测到,L1、L2、L3组测到少量,L4和L5组比L1增多有统计学意义。灌洗液里的MIP-2浓度:C、L1、L2、L3组量很少,L4组升高,L5组明显升高。
结论经气管滴入50-100μg/kg LPS不会导致大鼠肺结构损伤和炎性细胞浸润,但能引起TNF-α轻度升高;经气管滴入200μg/kg LPS不导致大鼠肺结构损伤,但有轻度炎性细胞浸润和TNF-α轻度升高;经气管滴入1000和5000μg/kg LPS则导致大鼠肺结构损伤和炎性细胞浸润,伴有TNF-α和MIP-2升高,PO2降低。
第二部分不同通气方式对大鼠肺及肺内毒素受体CD14的影响
目的观察不同的机械通气方式对大鼠肺及肺内毒素受体CD14的影响。
方法24只成年雄性SD大鼠采用3%戊巴比妥35-40mg/kg腹腔注射麻醉后,行气管切开并置入气管导管固定,将之随机分为4组(n=6):自主呼吸组(R组);机械通气组(M组),潮气量(VT)=12ml/kg,呼气末正压(PEEP)=0mmHg;保护性机械通气组(P组),潮气量VT=6ml/kg,呼气末正压PEEP=8mmHg;大潮气量机械通气组(N组),VT=40ml/kg,PEEP=0 mmHg。吸呼比1:1,根据PETCO2和血气结果调整呼吸频率(RR)。右颈动脉置管测血压并取血测血气,左股静脉置管输液给药。分别于机械通气前(基础值)、机械通气60、120、180min行动脉血气分析,实验3小时结束,放血处死大鼠。测定大鼠肺损伤评分、肺组织湿/干重比(W/D)、支气管灌洗液(BALF)炎性细胞计数、血管透性系数(LPI)。酶联免疫分析法(ELISA)法测BALF里肿瘤坏死因子α(TNF-α),及巨噬细胞炎性蛋白2(MIP-2)浓度。RT-PCR测肺组织内毒素受体CD14的表达,免疫组化法测肺组织的CD14表达。
结果肺损伤评分:R组和P组无变化,M组有轻度升高,N组比M组明显升高( P<0.01)。肺W/D:与R组比较,P组和M组无统计学差异; N组升高(p<0.01)。LPI:与R组比较,P组和M组差别无统计学意义;N组明显升高(P<0.01)。BALF中WBC:与P组无显著变化,M组升高(P<0.05),N组显著升高(P<0.001)。TNF-α在四组都没测到。MIP-2,与R组比较,P组差别无统计学意义, M组升高(P<0.05),N组明显升高(P<0.01)。肺组织CD14基因和蛋白表达:与R组比较,P组差别无统计学意义;M组蛋白表达差别无显著意义,但基因表达升高;N组二者表达都显著升高(P<0.01)。
结论常规机械通气导致大鼠肺部发生轻度损伤,并可使肺部CD14基因表达上调,但是肺部CD14蛋白表达无明显改变;大潮气量机械通气导致大鼠肺部损伤,使肺部CD14表达明显上调。保护性机械通气可使大鼠肺部避免上述改变的发生。
第三部分不同潮气量机械通气对大鼠肺泡巨噬细胞的影响
目的观察不同潮气量的机械通气对大鼠肺泡巨噬细胞和肺泡巨噬细胞CD14的影响。
方法清洁级成年雄性SD大鼠18只,随机分为3组:自主呼吸组(C组,n=6),保护性机械通气组(P组,n=6),潮气量(VT)=6ml/kg,呼气末正压(PEEP)=8mmHg;和大潮气量机械通气组(N组,n=6),VT=40ml/kg,PEEP=0 mmHg。吸呼比1:1,根据PETCO2和血气结果调整呼吸频率(RR)。右颈动脉置管测血压并取血测血气,左股静脉置管输液给药。分别于机械通气前(基础值)、机械通气60、120、180min行动脉血气分析,实验3小时结束,放血处死大鼠。测定大鼠肺损伤评分、肺组织湿/干重比(W/D)、支气管灌洗液(BALF)炎性细胞和肺泡巨噬细胞(AM)计数、蛋白透性系数(LPI)。酶联免疫分析法(ELISA法)测AM培养液里单核细胞趋化蛋白(MCP-1)及巨噬细胞炎性蛋白-2(MIP-2)浓度。RT-PCR测AM内毒素受体CD14的表达,免疫组化法测AM上CD14表达。
结果肺损伤评分、W/D、BALF里WBC和AM、LPI、CD14基因和蛋白表达及培养液里MCP-1和MIP-2浓度:与C组比较,P组无显著改变,N组升高有显著性差异(P<0.01)。
结论大潮气量机械通气大潮气量机械通气激活了肺泡巨噬细胞,导致巨噬细胞募集到肺泡并使肺泡巨噬细胞表达CD14上调;保护性机械通气对肺泡巨噬细胞无明显影响。
第四部分肺源性内毒素对大鼠机械通气肺损伤的影响及机制
目的观察经气管滴入LPS对机械通气大鼠肺损伤的影响并探讨其可能机制。
