摘要
目的通过了解缺氧诱导因子1α（hypoxia inducible factor-1 alpha，HIF-1α）及其调控因子：内皮素-1（endothelin-1，ET-1）、诱导型一氧化氮合酶（inducible nitric oxide synthase，iNOS）在新生大鼠缺氧性肺动脉高压（hypoxia induced pulmonary hypertension，HPH）血清及肺组织中的表达，探讨HIF-1α在新生大鼠HPH发病机制中的作用。方法建立新生大鼠HPH模型：将120只新生Wistar大鼠依照随机数字表法分为低氧组和正常对照组，分别于缺氧3、5、7、10、14、21d取低氧组及同日龄对照组新生大鼠各10只测定其平均肺动脉压（mean pulmonary arteria pressure，mPAP）、血清HIF-1α、iNOS、ET-1含量，及肺组织上述基因mRNA的表达水平。结果（1）缺氧3、5、7、10、14、21d，低氧组新生大鼠mPAP检测值分别为：[8．47±1．45，10．04±1．69，10．89±2．97，16．96±1．97，13．01±1．93，21．04±2．13（mmHg）（1mmHg=0．133kPa）]，较对照组检测值：[5．11±1．06，8．12±1．11，8．77±0．92，12．23±1．78，8．89±0．89，11．09±1．64（mmHg）]显著增高，差异有统计学意义（P〈0．05）；（2）低氧组新生大鼠血清HIF-1α含量在缺氧3、5、7、10、14d检测值分别为：[0．83±0．07，0．84±0．17，0．97±0．13，1．10±0．30，0．92±0．19（pg/nm01）]，明显高于对照组检测值：[0．26±0．20，0．37±0．16，0．44±0．18，0．41±0．23，0．66±0．18（pg／nmol）]，差异有统计学意义（P〈0．05）；肺组织HIF-1αmRNA表达在缺氧3、5、7d检测值为：1．301±0．47，1．032±0．47，1．453±0．76，明显高于对照组检测值：0．231±0．26，0．425±0．59，0．692±0．13，差异有统计学意义（P〈0．05）。血清ET-1含量在缺氧3、5、7、10、14、21d检测值分别为：[51．50±3．19，44．1±10．81，56．85±9．10，52．91±9．59，51．16±8．87，50．21±10．41（pg／nm01）]，均明显高于对照组检测值：[9．04±2．85，21．70±8．78，19．63±9．66，18．30±7．32，19．69±5．92，16．88±6．14（pg／nm01）]，差异有统计学意义（P〈0．01）；肺组织ET-1mRNA表达在缺氧3d检测值：0．037±0．018，较对照组：0．006±0．004显著增高，差异有统计学意义（P〈0．05）。缺氧3d血清iNOS含量：（5．62±0．79）μmol／L，明显高于对照组：（1．63±0．67）μmol／L，（P〈0．05），缺氧5、7、10d与对照组相比差异无统计学意义（P〉0．05），至缺氧14、21d血清iNOS含量分别为：（4．56±0．96，5．86±1．76）μmol／L低于对照组：（10．35±1．99，8．44±2．76）μmoL／L，差异有统计学意义（P〈0．05）；肺组织iNOSmRNA表达在缺氧3、5、7d检测值分别为：0．035±0．024，0．332±0．198，0．527±0．098，较对照组：0．005±0．0001，0．008±0．002，0．040±0．012，显著增高，差异有统计学意义（P〈0．05）。结论在新生大鼠HPH的发病过程中低氧作为始动因素诱导HIF-1α及其靶基因ET-1及iNOSmRNA的表达增强，致血清ET-1与NO平衡失调，在HPH发生中起了重要的作用。HIF-1α、ET-1及iNOS共同参与了新生大鼠HPH的发生、发展。
Objective To study the effect of hypoxia-inducible factor-1α （HIF-lcL） in the pathogenesis of hypoxia-indueed pulmonary hypertension （ HPH ） of the neonatal rats through the study on the expression level of HIF-1αand its regulation factors： endothelin-1 （ET-1） and inducible nitric oxide synthase （iNOS） in blood serum and lung tissue. Methods To make an HPH model of neonatal rats, 120 newborn Wistar rats were divided at random into two groups： HPH group and the regular oxygen controlled group with the same birthday. The rats of the two groups were put in the condition of hypoxia for 3, 5, 7, 10, 14,21 days and then 10 rats of HPH group and control group were picked up, their mean pulmonary arterial pressure （mPAP） , serum HIF-1α, and iNOS, and ET-1 content were tested, and finally their lung tissue was taken after they were sacrificed and the expression level of the gene mRNA of HIF-1α, iNOS and ET-1. Results （ 1 ） The rats experienced hypoxia for 3, 5,7, 10, 14 or 21 days had an increasing mPAP： [ 8.47 ± 1.45,10.04 ± 1.69,10. 