ACE2及Ang1-7对LPS诱导的大鼠ALI的影响及机制
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摘要
目的
观察血管紧张素转化酶2 ( ACE2 )、血管紧张素1-7 ( Ang 1-7 )对血管紧张素Ⅱ( AngⅡ)致体外大鼠肺微血管内皮细胞( PMEVC )单层通透性增高的影响以及对脂多糖( LPS)致急性肺损伤( ALI)大鼠肺组织的作用;研究ACE2对LPS性ALI大鼠PMEVC及肺组织保护作用的机制;了解Ang 1-7在ACE2对LPS性ALI大鼠PMEVC及肺组织影响机制中的作用。
方法
体外部分:体外成功分离、培养大鼠PMVEC ,待行成细胞单层后进行分组,分别予LPS ( 10μg / ml )、AngⅡ( 10-7 mmol / L )刺激细胞单层90 min;以及予ACE2抑制剂MLN-4760 ( 10-7 mmol / L)或Ang 1-7受体激动剂AVE0991 ( 10-6 mmol / L )预干预30 min,再予AngⅡ( 10-7 mmol / L )孵育90 min,用针头式滤器检测各组PMVEC单层通透性变化。
体内部分:予大鼠尾静脉注射LPS复制建立ALI模型,用LPS ( 5 mg / kg )单独作用6 h,以及先予LPS刺激30 min,再分别予①MLN-4760 ( 10 mg / kg )、②MLN-4760 ( 10 mg / kg ) + Ang 1-7受体阻滞剂( A779,10μg / kg )、③AVE0991 ( 1 mg / kg )干预共6 h,观察肺组织湿/干重比及病理学变化。
结果
1.体外成功分离培养大鼠PMVEC;
2. LPS、AngⅡ均可增加大鼠PMVEC单层通透系数( Kf );
3. ACE2抑制剂有加剧AngⅡ致大鼠PMVEC单层Kf增高作用;
4. Ang 1-7受体激动剂可抑制AngⅡ致单层Kf增高;
5.建立LPS致ALI大鼠模型;
6.在LPS诱导的大鼠ALI体内,ACE2抑制剂单独或协同Ang 1-7受体拮抗剂,有加剧LPS所致肺组织湿/干重比(W / D)增高和ALI病理改变的作用;
7. Ang 1-7受体激动剂可抑制LPS诱导的W / D增高并改善其病理损伤改变。
结论
1. LPS、AngⅡ均对体外培养的大鼠PMEVC单层通透性具损伤作用;
2. LPS诱导大鼠ALI,表现为肺水肿及炎症细胞浸润、透明膜形成等病理改变;
3. Ang 1-7对LPS致大鼠ALI有保护作用;
4. ACE2可通过促进Ang 1-7的生成,对大鼠LPS性ALI发挥保护作用。
Objective
To observe the effects of ACE2 and Ang 1-7 on cultured rat PMVEC stimulated by AngⅡand lung tissue in LPS-induced ALI, and to investigate the possible mechanism of ACE 2 on PMVEC and lung tissue in rat ALI induced by LPS. Meanwhile, to study the role of Ang 1-7 in the protective mechanism of ACE2 in LPS-induced rat ALI.
Methods
In vitro, rat PMVEC were isolated and cultured and incubated with LPS ( 10μg / ml ) or AngⅡ( 10-7 mmol / L ) for 90 min; PMVEC monolayer were pre-exposured to ACE2 inhibitor ( 10-7 mmol / L ) and Ang 1-7 receptor agonist ( 10-6 mmol / L ) for 30 min respectively, after then, the cells were incubated with AngⅡ( 10-7 mmol / L ) for 90 min. Microfiltrator was used to measure the changes of PMVEC monolayer permeability coefficient.
In vivo,Wistar rats were intravenous administration of LPS ( 5 mg / kg ) for 30 min, after then treated with①ACE2 inhibitor ( 10 mg / kg ),②ACE2 inhibitor (10 mg / kg ) + Ang 1-7 receptor antagonist ( 10μg / kg ), and③Ang 1-7 receptor agonist ( 1 mg / kg ) for 5.5 h respectively. Lung wet / dry weight ratio was measured, and the pathologic changes of lung tissue were observed microscopically.
Results
1. Rat PMEVC was isolated and cultured in vitro successfully.
2. Both LPS and AngⅡincreased the permeability of PMVEC monolayer significantly.
3. In vitro, ACE2 inhibitor could enhance the AngⅡinduced PMVEC monolayer Kf increase, on the contrary, Ang 1-7 receptor agonist inhibited it.
4. The model of acute lung injury was made by LPS injection.
5. Both ACE2 inhibitor and/or Ang 1-7 receptor antagonist could enhance the increased wet / dry weight ratio of lung tissue induced by LPS and exacerbate the pathologic changes.
