Research On The Effect Of Hypoxia-inducible Factor-1α, Endothelin-1and Inducible Nitric Oxide Synthase In The Pathogenesis Of Hypoxia-induced Pulmonary Hypertension Of The Neonatal Rats

Objective: To discuss the effect of HIF-1α through the research on the expressionlevel of hypoxia-inducible factor-1α(HIF-1α) and its regulation factors:endothelin-1(ET-1)and inducible nitic oxide synthase (iNOS) in blood serum and lung tissue, and the changesof pulmonary vascular remodeling of the neonatal rats as they were in the period ofpathogenesis by building up the model of hypoxia-induced pulmonary hypertension(HPH). Methods: To make a HPH model of neonatal rats:120newborn Wistar rats weredivided in random into two groups: HPH group and the regular oxygen controlled groupwith the same birthday.The rats of the two groups were put in the condition of hypoxia by3,5,7,10,14and21days and then10rats of HPH group and control group were pickedup, their average pulmonary hypertension pressure (mean pulmonary arteria pressure,mPAP), right ventricle hypertrophy index (RVHI), serum HIF-1α, and iNOS, and ET-1content were tested, and their lung tissue was taken as they were killed and determine theexpression level of the above gene mRNA,vascular remodeling index: MT%and MA%were tested, and finally their ultrastructure of pulmonary vascular were observed. Results:1) the rats with hypoxia of3,5,7,10,14and21days had an increasing mPAP, which gota significant differences compared with control groups (P＜0.05).2) the rats in hypoxiagroup had a higher serum HIF-1α than the controlled group as they experienced hypoxiaof3,5,7,10and14days (P＜0.05); HIF-1α mRNA expression in lung tissue was alsosignificantly higher than the control group,(P＜0.05); Serum ET-1levels were clearlyhigher than the control group (P＜0.01). ET-1mRNA expression in lung tissue was significantly increased after3-day hypoxia, a significant difference in statistics (P＜0.05).Serum content of iNOS was significantly higher than the control group (P＜0.05) after a3-day hypoxia, but there was no significant difference after a hypoxia of5,7or10days,compared with the control group (P＞0.05), and the content of serum iNOS to hypoxia,14days was lower than the control group after a14-day hypoxia, which was statisticallydifferent (P＜0.05); iNOS mRNA expression in lung tissue was significantly increasedafter hypoxia of3,5or7days, a significant difference on statistics (P＜0.05).3) The ratsin hypoxia group had a right ventricle hypertrophic and hypoxic pulmonary vascularremodeling as they experienced hypoxia after7days, and their MT%, MA%, RVHI wereincreased, a significant difference in statistics (P＜0.05). Conclusion: As a key factor,HIF-1α made ET-1and iNOS expression raised in the pathogenesis of hypoxia-inducedpulmonary hypertension (HPH) of the neonatal rats and caused a unbalance of ET-1andNO. Thus HIF-1α played an important role in neonatal rats and HIF-1α, ET-1and iNOSaltogether contributed to the occurrence and development of HPH in neonatal rats. Therats with hypoxia of3~5days had an increasing mPAP, and they were in pulmonaryvascular spasm stage. After hypoxia of7days, their mPAP got a further increase, theirpulmonary vascular began to remodel and their right ventricle became irreversiblyhypertrophic. These changes were intensified as the hypoxia time prolonged.