不同剂量阿托伐他汀对脂多糖致大鼠急性肺损伤的影响
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摘要
目的：观察不同剂量阿托伐他汀钙对脂多糖(LPS)所致的急性肺损伤大鼠外周血中性粒细胞凋亡和肺组织细胞间粘附分子-1(ICAM-1)、血管细胞粘附分子-1(VCAM-1)及支气管肺泡灌洗液中白介素-8(IL-8)表达的影响及其相关性；探讨阿托伐他汀钙在脂多糖所致大鼠急性肺损伤中的作用及可能机制。方法：通过SD大鼠尾静脉注射LPS建立急性肺损伤模型。90只雄性SD大鼠随机分为模型组(18只,简称L组)、空白对照组(18只,简称N组,)、干预组(即不同剂量阿托伐他汀组,简称T组)[分3个亚组：阿托伐他汀5mg/kg组(简称T1组,18只)、阿托伐他汀10mg/kg组(简称T2组,18只)、阿托伐他汀20mg/kg组(简称T3组,18只)],模型组和干预组尾静脉注射LPS(6mg/kg)复制大鼠急性肺损伤模型,对照组尾静脉注射生理盐水,各组又在注射脂多糖2小时、4小时和8小时后分别处死6只大鼠。取大鼠右肺下叶HE染色观察病理改变,并根据病理学改变进行相应评分；采用原位缺口末端标记技术(TUNEL)法检测外周血中性粒细胞凋亡率；并使用实时荧光定量PCR即(Real-time RT-PCR)法检测左肺组织匀浆中细胞间粘附分子-1 (ICAM-1) mRNA和血管细胞粘附分子-1(VCAM-1) mRNA的表达及双抗体夹心酶联免疫吸附测定法(ELISA)测定支气管肺泡灌洗液中IL-8的表达水平。结果：1.200倍光镜下大鼠右肺组织HE染色病理结果显示N组大鼠肺组织的小叶结构清晰,肺泡腔干净,肺泡间质无炎性细胞浸润,支气管黏膜上皮完整,L组、T组肺内大量炎性细胞浸润,伴出血、透明膜形成,提示肺损伤模型成功。肺损伤的五级分类依据肺泡和间质炎症及出血、肺水肿、肺不张和透明膜形成；各组间病理改变严重程度依次为L>T1>T2>T3>N,且两两比较有统计学意义(P<0.05)。2.大鼠外周血中性粒细胞凋亡率N组最高,T组和L组都低于N组,有显著性差异(P<0.05),T组表达高于L组,有显著性差异(P<0.05),T组各亚组之间表达:T1T2>T3,各组之间有显著性差异(P<0.05)。在时间表达趋势为2小时最低,8小时最高,呈递增趋势。4.支气管肺泡灌洗液中IL-8表达为N组最低,T组和L组表达都高于N组,有显著性差异(P<0.05),T组表达低于L组,有显著性差异(P<0.05),T组各亚组之间表达T1>T2>T3,各组之间有显著性差异(P<0.05)。时间表达趋势为4小时最高,2小时最低。5.根据统计学同质性原则,用SPSS软件对T组和L组外周血中性粒细胞凋亡数据和肺组织ICAM-1、VCAM-1mRNA表达数据及支气管肺泡灌洗液IL-8表达数据分别进行直线相关分析,提示它们呈负相关(r=-0.483,p<0.05;r=-0.633,p<0.05;r=r=-0.765,p<0.05)。结论：提前给予阿托伐他汀钙可以减轻肺损伤,其效应具有浓度依赖性。机制可能与阿托伐他汀钙影响细胞间粘附分子(ICAM-1)和血管细胞粘附分子(VCAM-1)及白介素-8(IL-8)表达、促进中性粒细胞凋亡有关。
Objective:To observe the effect of the different doses of atorvastatin calcium on the expression of granulocyte apoptosis in peripheral blood centers and intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) in lung tissue and interleukin-8 (IL-8) in bronchoalveolar lavage fluid and their correlation in rats with acute lung injury induced by lipopolysaccharide (LPS); and to investigate the effects of atorvastatin calcium in SD rats with acute lung injury induced by LPS.Methods:Establish acute lung injury SD rats model by LPS through intravenous injection.90 male SD rats were randomly divided into control group (n=18, referred to as the N group),model group (n=18, referred to as L), the intervention group (Different doses of atorvastatin groups, referred to as T group)[Divided into 3 subgroups:5mg/kg atorvastatin group (referred to as T1 group,18), 10mg/kg atorvastatin group (referred to as T2 group,18) 20mg/kg atorvastatin group (referred to as T3 group,18)], LPS (6mg/kg) were injected into Model group and intervention groups through tail vein copying acute lung injury model, saline were injected into control group through tail vein, each group were sacrificed 6 rats in 2 hours,4 hours and 8 hours after injecting LPS. To observe the pathology of right lung lower lobe lung tissue of rats through HE staining, and to score pathology; Detecte neutrophil apoptosis in peripheral blood by TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay; The expression of Vascular cell adhesion molecule-1 (VCAM-1)mRNA and Intercellular adhesion molecule-1(VCAM-1)mRNA in the left lung tissue homogenate was measured by Real-time Fluorescence Quantitative Polymerase Chain Reaction(Real Time PCR) assay and the concentrations of IL-8 in BALF were detected by the double-antibody sandwich enzyme-linked immunosorbent assay (ELISA)。Results:1:The pathology of the right lung in SD rats was observed under HE staining 200 times microscope group L、group T were a large number of neutrophil infiltration companying with hemorrhage、formation of hyaline membrane. The lobular lung tissue structure The group N was clear, alveolar space was clean, alveolar interstitial was no inflammatory cells infiltration, bronchial epithelial was integrity, suggesting a successful model of lung injury. Five-category classification based on lung injury、interstitial inflammation、alveolar hemorrhage、pulmonary edema、atelectasis and hyaline membrane formation, the severity of pathological changes between the groups wereL>T1>T2>T3>N (P<0.05).