6. Ang 1-7 receptor agonist inhibited the lung edema and improved the pathologic changes of LPS-induced ALI significantly.
Conclusions
1. Both LPS and AngⅡcould induced lung endothelial permeability increase significantly in cultured PMVEC.
2. The lung wet/dry weight ratio increased markedly by LPS challenge. The lung tissue showed the pathologic changes of ALI induced by LPS in rat.
3. Ang 1-7 relieved ALI in LPS-induced rat.
4. ACE2 showed a protective effect on LPS-induced ALI through probably the positive regulation of Ang 1-7 levels.
观察血管紧张素转化酶2 ( ACE2 )、血管紧张素1-7 ( Ang 1-7 )对血管紧张素Ⅱ( AngⅡ)致体外大鼠肺微血管内皮细胞( PMEVC )单层通透性增高的影响以及对脂多糖( LPS)致急性肺损伤( ALI)大鼠肺组织的作用;研究ACE2对LPS性ALI大鼠PMEVC及肺组织保护作用的机制;了解Ang 1-7在ACE2对LPS性ALI大鼠PMEVC及肺组织影响机制中的作用。
方法
体外部分:体外成功分离、培养大鼠PMVEC ,待行成细胞单层后进行分组,分别予LPS ( 10μg / ml )、AngⅡ( 10-7 mmol / L )刺激细胞单层90 min;以及予ACE2抑制剂MLN-4760 ( 10-7 mmol / L)或Ang 1-7受体激动剂AVE0991 ( 10-6 mmol / L )预干预30 min,再予AngⅡ( 10-7 mmol / L )孵育90 min,用针头式滤器检测各组PMVEC单层通透性变化。
体内部分:予大鼠尾静脉注射LPS复制建立ALI模型,用LPS ( 5 mg / kg )单独作用6 h,以及先予LPS刺激30 min,再分别予①MLN-4760 ( 10 mg / kg )、②MLN-4760 ( 10 mg / kg ) + Ang 1-7受体阻滞剂( A779,10μg / kg )、③AVE0991 ( 1 mg / kg )干预共6 h,观察肺组织湿/干重比及病理学变化。
结果
1.体外成功分离培养大鼠PMVEC;
2. LPS、AngⅡ均可增加大鼠PMVEC单层通透系数( Kf );
3. ACE2抑制剂有加剧AngⅡ致大鼠PMVEC单层Kf增高作用;
4. Ang 1-7受体激动剂可抑制AngⅡ致单层Kf增高;
5.建立LPS致ALI大鼠模型;
6.在LPS诱导的大鼠ALI体内,ACE2抑制剂单独或协同Ang 1-7受体拮抗剂,有加剧LPS所致肺组织湿/干重比(W / D)增高和ALI病理改变的作用;
7. Ang 1-7受体激动剂可抑制LPS诱导的W / D增高并改善其病理损伤改变。
结论
1. LPS、AngⅡ均对体外培养的大鼠PMEVC单层通透性具损伤作用;
2. LPS诱导大鼠ALI,表现为肺水肿及炎症细胞浸润、透明膜形成等病理改变;
3. Ang 1-7对LPS致大鼠ALI有保护作用;
4. ACE2可通过促进Ang 1-7的生成,对大鼠LPS性ALI发挥保护作用。
Objective
To observe the effects of ACE2 and Ang 1-7 on cultured rat PMVEC stimulated by AngⅡand lung tissue in LPS-induced ALI, and to investigate the possible mechanism of ACE 2 on PMVEC and lung tissue in rat ALI induced by LPS. Meanwhile, to study the role of Ang 1-7 in the protective mechanism of ACE2 in LPS-induced rat ALI.
Methods
In vitro, rat PMVEC were isolated and cultured and incubated with LPS ( 10μg / ml ) or AngⅡ( 10-7 mmol / L ) for 90 min; PMVEC monolayer were pre-exposured to ACE2 inhibitor ( 10-7 mmol / L ) and Ang 1-7 receptor agonist ( 10-6 mmol / L ) for 30 min respectively, after then, the cells were incubated with AngⅡ( 10-7 mmol / L ) for 90 min. Microfiltrator was used to measure the changes of PMVEC monolayer permeability coefficient.
In vivo,Wistar rats were intravenous administration of LPS ( 5 mg / kg ) for 30 min, after then treated with①ACE2 inhibitor ( 10 mg / kg ),②ACE2 inhibitor (10 mg / kg ) + Ang 1-7 receptor antagonist ( 10μg / kg ), and③Ang 1-7 receptor agonist ( 1 mg / kg ) for 5.5 h respectively. Lung wet / dry weight ratio was measured, and the pathologic changes of lung tissue were observed microscopically.