方法成年雄性SD大鼠24只,随机分为自然呼吸组(C组,n=6)、内毒素加自然呼吸组(C1组,n=6)、机械通气组(M组,n=6)和内毒素加机械通气组(M1组,n=6)。C1组和M1组经气管滴入100μg/kg LPS,M组和M1组接小动物呼吸机行机械通气。呼吸参数设定:潮气量(VT)=20ml/kg,PEEP=0mmHg,吸/呼为1:1,调节呼吸频率(RR)使PETCO2维持在35-45mmHg。C组和C1组保持自主呼吸。四组都吸入空气。监测动物血压、心率、心电图和PET CO2。实验开始、60min、120min和180min测血气。整个实验严格执行无菌操作。实验3h结束,放血处死大鼠。测定大鼠肺损伤评分、肺组织湿/干重比(W/D)、支气管灌洗液(BALF)炎性细胞数和肺泡巨噬细胞数(AM)、肺蛋白透性系数。酶联免疫分析法(ELISA法)测BALF里肿瘤坏死因子-α(TNF-α)及巨噬细胞炎性蛋白-2(MIP-2)浓度。RT-PCR法测肺组织内毒素受体CD14 mRNA的表达,免疫组化法测BALF里巨噬细胞的CD14表达。
结果肺W/D和肺蛋白透性系数:与C组比, C1组和M组无统计学意义(P>0.05),M1组升高(P<0.01);与M组比,M1组升高(P<0.01)。BALF中WBC和AM、病理学积分和MIP-2:与C组比, C1组无明显改变,M组和M1组升高(P<0.01);与M组比,M1组升高(P<0.01)。TNF-α:C组和M组未检测到, C1组和M1组升高,M1组比C1组升高更显著(P<0.01)。肺组织CD14基因表达和BALF里巨噬细胞的CD14:M组比C组升高(P<0.01)。
结论微量肺源性内毒素能加重机械通气肺损伤。微量肺源性内毒素加重机械通气肺损伤的部分机制可能是由于机械通气导致肺泡巨噬细胞增加和肺内毒素受体CD14表达上调,增加了肺对内毒素的敏感性所致。
Party I The model of pulmonary source lipopolysaccharide induced lung injury in rats in vivo
Objective To observe the effects of various dose lipopolysaccharide-instilled lungs on lung in rats in vivo and to investigate the pathophysiological changes and the mechanisms of the injurious lungs induced by pulmonary source lipopolysaccharide.
Method 36 male, adult SD rats were randomly divided into 6 groups:control group(groupC,n=6);intratracheal instillation of 50 ug/kg body weight LPS group(group L1,n=6); intratracheal instillation of 100μg/kg body weight LPS group( group L2, n=6); intratracheal instillation of 200μg/kg body weight LPS group group(group L3,n=6); intratracheal instillation of 1000μg/kg body weight LPS group ( group L4,n=6).intratracheal instillation of 5000μg/kg body weight LPS group(group L5,n=6). The spontaneously breathing was keeped and the air was inhaled in the 6 groups’rats. Three hours after experiment, The rats were killed by exsanguination via arteria carotis interna. Then the rats’pulmonary pathomorphology scores,pulmonary tissue wet/dry weight ratio, white blood cell(WBC) count in bronchial lavage fluid(BALF), lung permeability index (LPI)were determined. The tumor necrosis factor-α(TNF-α)and macrophage inflammatory protein -2(MIP-2) concentrations in BALF were detected with a enzyme-linked immuno assay(ELISA method).
