血晶素对先天性膈疝大鼠模型胎仔肺发育肺血管重构的影响

Effect of hemin on the lung development and pulmonary arterial structural remodeling in congenital diaphragmatic hernia： experiment with rats

目的探讨血晶素对先天性膈疝（CDH）动物模型胎仔肺发育不良和肺血管重构的影响。方法将6只SD大鼠配种后第9．5天随机分为对照组、膈疝组和干预组。以除草醚诱导建立大鼠CDH动物模型，并以血晶素进行干预，第21天剖宫取出胎鼠及其肺，进行HE、弹力纤维染色观察，并进行图像分析。结果除草醚诱导膈疝的发生率达63．6％（28／44），干预组胎肺发育接近对照组，其右肺重／体重值[（16．6±1．0）mg／g]和肺泡面积比[（45±6）％]均大于膈疝组[（14．6±1．7）mg／g、（28±6）％，P=0．03、P〈0．01]，而肺泡间隔面积比[（44±6）％]低于膈疝组[（64±8）％，P〈0．01]；同时腺泡前／内动脉（PAPA／IAPA）的平均中膜厚度百分比[（21．2±2．2）％、（18．2±2．1）％]低于膈疝组[（24．3±4．0）％、（21．9±3．9）％，P=0．03、P=0．006]；单位视野内腺泡内动脉（IAPA）非肌型血管的比例[（78．2±3．0）％]高于膈疝组[（72．8±3．2）％，P=0．001]，小动脉的肌化受到抑制。结论血晶素产前干预虽不能降低CDH大鼠模型胎仔膈疝的发生率，但有助于促进CDH胎仔肺的发育，抑制其血管重构。

Objective To assay the effects of prenatal hemin therapy on pulmonary hypoplasia （PH） and pulmonary arterial structural remodeling in congenital diaphragmatic hernia （CDH）. Methods Six pregnant female SD rats were randomly divided into 3 equal groups： control group, undergoing gastric perfusion of olive oil once on day 9.5 and intraperitoneal injection of normal saline on days 11 - 14 ; CDH group, undergoing gastric perfusion of nitrofen 125 mg once on day 9. 5 and intraperitoneal injection of normal saline on days 11 - 14; and hemin group, undergoing gastric perfusion of nitrofen 125 mg once on day 9.5 and intraperitoneal injection of hemin 15 mg·kg^-1·d^-1 on days 11-14. On the gestational day 21 caesarean section was performed to take out the fetuses to undergo histological examination and image analysis. Results CDH were detected in 28 of the 44 （ 63.6% ） fetuses from the 2 groups receiving nitrofen. The lungs of all CDH group fetuses were hypoplastic, and the fetuses of the hemin group showed improved lung development. The right lung/body weight ratio and pulmonary alveolar area ratio（ PAA% ） of the hemin group were （ 16.6 ± 1.0） mg/g and （45 ± 6） % respectively, both significantly higher than those of the CDH group [（14.6±1.7） mg/g and （28 ±6）% respectively, P=0.03 andP〈0.01] . The alveolar septum area ratio （ASA%） of the hemin group was （44 ± 6） %, significantly lower than that of the CDH group [ （64 ± 8） %, P 〈 0.01 ]. The media thickness percentages （ MT% ） of pre-acinar artery （PAPA） and intra-acinar artery （IAPA） of the fetuses of the hemin group were （21.2 ± 2.2）% and （ 18.2 ± 2.1 ） % respectively, both significantly lower than those of the CDH group [ （ 24.3 ± 4.0） % and （21.9 ± 3.9） % respectively, both P 〈 0.05 ], which were significantly higher than those of the control group [ （20.0 ± 2.4）% and （ 17.2 ± 2.3）% respectively, both P 〈 0.01 ]. The component ratio of nonmuscularized artery （NMA） in the IAPA level of the heroin group was （ 78.2 ± 3.0 ） % , significantly higher than that of the CDH group [ （72.8 ± 3.2） %, P = 0.001 ]. Conclusion PH and pulmonary arterial structural remodeling are present in CDH. Although prenatal administration of hemin cannot prevent the genesis of CDH in rats, it may improve the pulmonary development, inhibit medial hypertrophy, and reduce the percentage of muscularized IAPA.