MKP-1/MAPK/cPLA2信号通路在宫内感染引起的早产儿肺发育不良中的作用及L-谷氨酰胺的干预机制

Intrauterine infection can lead to intrautetine inflammation which not only triggers premature birth as an important independent risk factor but also plays an important role in the development of bronchopulmonary dysplasia (BPD). Inflammatory cascade is a key factor in the occurrence of BPD, and adequate nutrition can reduce the risk of BPD. L-glutamine (Gln) has the role of nutritional immunity. Our previous study found that Gln inhibited the infiltration of inflammatory cells, the secretion of IL-1βand TNF-α, the phosphorylation of JNK and p38MAPK induced by hyperoxia in neonatal rats. Mitogen activated protein kinase / cytosolic phospholipase A2 (MAPK/cPLA2) signaling pathway is involved in various inflammatory reaction, The upstream MAPK phosphatase-1 (MKP-1) plays an important role in the negative regulation of immune regulation. However, the role of MKP-1/MAPK/cPLA2 signaling pathway in BPD inflammatory response and the effect of Gln intervention have not been reported. Therefore, in this study, we prepared a rat model which intrauterine infection induced lung injury, and discussed the role of the mkp-1 /MAPK/cPLA2 signaling pathway in the induction of BPD inflammatory response in intrauterine infection, and clarified the role of Gln intervention and its target，to provides a scientific theoretical basis for the clinical application of Gln in the prevention and treatment of BPD.

宫内感染可导致宫内炎症反应而触发早产，而且是早产儿支气管肺发育不良（BPD）的重要因素。炎症级联反应是BPD发生的关键因素，而充足的营养可降低BPD发生的风险。L-谷氨酰胺（Gln）具有营养免疫调节作用，我们的前期研究发现Gln抑制高氧诱导的新生大鼠肺部炎症细胞的浸润、IL-1β和TNF-α的分泌及JNK、p38MAPK磷酸化。丝裂原活化蛋白激酶/胞浆型磷脂酶A2（MAPK/cPLA2）信号通路参与各种炎症反应，其上游的MAPK磷酸酶-1（MKP-1）在免疫调控中起着非常重要的负调控作用，但是MKP-1/MAPK/cPLA2信号通路在BPD炎症反应中的作用及Gln干预效应研究尚未见报道。因此，本课题拟制备宫内感染肺损伤大鼠模型，探讨MKP-1/MAPK/cPLA2信号通路在宫内感染诱导BPD炎症反应中的作用，并明确Gln干预作用及其作用靶点。为Gln防治BPD的临床应用提供科学的理论依据。

支气管肺发育不良（BPD）是新生儿，特别是早产儿慢性进行性呼吸系统疾病，而炎症级联反应是BPD发生的关键因素，而充足的营养可降低BPD发生的风险。L-谷氨酰胺（Gln）具有营养免疫调节作用，但是Gln在早产BPD发生中的作用及其机制尚不清楚。本课题制备宫内感染肺损伤新生大鼠模型，检测早产新生大鼠肺组织中炎症相关信号分子的表达及Gln对BPD的治疗作用。在此基础上，观察丝裂原活化蛋白激酶/胞浆型磷脂酶A2（MAPK/cPLA2）信号通路参与各种炎症反应在Gln保护早产新生大鼠BPD中的作用，探讨Gln保护BPD的作用通过MKP-1/MAPK/cPLA2信号通路的可能分子机制。结果，（1）腹腔注射LPS的方法制备宫内感染导致的早产新生大鼠，对其肺组织进行PCR-array检测筛选了23个高表达和21个低表达差异表达mRNA，其中包括MKP-1/MAPK信号通路；（2）Gln处理明显增加早产新生大鼠体质量、肺组织明显修复、肺组织较清晰，肺组织含水量降低，肺功能明显改善；（3）Gln可能通过MKP-1/MAPK/ cPLA2信号通路改善宫内感染导致的早产新生大鼠BPD；（4）Gln保护早产新生大鼠高氧刺激的BPD发生，其作用机制可能通过抑制ROS介导的线粒体自噬有关。本项研究我们发现并证实Gln通过MKP-1/MAPK/ cPLA2信号通路和线粒体自噬途径保护宫内感染诱导的早产新生大鼠BPD，为Gln防治BPD的临床应用提供新的作用靶点和实验依据。