Results pulmonary pathomorphology scores ,W/D and LPI: there was no significant difference in groupL1 , group L2and group L3 as compared to group C,but the elevation of groupL4 and groupL5 was significantly differen(tP<0.05or P<0.01);the elevation of group L5 had significant difference vs. group L4(P<0.05or P<0.01). BALF WBC: there was no significant difference in groupL1 and group L2 as compared to group C,but the group L3 was increased(P<0.05),and the group L4and group L5 were significant increased(P<0.01). TNF-αwas not detected in group C, there were a small quantity TNF-αin the groupL1 , group L2and group L3, but it was elevated in group L4 and group L5 vs. group L1(P<0.01). MIP-2: there was no significant difference in groupL1 , group L2and group L3 as compared to group C, but the elevation of groupL4 and groupL5 was significantly differen(tP<0.05or P<0.01);the elevation of group L5 had significant difference vs. group L4(P<0.05).
Conclusions 50-100μg/kg body weight LPS instilled lung don't induce lung structural injury and inflammatory cell infiltrate, but there are some slight elevation of TNF-αconcentration . 200μg/kg body weight LPS instilled lung don't induce lung structural injury, but it induce a slight inflammatory cell infiltrate and elevation of TNF-αconcentration. 1000 -5000μg/kg body weight LPS instilled lung induce lung structural injury, inflammatory cell infiltrate, elevation of TNF-αconcentration, and decrease of PO2.
Party II Effect of various ventilation manier on lung tissue and the expression of CD14 receptor in rats in vivo
Objective To investigate the effects of mechanical ventilation (MV)on rat’s lung and the expression changes of lung endotoxin receptor CD14.
Methods 24 male Sprague-Dawley rats weighing 330-360g were randomly divided into 4 groups (n=6):group R received no mechanical ventilation, group P received small MV (VT=6ml/kg, PEEP=8mmHg) , group M received conventional MV (VT=12ml/kg, PEEP=0mmHg) , and group N received large tidal volume mechanical ventilation(VT =40ml/kg, PEEP=0mmHg). The animals were anesthetized with intraperitoneal pentobarbital 35-40mg.kg-1, tracheotomized and mechanically ventilated (I:E=1:1,FiO2=21%). The respiratory rate (RR) of MV was adjusted to maintain the end-tidal carbon dioxide in the rang of 35-45mm Hg throughout the procedure. Right carotid artery and left femoral vein were cannulated for BP monitoring and fluid and drug administration.. The experiment was culminated in 3 hours, then the rats were killed by by exsanguination via arteria carotis interna. Morphologic change scores of the rats’lungs, wet/dry weight ratio of lung tissue(W/D),bronchial lavage fluid(BALF)inflammtory cell population, and lung permeability index(LPI) were evaluated. The concentration of TNF-αand MIP-2 in the plasma were determined by enzyme immunoassay method(ELISA). The expressions of lung tissue endotoxin receptor CD14 were detected by RT-PCR, macrophage CD14 in BALF was also detected by immunohistochemistry.
Results pulmonary pathomorphology scores:there were no alteration in R group and P group,but it were slightly increased in M group,there was significantly elevated in N group as compare to M group(P<0.01). pulmonary tissue wet/dry weight ratio(W/D):Compare with R group,There was no statistically significant difference in P group and M group; the elevation in N group(,P<0.05),LPI: Compare with R group, There was no statistically significant difference in P group and M group; the obviously elevation in N group (P<0.01).WBC in BALF:Compare with R group,there was no change in P group, the elevation in M group ( P<0.05 ) ,there was significantly elevated in N group (P<0.01).TNF-αhad no manifest variation in 4 groups.MIP-2:compare with R grroup, There was no statistically significant difference in P group, the elevation in M group, there was significantly elevated in N group(P<0.01)。The expressions of macrophage CD14 protein in BALF and lung tissue CD14 mRNA were fundamentally coincident in R group and P group; the expressions of CD14 mRNA were elevated, but the expressions of CD14 protein were no change in M group; the expressions of CD14 in N group manifestly elevated (P<0.01).
Conclusions conventional MV induces minor injury in rat’s lung and can up regulate the expression of CD14 mRNA in the lung, but no up regulate the expression of CD14 protein;large tidal volume MV induces injury of rat’s lung and evidently up regulates CD14 expression in the lung. Protective MV can avoid the above mentioned variations in rat’s lung.
Party III Effect of mechanical ventilation with different tidal volumes on alveolar macrophage and CD14 receptor expression in alveolar macrophage in rats
Objective To investigate the effect of mechanical ventilation with different tidal volumes on alveolar macrophage and the expression changes of alveolar macrophage endotoxin receptor CD14 in rats.
