Nitric oxide-mediated the therapeutic properties of induced pluripotent stem cell for paraquat-induced acute lung injury.
Nitric oxide-mediated the therapeutic properties of induced pluripotent stem cell for paraquat-induced acute lung injury.
复制标题
DOI：
10.3389/fimmu.2023.1136290
复制
发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
与急性肺损伤(ALI)及其严重形式--急性呼吸窘迫综合征相关的死亡率很高。诱导多能干细胞(IPSC)治疗ALI是一种很有潜力的治疗方法，但对损伤肺的治疗效果有限。一氧化氮(NO)具有多种生理作用。本研究观察了在百草枯(PQ)诱导的小鼠ALI模型中，未加入NO供体的IPSCs的作用。雄性C57BL/6小鼠腹腔注射PQ后，经尾静脉注入磷酸盐缓冲液、IPSCs、L-精氨酸处理的IPSCs或硝基-L-精氨酸甲酯(L)处理的IPSCs。分别于术后3d和28d观察肺组织病理变化、肺微血管通透性和炎性细胞因子水平，并观察其对IPSC增殖、迁移和黏附的影响。经L-精氨酸处理的IPSCs选择性地进入内毒素诱导的ALI小鼠损伤肺组织，组织病理学改变和炎性细胞因子(IL-1、β和IL-6)水平显著降低。肺微血管通透性和肺功能也有明显改善。NO抑制剂可阻断IPSCs的保护作用。此外，L精氨酸促进IPSC增殖和迁移的能力被L抑制，提示NO可能介导了IPSC的治疗作用。内源性气体分子NO改善IPSC的生理变化，减轻肺损伤程度。L-精氨酸代表了增强IPSCs治疗潜力的重要药理学策略。
The mortality rate associated with acute lung injury (ALI) and its severe form, acute respiratory distress syndrome, is high. Induced pluripotent stem cell (iPSC) therapy is a potential treatment method for ALI, but its therapeutic efficacy is limited in injured lungs. Nitric oxide (NO) has various physiological actions. The current study investigated the effect of iPSCs pretreated with NO donors in paraquat (PQ)-induced ALI mouse model. Male C57BL/6 mice were intraperitoneally injected with PQ, followed by infusion of phosphate-buffered saline, iPSCs, L-arginine pretreated iPSCs, or Nitro-L-arginine methylester (L-NAME) pretreated iPSCs through the tail veins. Histopathological changes, pulmonary microvascular permeability, and inflammatory cytokine levels were analyzed after 3 or 28 d. The effects on iPSC proliferation, migration, and adhesion were evaluated in vitro. More L-arginine-pretreated iPSCs were selectively trafficked into the injured pulmonary tissue of mice with LPS-induced ALI, drastically diminishing the histopathologic changes and inflammatory cytokine levels (IL-1β and IL-6). There was also markedly improved pulmonary microvascular permeability and pulmonary function. The NO inhibitor abolished the protective effects of iPSCs. In addition, the ability of L-arginine to promote the proliferation and migration of iPSCs was decreased by L-NAME pretreatment, suggesting that NO might mediate the therapeutic benefits of iPSC. The improvement of the iPSC physiological changes by the endogenous gaseous molecule NO reduces lung injury severity. L-Arginine represents a pharmacologically important strategy for enhancing the therapeutic potential of iPSCs.