2. Neutrophil apoptosis of rates in group T and group L are lower than the group N, there was significant difference (P<0.05), group T was higher than group L, there was significant difference (P<0.05), the subgroups of group T expressed:T10.05). Expression in the time trend was that the lowest point was 4 hours and the highest point was 2 hours.
3. The expression between the ICAM-1 and VCAM-1 was the same trend. group T and group L were higher than the group N, there was significant difference (P<0.05), group T was lower than group L, there was significant difference (P<0.05), the subgroups of group T expressed: T1>T2>T3, group T1 and group T3 are significantly different (P<0.05), T1 and T2, T2 and T3 showed no significant difference (P>0.05). Expression in the time trend was that the lowest point was 4 hours and the highest point was 2 hours,which gradually increased.
4. The expression of IL-8 in Bronchoalveolar lavage fluid(BALF) was contrast with the apoptosis of neutrophils, group T and group L were higher than the expression of group N, there was significant difference (P<0.05), group T was lower than group L There was significant difference (P<0.05), the subgroups of group T expressed:T1>T2>T3, group T1 and group T3 are significantly different (PL0.05), T1 and T2, T2 and T3 showed no significant difference (P>0.05). Expression in the time trend was that the lowest point was 2 hours and the highest point was 4 hours.
5. The data of neutrophil apoptosis and lung ICAM-1, VCAM-1 mRNA expression data and bronchoalveolar lavage fluid IL-8 expression was analysed by Linear correlation analysis with SPSS software, suggesting that they were negatively correlated (r=-0.483,p<0.05; r=-0.633,p<0.05; r=r=-0.765,p<0.05)
Conclusion:given atorvastatin calcium early can reduce lung injury, and its effect Characterizes concentration dependent manner.The mechanism may be atorvastatin calcium tablets affected the expression of atorvastatin; cell adhesion molecule (ICAM-1)、vascular cell adhesion molecule (VCAM-1) and Interleukin-8 (IL-8), promoted neutrophils apoptosis.
Objective:To observe the effect of the different doses of atorvastatin calcium on the expression of granulocyte apoptosis in peripheral blood centers and intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) in lung tissue and interleukin-8 (IL-8) in bronchoalveolar lavage fluid and their correlation in rats with acute lung injury induced by lipopolysaccharide (LPS); and to investigate the effects of atorvastatin calcium in SD rats with acute lung injury induced by LPS.Methods:Establish acute lung injury SD rats model by LPS through intravenous injection.90 male SD rats were randomly divided into control group (n=18, referred to as the N group),model group (n=18, referred to as L), the intervention group (Different doses of atorvastatin groups, referred to as T group)[Divided into 3 subgroups:5mg/kg atorvastatin group (referred to as T1 group,18), 10mg/kg atorvastatin group (referred to as T2 group,18) 20mg/kg atorvastatin group (referred to as T3 group,18)], LPS (6mg/kg) were injected into Model group and intervention groups through tail vein copying acute lung injury model, saline were injected into control group through tail vein, each group were sacrificed 6 rats in 2 hours,4 hours and 8 hours after injecting LPS. To observe the pathology of right lung lower lobe lung tissue of rats through HE staining, and to score pathology; Detecte neutrophil apoptosis in peripheral blood by TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay; The expression of Vascular cell adhesion molecule-1 (VCAM-1)mRNA and Intercellular adhesion molecule-1(VCAM-1)mRNA in the left lung tissue homogenate was measured by Real-time Fluorescence Quantitative Polymerase Chain Reaction(Real Time PCR) assay and the concentrations of IL-8 in BALF were detected by the double-antibody sandwich enzyme-linked immunosorbent assay (ELISA)。Results:1:The pathology of the right lung in SD rats was observed under HE staining 200 times microscope group L、group T were a large number of neutrophil infiltration companying with hemorrhage、formation of hyaline membrane. The lobular lung tissue structure The group N was clear, alveolar space was clean, alveolar interstitial was no inflammatory cells infiltration, bronchial epithelial was integrity, suggesting a successful model of lung injury. Five-category classification based on lung injury、interstitial inflammation、alveolar hemorrhage、pulmonary edema、atelectasis and hyaline membrane formation, the severity of pathological changes between the groups wereL>T1>T2>T3>N (P<0.05).