Methods 18 male, adult SD rats weighing 230-240g were randomly divided into 3 groups (n=6 each): groupC (control) received no mechanical ventilation; group P received mechanical ventilation with small tidal volume (VT =8 ml·kg-1,PEEP=8mmHg) and group N received mechanical ventilation with large tidal volume (VT =40 ml·kg-1,PEEP=0 ). The animals were anesthetized with intraperitoneal 3% pentobarbital 35-40 mg·kg-1 , tracheostomized and mechanically ventilated (I:E=1:1, FiO2 =21%). The respiratory rate (RR) was adjusted to maintain the PET CO2 at 35-45 mmHg. The rats were killed by exsanguination after 3h mechanical ventilation. Morphologic change scores of the rats’lungs, wet/dry weight ratio of lung tissue(W/D),and lung permeability index(LPI) were evaluated. The left lung was lavaged, the number of inflammatory cells and alveolar macrophage in broncho-alveolar lavage fluid (BALF) were counted in light microscope, and the AM separated from BALF was cultivanted in the incubator for 2h. Then the expression of CD14 protein on the AM collected from BALF was determined by immuno-histochemistry. The CD14 receptor mRNA expression in AM was determined by RT-PCR.The concentration of MIP-2 and MCP-1 in culture fluid were determined by enzyme immunoassay method(ELISA).
Results The pathological scores of lung, W/D lung weight ratio, the number of inflammatory cells and AM in BALF, the expression of CD14 receptor mRNA in AM and CD14 receptor protein on macrophage were significantly higher in large tidal volume group than in control group while there was no significant difference between small tidal volume and control group.
Conclusion Mechanical ventilation with large tidal volume for 3h induces lung injury and up-regulation of CD14 receptor expression on alveolar macrophage. Protective MV can avoid the above mentioned variations .
Party IV Effects and mechanisms of pulmonary source lipopolysaccharide on ventilator-induced lung injury
Objective To investigate the effects and mechanisms of lipopolysaccharide-instilled lungs on ventilator-induced lung injury.
Method 24 male, adult SD rats were randomly divided into 4 groups:a spontaneously breathing group(groupC,n=6);intratracheal instillation of LPS+ spontaneously breathing group(group C1,n=6); mechanical ventilation group( group M, n=6); intratracheal instillation of LPS +ventilation group(group M1,n=6); group M and M1 group: Vt=20ml/kg, PEEP=0mmHg; group C1 and group M1: 100μg/kg of LPS was dropped in the trachea. The air was inhaled in the 4 groups’rats. Three hours after experiment, The rats were killed by exsanguination via arteria carotis interna. Then the rats’pulmonary pathomorphology scores,pulmonary tissue wet/dry weight ratio, bronchial lavage fluid(BALF)white blood cell(WBC) count and AM count, lung permeability index, LPI were determined. The tumor necrosis factor-α(TNF-α)and macrophage inflammatory protein -2(MIP-2) concentrations in BALF were detected with a enzyme-linked immuno assay(ELISA method).Lung tissue endotoxin receptor CD14 mRNA expression was determined with RT-PCR, BALF macrophage CD14 expression was determined with immunohistochemistry.
Results W/D and LPI: there was no significant difference in group C1 and group M as compared to group C,but the elevation of group M1 was significantly different(P<0.01);the elevation of group M1 had significant difference vs. group M(P<0.01). Pulmonary pathomorphology score, BALF WBC,AM, and MIP-2: there was no significant difference between group C and group C1,the above values of group M and group C1 significantly increased than those of group(P<0.01);the above values of group M1 significantly increased than those of group M(P<0.01).TNF-αwas not detected in C group and M group,but it was elevated in group C1 and group M1,the increase in M1 group was more predominant than that of C1 group(P<0.01).Pulmonary tissue endotoxin receptor CD14 mRNA and BALF macrophage CD14 expressions were all elevated(P<0.01)in group M as compared to group C.
Conclusions Microamount pulmonary source endotoxin can aggravate ventilator induced lung injury ,the possible cause is that mechanical ventilation of a large Vt sensitizes the lung to LPS stimulation, a phenomenon that may occur via the up regulation of CD14 and the increase of AM.
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15.薛昀,吴新民,张生锁,等.内毒素预处理对大鼠急性肺损伤的影响.中国危重病急救医学, 2004；16(6)：361-363.
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