中文摘要：

目的探讨维甲酸（RA）对高氧肺损伤保护作用机制及其与调控丝裂原活化蛋白激酶（MAPKs）关系。方法建立高氧（85％）暴露早产SD大鼠肺损伤模型，运用RT—PCR方法检测基质金属蛋白酶2．9（MMP-2、-9）mRNA表达，采用明胶酶谱法检测MMP-2和MMP-9酶原及活酶表达，采用Westemblot技术检测磷酸化和非磷酸化总的ERK1／2、JNK1／2和p38蛋白质表达。结果与空气组比较，高氧暴露4、7、14d，MMP-2和MMP-9mRNA的表达均显著提高（P均〈0．01），MMP-2活酶（除4d外）、MMP-9酶原及活酶的表达明显上调（P〈0．05或P〈0．01），磷酸化ERK1／2、JNK1／2和p38表达显著增加（P均〈0．01）；与高氧组比较，4、7、14d时，RA明显下调高氧暴露后MMP-2（除14d外）、MMP-9mRNA的表达（P〈0．01或P〈0．05），不同程度降低MMP-2活酶、MMP-9酶原及活酶的表达和显著下调磷酸化JNK1／2、p38水平，进一步上调磷酸化ERK1／2表达。结论高氧暴露显著提高MMP-2和MMP-9表达，是造成肺损伤的重要因素；JNK1／2和p38信号途径可能参与了高氧暴露下早产大鼠肺组织MMP-2和MMP-9的表达调控；RA可通过降低JNK1／2和p38磷酸化水平，抑制MMP-2和MMP-9的高表达和活化，从而发挥高氧肺损伤保护作用。

英文摘要：

Objective To further investigate the protective effect of retinoic acid （RA） on hyperoxia induced lung injury and the role of RA as a modulator on mitogen-activated protein kinases （MAPKs）. Methods Establishment of hyperoxia （85%） induced lung injury model of premature Sprague- Dawley （SD）rats： 21 d gestational age SD rat＇s fetuses （term = 22 d） were delivered by hysterectomy. Within 12-24 h after birth, the premature rat pups were randomly divided into 4 groups： Group Ⅰ , airexposed control group; Group Ⅱ, hyperoxia-expoeed group; GroupⅢ, air plus RA-exposed group, Group Ⅳ, hyperoxia plus RA-exposed group. Group Ⅰ and Ⅲ were remained in room air, and group Ⅱ and Ⅳ were placed in 85% oxygen. The pups in Group Ⅲ and Ⅳ were injected with RA （500 μg/kg, every day） intraperitoneally. The entire lung tissues of premature rat pups were collected at 4 d, 7 d and 14 d. The mRNA levels of MMP-2 and MMP-9 were detected by semi-quantitative reverse transcription polymerase chain reaction （RT-PCR）. MMP-2 and MMP-9 activities were measured by zymography. Western blot was used to detect phosphorylated and total nonphosphorylated form of ERKs, JNKs and p38. Results Exposure to oxygen for 4 d, 7 d, and 14 d resulted in increased mRNA levels of MMP-2 and MMP-9 compared with air-exposed control group （P 〈0.01 for all）. The mean protein levels of active MMP-2 and pro/active MMP-9 after exposure to O2 were higher than air control groups on each experimental day （P 〈0. 01 or 〈 0. 05）. The phosphorylated ERK1/2, JNK1/2 and p38 proteins in hyperoxia-exposed group increased markedly compared with air-exposed control group（P 〈 0. 01 for all）. The pups treated with RA in the hyperoxic environment expressed significantly lower mRNA levels of MMP-2 and MMP-9 than the hyperoxic control pups on each experimental day （P 〈0.05 for all）. The levels of active MMP-2 and pro/active MMP- 9 decreased to a different degree after RA treatment in hyperoxia exposure rat pups