2. Neutrophil apoptosis of rates in group T and group L are lower than the group N, there was significant difference (P<0.05), group T was higher than group L, there was significant difference (P<0.05), the subgroups of group T expressed:T1
3. The expression between the ICAM-1 and VCAM-1 was the same trend. group T and group L were higher than the group N, there was significant difference (P<0.05), group T was lower than group L, there was significant difference (P<0.05), the subgroups of group T expressed: T1>T2>T3, group T1 and group T3 are significantly different (P<0.05), T1 and T2, T2 and T3 showed no significant difference (P>0.05). Expression in the time trend was that the lowest point was 4 hours and the highest point was 2 hours,which gradually increased.
4. The expression of IL-8 in Bronchoalveolar lavage fluid(BALF) was contrast with the apoptosis of neutrophils, group T and group L were higher than the expression of group N, there was significant difference (P<0.05), group T was lower than group L There was significant difference (P<0.05), the subgroups of group T expressed:T1>T2>T3, group T1 and group T3 are significantly different (PL0.05), T1 and T2, T2 and T3 showed no significant difference (P>0.05). Expression in the time trend was that the lowest point was 2 hours and the highest point was 4 hours.
5. The data of neutrophil apoptosis and lung ICAM-1, VCAM-1 mRNA expression data and bronchoalveolar lavage fluid IL-8 expression was analysed by Linear correlation analysis with SPSS software, suggesting that they were negatively correlated (r=-0.483,p<0.05; r=-0.633,p<0.05; r=r=-0.765,p<0.05)
Conclusion:given atorvastatin calcium early can reduce lung injury, and its effect Characterizes concentration dependent manner.The mechanism may be atorvastatin calcium tablets affected the expression of atorvastatin; cell adhesion molecule (ICAM-1)、vascular cell adhesion molecule (VCAM-1) and Interleukin-8 (IL-8), promoted neutrophils apoptosis.
引文
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2. Luh SP, Chiang CH. Acute lung injury/acute respiratory distress syndrome(ALI/ARDS):the mechanism, present strategies and future perspectives oftherapies[J]. Jhejiang Univ Sci B,2007,8(1):60-69.
3.邱海波.规范和提高我国急性呼吸窘迫综合征的诊断和治疗[J].中国危重病急救医学,2006,18(12)：705.
4.急性肺损伤/急性呼吸窘迫综合征诊断和治疗指南(2006)[J]中华急诊医学杂志2007年4月第16卷第4期343-349
[5]Shames BD, Zallen GS, Mclntyre RC, et al. Chemokines as mediators of diseases related to surgical conditions[J]. Shock,2000,14 (Ⅰ):1-7.
[6]Doerschuk CM, Mizgerd JP, Kubo H, et al. Adhension molecules and cellular biomechanical changes in acute lung injur,[J]. Chest.1999.166 (suppl 1):37s-43s.
[7]Lowel CA,Berton G.Integrin signal transduction in myeloid leukocytes [J].J Leukoc Biol,1999,65:313-320
[8]Fujishima S, Mkawa N. Neutrophil-mediated tissue injure and its modu-lation[J]. Intensive Care Med,1995,21(3):277-285.
[9]韩守信,陈复辉,周丹,急性肺损伤中性粒细胞凋亡异常及甲基强的松龙调控的研究,中国现代医学杂志,Vol.17 No.2 Jan.2007 1005—8982(2007)02—0169—03
[10]柯永胜他汀类药物的非降脂作用研究进展[J]中国医院药学杂志2003年第23卷第7期Chin Hosp Pharm J,2003 Jul,No123,No.7,424-426
[11]Wagner AH, Gebauer M, Guldenzonph B,et al.3-hydroxy-3-methyl glutaryl eoenzyme A reduetase-independent inhibition of CIMO expression by atorvastatin in human endothelia cells[J]. Arterioscler Thromb Vasc Biol,2002,22(11):1784-1789.
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