摘要
目的探讨硫化氢（H2S）对高肺血流性肺动脉高压大鼠血管炎症反应的调节作用。方法44只雄性SD大鼠，随机分为4周对照组（7只）、4周分流组（7只）、4周分流＋炔丙基甘氨酸（PPG）组（8只）、11周对照组（7只）、11周分流组（7只）及11周分流＋硫氢化钠（NariS）组（8只）。采用右心导管测定肺动脉平均压（mPAP），应用免疫组织化学方法检测肺动脉内皮细胞炎症分子细胞间黏附分子1（ICAM-1）、核因子-κB信号转导通路关键分子核因子-κBp65和核因子-κB抑制蛋白（IKBd）的表达，通过酶联免疫吸附试验（ELISA）检测大鼠血浆及肺组织ICAM-1、白细胞介素8（IL-8）、单核细胞趋化蛋白1（MCP-1）含量。结果4周分流组大鼠血浆和肺组织中ICAM-1、IL-8及MCP-1含量均明显高于4周对照组大鼠（P〈0．05或P〈0．01）；4周分流＋PPG组大鼠mPAP，中、小型肺动脉内皮细胞ICAM-1和核因子-κBp65蛋白表达均显著高于4周分流组（P〈0．05或P〈0．01），而中、小型肺动脉内皮细胞IKBd蛋白表达均低于4周分流组（P〈0．05），肺组织ICAM-1含量，血浆IL-8含量和肺组织MCP-1含量均高于4周分流组[（27．3±5．0）μmol／g蛋白VS（21．9±2．1）μmol／g蛋白，（148±29）μmol／LVS（118±23）μmol／L，（12．9±1．1）μmol／g蛋白VS（10．2±1．4）μmol／g蛋白，P〈0．05或P〈0．01]。11周分流组大鼠mPAP高于11周对照组（P〈0．01），大、中、小型肺动脉内皮细胞ICAM-1和核因子-κBp65蛋白表达均高于11周对照组（P〈0．05或P〈0．01），但IκBα蛋白表达低于11周对照组（P〈0．05或P〈0．01），血浆和肺组织中ICAM-1、IL-8及MCP-1均高于11周对照组（均P〈0．01）；11周分流＋NaHS组mPAP明显低于11周分流组[（23、2±3．0）mmHgVS（27．5±1．9）mmHg，1mmHg=0．133kPa，P〈0．05]，大、中、小型肺动脉内皮细胞ICAM-1和核因子-κBp65蛋白表达均低于11周分流组（P〈0．05或P〈0．01），而中、小型肺动脉内皮细胞IκBα蛋白表达高于11周分流组（均P〈0．05），血浆和肺组织中ICAM-1以及IL-8均低于11周分流组[（124±11）μmol／L VS（154±20）μmol／L、（19．9±2．5）μmol／g蛋白VS（23．9±3．6）μmol／g蛋白，（92±11）μmol／LVS（121±17）μmol／L、（15．0±1．7）μmol／g蛋白VS（19．0±3．9）μmol／g蛋白，均P〈0．01]，肺组织MCP-1也低于11周分流组[（10．8±1．6）μmol／g蛋白VS（13．5±1．4）μmol／g蛋白，P〈0．01]。结论H2S可通过抑制高肺血流性肺动脉高压大鼠血管炎症反应拮抗肺动脉高压形成。H2S的抗血管炎症效应可能通过上调肺动脉内皮细胞IκBα的表达，降低核因子-κBp65的表达，进而抑制相关炎症因子的表达来实现。
Objective To investigate the effects of hydrogen sulfide （H2S） on vascular inflammation in pulmonary hypertension induced by high pulmonary blood flow. Methods Forty-four male SD rats were randomly divided into 8 groups ： 4-week control group （ n = 7）, 4-week shunt group （ n = 7 ）, 4-week shunt ± propargylglycine （PPG, an endogenous H2 S release inhibitor） intraperitoneal injection group （n = 8）, 11-week control group （ n = 7 ）, 11-week shunt group （ n = 7 ）, and 11-week shunt ＋ sodium hydrosulfide （NaHS, a H2 S donor） intraperitoneal injection group （n = 8）. Right ventricular catheterization was used to measure the mean pulmonary arterial pressure （mPAP）. Immunohistochemistry was used to detect the expression of inflammatory related factor intercellular adhesion molecule-1 （ ICAM-1 ）, and the key molecules of nuclear factor-κB （NF-κB） signal transduction pathway, including NF-κB p65 and inhibitor of NF-κB （IκBα）, in the pulmonary artery, and ELISA was used to detect the concentrations of the inflammatory related factors, including ICAM-1, interleukin-8 （IL-8）, and monocyte chemoattractant protein-1 （MCP-1） in blood plasma and lung tissues so as to reflect the corresponding inflammatory responsiveness. Results The plasma and lung tissue ICAM-1, IL-8 and MCP-1 contents of the 4-week shunt group were all significantly higher than those of the 4-week control group （ P 〈 0.05 or P 〈 0. 01 ）. The mPAP of the 4 week shunt ± PPG group was （20.3 ± 1.7 ） mm Hg, significantly higher than that of the 4- week shunt group [ （ 16. 2 ± 1.5 ） mm Hg, P 〈0. 01 ]. The expression levels of ICAM-1 and NF-κB p65 in the small and median pulmonary artery endothelin cells of the 4-week shunt ＋ PPG group were both significantly stronger than those of the 4-week shunt group （P 〈 0. 