Li Xiao-Hong, Huang Pu, Cheng Hai-Peng, Zhou Yan, Feng Dan-Dan, Yue Shao-Jie, Han Yang, Luo Zi-Qiang
Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China.
Heliyon. 2023 Dec 19;10(1):e23723. doi: 10.1016/j.heliyon.2023.e23723. eCollection 2024 Jan 15.
N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation mediates glutamate (Glu) toxicity and involves bleomycin (BLM)-induced acute lung injury (ALI). We have reported that bone marrow-derived mesenchymal stem cells (BM-MSCs) are NMDAR-regulated target cells, and NMDAR activation inhibits the protective effect of BM-MSCs on BLM-induced pulmonary fibrosis, but its effect on ALI remains unknown. Here, we found that Glu release was significantly elevated in plasma of mice at d 7 after intratracheally injected with BLM. BM-MSCs were pretreated with NMDA (the selective agonist of NMDAR) and transplanted into the recipient mice after the BLM challenge. BM-MSCs administration significantly alleviated the pathological changes, inflammatory response, myeloperoxidase activity, and malondialdehyde content in the damaged lungs, but NMDA-pretreated BM-MSCs did not ameliorate BLM-induced lung injury . Moreover, NMDA down-regulated prostaglandin E (PGE) secretion and cyclooxygenase (COX)-2 expression instead of COX-1 expression in BM-MSCs . We also found that NMDAR1 expression was increased and COX-2 expression was decreased, but COX-1 expression was not changed in primary BM-MSCs of BLM-induced ALI mice. Further, the cultured supernatants of lipopolysaccharide (LPS)-pretreated RAW264.7 macrophages were collected to detect inflammatory factors after co-culture with NMDA-pretreated BM-MSCs. The co-culture experiments showed that NMDA precondition inhibited the anti-inflammatory effect of BM-MSCs on LPS-induced macrophage inflammation, and PGE could partially alleviate this inhibition. Our findings suggest that NMDAR activation attenuated the protective effect of BM-MSCs on BLM-induced ALI . NMDAR activation inhibited COX-2 expression and PGE secretion in BM-MSCs and weakened the anti-inflammatory effect of BM-MSCs on LPS-induced macrophage inflammation . In conclusion, NMDAR activation attenuates the protective effect of BM-MSCs on BLM-induced ALI via the COX-2/PGE pathway. : Acute Lung Injury, BM-MSCs, NMDA receptor, COX-1/2, PGE.
N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）的激活介导谷氨酸（Glu）毒性，并参与博来霉素（BLM）诱导的急性肺损伤（ALI）。我们曾报道，骨髓间充质干细胞（BM-MSCs）是受NMDAR调节的靶细胞，NMDAR激活会抑制BM-MSCs对BLM诱导的肺纤维化的保护作用，但其对ALI的影响尚不清楚。在此，我们发现气管内注射BLM后第7天，小鼠血浆中的Glu释放显著升高。将BM-MSCs用NMDA（NMDAR的选择性激动剂）预处理，在BLM攻击后移植到受体小鼠体内。给予BM-MSCs可显著减轻受损肺组织的病理变化、炎症反应、髓过氧化物酶活性和丙二醛含量，但经NMDA预处理的BM-MSCs并不能改善BLM诱导的肺损伤。此外，NMDA下调了BM-MSCs中前列腺素E（PGE）的分泌和环氧化酶（COX）-2的表达，而非COX-1的表达。我们还发现，在BLM诱导的ALI小鼠的原代BM-MSCs中，NMDAR1表达增加，COX-2表达减少，但COX-1表达未改变。此外，收集脂多糖（LPS）预处理的RAW264.7巨噬细胞的培养上清液，在与经NMDA预处理的BM-MSCs共培养后检测炎症因子。共培养实验表明，NMDA预处理抑制了BM-MSCs对LPS诱导的巨噬细胞炎症的抗炎作用，而PGE可部分缓解这种抑制。我们的研究结果表明，NMDAR激活减弱了BM-MSCs对BLM诱导的ALI的保护作用。NMDAR激活抑制了BM-MSCs中COX-2的表达和PGE的分泌，并削弱了BM-MSCs对LPS诱导的巨噬细胞炎症的抗炎作用。总之，NMDAR激活通过COX-2/PGE途径减弱了BM-MSCs对BLM诱导的ALI的保护作用。：急性肺损伤、BM-MSCs、NMDA受体、COX-1/2、PGE
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