89 ± 2. 97,16. 96 ± 1.97,13.01 ± 1.93, 21.04 ± 2. 13 （mm Hg） ], which had a significant differences compared with control groups[ 5.11 ± 1.06,8. 12 ± 1.11,8.77 ±0. 92,12. 23 ± 1.78,8. 89 ± 0. 89,11.09 ± 1.64 （ mm Hg） ] （P 〈 0.05）. （2） The rats in hypoxia group had a higher serum HIF-1α[0. 83 ±0.07,0.84 ±0. 17,0.97 ±0. 13,1.10 ±0.30,0.92 ±0. 19 （pg/nmol） ] than the control group [0.26 ±0.20,0.37 ±0.16,0.44 ±0.18,0.41 ± 0. 23 , 0. 66 ± 0.18 （ pg/nmol ） ] as they experienced hypoxia for 3, 5, 7, 10, and 14 days （P 〈0. 05） ; HIF-1α mRNA expression in lung tissue （ 1. 301 ± 0.47,1. 032 ± 0. 47,1. 453 ± 0.76 ） was also significantly higher than that of the control group （0.231 ±0.26,0.425 ±0.59,0.692 ±0.13） （P〈0.05）; serum ET-1 levels [51.50±3.19,44.1 ± 10. 81,56. 85 ± 9. 10, 52. 91 ± 9.59,51.16 ± 8. 87, 50. 21 ± 10.41 （pg/nmol） ] were clearly higher than that of the control group [9. 04 ±2. 85, 21.70 ±8. 78,19. 63 ±9. 66,18. 30 ±7.32,19.69 ±5.92,16. 88 ± 6. 14 （pg/nmol） ] （ P 〈 0. 01 ） ; ET-1 mRNA expression in lung tissue （ 0. 037 ± 0. 018 ） was significantly increased after 3-day hypoxia as compared with control group（0. 006 ±0. 004） （P 〈0. 05）. Serum content of iNOS（5.62 ± 0.79 ） μmol/L was significantly higher than the control group （ 1.63 ± 0. 67 ） μmol/L （ P 〈 0.05 ） after a 3-day hypoxia, but there was no significant difference after a hypoxia for 5,7 or 10 days, compared with the control group （ P 〉0. 05 ） , and the content of serum iNOS after hypoxia for 14 or 21 days （4. 56 ± 0. 96,5.86 ± 1.76） μmol/L was lower than that of the control group （ 10. 35 ± 1.99,8.44 ± 2.76） μmol/L （P 〈 0. 05 ）. iNOS mRNA expression in lung tissue （ 0. 035 ± 0. 024,0. 332 ± 0. 198,0. 527 ± 0. 098 ）significantly increased after hypoxia for 3, 5 or 7 days as compared with the control group（ 0. 005 ± 0.0001,0.008 ±0.002, 0.040 ±0.012） （P〈0.05）. Conclusion As an initial factor, low oxygen made HIF-1α,ET-1 and iNOS expression raised in the pathogenesis of HPH of the neonatal rats and causedn a imbalance of ET-1 and NO. HIF-1α, ET-1 and iNOS altogether contributed to the occurrence and development of HPH in neonatal rats.
出处
《中华儿科杂志》
CAS
CSCD
北大核心
2012年第12期919-924,共6页
Chinese Journal of Pediatrics
基金
国家自然科学基金资助项目（30960410）