05 or P 〈 0. 01 ）, whereas the expression of IκBα was weaker than that of the 4-week shunt group （ P 〈 0. 05 ）. The plasma IL-8 content of the 4-week shunt ＋ PPG group was （ 148 ± 29 ） μ mol/L, significantly higher than that of the 4 week-shunt group [ （ 118 ± 23 ） μ mol/L, P 〈 0.05 ], and the lung tissue ICAM-1 and MCP-1 levels of the 4-week shunt ＋ PPG group were （27.3 ±5.0） μ mol/g and （ 12. 9 ± 1.1 ） μ mol/g respectively, both significantly higher than those of the 4-week shunt group [ （21.9 ± 2. 1 ） and （ 10. 2 ± 1.4） μ mol/g respectively, both P 〈 0. 05 ]. The mPAP and expression levels of ICAM-1 and NF-κB 065 of the large, median, and small pulmonary artery endothelia cells of the 11-week shunt group were all higher than those of the 11-week control group （P 〈 0. 05 or P 〈 0. 01 ）, whereas the expression levels of IκBα were all less obvious （ P 〈 0.05 or P 〈 0.01 ）. The plasma and lung tissue ICAM-I, IL-8, and MCP-1 levels of the ll-week shunt group were all significantly higher than those of the ll-week control group （all P 〈0.01 ）. The mPAP of the 11 week shunt ＋ Naris group was （23.2 ± 3. 0 ） mm Hg, significantly lower than that of the 11-week shunt group [ （27.5 ± 1.9） mm Hg, P 〈0. 05]. The ICAM-1 and NF-κB p65 expression levels of large, median, and small pulmonary artery endothelia cells of the 11-week shunt Naris group were all significantly weaker than those of the 11-week shunt group （P 〈0. 05 or P 〈0.01 ）, whereas the protein expression levels of IκBα in small and median pulmonary artery endothelia cells of the ll-week shunt ＋ NaHS group were significantly higher than those of the 11-week shunt group （both P 〈 0.05 ）. The plasma and lung tissue ICAM-1 contents of the 11-week shunt ＋ NaHS group were （ 124 ± 11 ） μ mol/L and （ 19. 9 ± 2. 5 ） μ mol/g, both significantly lower than those of the 11-week shunt group [ （ 154 ± 20 ） μmol/L and （ 23.9 ± 3.6 ） μ mol/g respectively, both P 〈 0. 01 ]. The plasma and lung tissue IL-8 contents of the l 1-week shunt ＋ NaHS group were （92 ± 11 ） μ mol/L and （ 15.0 ± 1.7） μ mol/g, both significantly lower than those of the 11-week shunt group [ （ 121 ± 17 ） μ mol/L and （ 19.0 ± 3.9 ） μ mol/g respectively, both P 〈 0. 01 ]. The lung tissue MCP-1 content of the ll-week shunt ＋ NaHS group was （10. 8 ± 1.6） μmol/g, significantly lower than that of the 11-week shunt group [ （ 13.5 ± 1.4） μ mol/g, P 〈 0.01 ]. Conclusion H2 S attenuates the development of pulmonary hypertension induced by high pulmonary blood flow through ameliorating pulmonary vascular inflammation. The inhibitory effect of H2S on the pulmonary vascular inflammation involves elevating IκBα expression, down-regulating NF-κB p65 expression and then inhibiting the expression of inflammatory related factors.
出处
《中华医学杂志》
CAS
CSCD
北大核心
2008年第32期2235-2239,共5页
National Medical Journal of China
基金
国家自然科学基金资助项目（30425010、30630031、30571971）
国家重点基础研究发展规划基金资助项目（2006CB503807）
国家长江学者奖励计划基金资助项目（985-2-087-111）
北京市自然科学基金资助项目（7072082、7082095）
教育部博士点基金（20070001702、20070001770）
关键词
硫化氢
高血压
肺性
炎症
Hydrogen sulfide
Hypertension,pulmonary
Inflammation