Results
1. Rat PMEVC was isolated and cultured in vitro successfully.
2. Both LPS and AngⅡincreased the permeability of PMVEC monolayer significantly.
3. In vitro, ACE2 inhibitor could enhance the AngⅡinduced PMVEC monolayer Kf increase, on the contrary, Ang 1-7 receptor agonist inhibited it.
4. The model of acute lung injury was made by LPS injection.
5. Both ACE2 inhibitor and/or Ang 1-7 receptor antagonist could enhance the increased wet / dry weight ratio of lung tissue induced by LPS and exacerbate the pathologic changes.
6. Ang 1-7 receptor agonist inhibited the lung edema and improved the pathologic changes of LPS-induced ALI significantly.
Conclusions
1. Both LPS and AngⅡcould induced lung endothelial permeability increase significantly in cultured PMVEC.
2. The lung wet/dry weight ratio increased markedly by LPS challenge. The lung tissue showed the pathologic changes of ALI induced by LPS in rat.
3. Ang 1-7 relieved ALI in LPS-induced rat.
4. ACE2 showed a protective effect on LPS-induced ALI through probably the positive regulation of Ang 1-7 levels.
引文
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6.张泓,孙耕耘.血管紧张素Ⅱ及其受体拮抗剂对大鼠肺微血管内皮炎性损伤效应的影响[J].中国危重病急救医学.2004;16(10):608-610.
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11.徐俊,张泓,宋志友,等.脂多糖性急性肺损伤血管紧张素转化酶2表达变化及血管紧张素1型受体拮抗剂的干预作用[J].中华结核和呼吸杂志.2009;32(3):223-224.
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13.朱钟鸣,孙耕耘.蛋白激酶Cδ亚型抑制剂对脂多糖诱导肺微血管内皮细胞损伤的影响[J].中国药理学通报.2006;22 (7):800-3.
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1.Zhang H, Sun GY. LPS induces permeability injury in lung microvascular endothelium via AT(1) receptor[J].Arch Biochem Biophys. 2005;441(1):75-83.
2.张泓,孙耕耘.血管紧张素Ⅱ及其受体拮抗剂对大鼠肺微血管内皮炎性损伤效应的影响[J].中国危重病急救医学.2004; 16(10):608-610.
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2. Brun - Buisson C ,Minelli C ,Bertolini G, et al .Epidemiology and outcome of acute lung injury in European intensive care unit [J] .Intensive Care Med ,2004;30 (1) :51 - 61.
3.孙秀泓,罗自强.肺的非呼吸功能基础与临床.北京:人民卫生出版社,2003; 297-309.
4. Helena L. Wang I. Ozkan Akinci, et al. The Intrinsic Apoptotic Pathway Is Required for Lipopolysaccharide-Induced Lung Endothelial Cell Death [J]. The Journal of Immunology. 2007; 179: 1834–1841.
5. Zhang H, Sun GY. LPS induces permeability injury in lung microvascular endothelium via AT(1) receptor [J]. Arch Biochem Biophys. 2005;441(1):75-83.
6.张泓,孙耕耘.血管紧张素Ⅱ及其受体拮抗剂对大鼠肺微血管内皮炎性损伤效应的影响[J].中国危重病急救医学.2004;16(10):608-610.
7. Santos RAS, Sim?es e Silva AC, Maric C, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas [J]. Proceedings of the National Academy of Sciences, USA, 2003;100:8258-8263.
8. Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9 [J]. Cir Res, 2000;87(5):1-9.
9. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure[J]. Nature,2005;436, 112–116.
10.王楠,孙耕耘,张泓.血管紧张素转化酶2在大鼠肺微血管内皮细胞上的表达[J].安徽医科大学学报.2007;42(2):136-139.
11.徐俊,张泓,宋志友,等.脂多糖性急性肺损伤血管紧张素转化酶2表达变化及血管紧张素1型受体拮抗剂的干预作用[J].中华结核和呼吸杂志.2009;32(3):223-224.
12.徐俊,张泓,宋志友,等.LPS对体外培养大鼠肺微血管内皮细胞ACE2表达的影响[J].安徽医科大学学报.2009,44(5):546-50.
13.朱钟鸣,孙耕耘.蛋白激酶Cδ亚型抑制剂对脂多糖诱导肺微血管内皮细胞损伤的影响[J].中国药理学通报.2006;22 (7):800-3.
14. Murakami K, B JertnaesLJ, Sclmalstieg FC, McGuire R, Cox RA, Hawkins HK, et al. A novel animal model of sepsis after acute lung injury in sheep[J]. Crit Care Med. 2002;30(9):2083-90.
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