Clinical Medical College of Ningxia Medical University, Yinchuan Province 750004, China; Ningxia Institute of Human Stem Cells, Yinchuan Province 750004, China; Intensive Care Unit, Cardiocerebral Vascular Disease Hospital of General Hospital of Ningxia Medical University, Yinchuan Province 750002, China.
Clinical Medical College of Ningxia Medical University, Yinchuan Province 750004, China; Intensive Care Unit, Cardiocerebral Vascular Disease Hospital of General Hospital of Ningxia Medical University, Yinchuan Province 750002, China.
Biochem Pharmacol. 2024 Nov;229:116547. doi: 10.1016/j.bcp.2024.116547. Epub 2024 Sep 19.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are accompanied by high mortality rates and few effective treatments. Transplantation of human placental mesenchymal stem cells (hPMSCs) may attenuate ALI and the mechanism is still unclear. Our study aimed to elucidate the potential protective effect and therapeutic mechanism of hPMSCs against lipopolysaccharide (LPS)-induced ALI, An ALI model was induced by tracheal instillation of LPS into wild-type (WT) and angiotensin-converting enzyme 2 (ACE2) knockout (KO) male mice, followed by injection of hPMSCs by tail vein. Treatment with hPMSCs improved pulmonary histopathological injury, reduced pulmonary injury scores, decreased leukocyte count and protein levels in bronchoalveolar lavage fluid(BALF), protected the damaged alveolar epithelial barrier, and reversed LPS-induced upregulation of pro-inflammatory factors Interleukin-6 (IL-6) and Tumor necrosis factor-α(TNF-α) and downregulation of anti-inflammatory factor Interleukin-6(IL-10) in BALF. Moreover, administration of hPMSCs inhibited Angiotensin (Ang)II activation and promoted the expression levels of ACE2 and Ang (1-7) in ALI mice. Pathological damage, inflammation levels, and disruption of alveolar epithelial barrier in ALI mice were elevated after the deletion of ACE2 gene, and the Renin angiotensin system (RAS) imbalance was exacerbated. The therapeutic effect of hPMSCs was significantly reduced in ACE2 KO mice. Our findings suggest that ACE2 plays a key role in hPMSCs repairing the alveolar epithelial barrier to protect against ALI, laying a new foundation for the clinical treatment of ALI.
急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的死亡率较高，且治疗方法有限。人胎盘间充质干细胞（hPMSCs）的移植可能减轻 ALI，但具体机制尚不清楚。本研究旨在阐明 hPMSCs 对脂多糖（LPS）诱导的 ALI 的潜在保护作用和治疗机制，通过气管内滴注 LPS 诱导野生型（WT）和血管紧张素转换酶 2（ACE2）敲除（KO）雄性小鼠的 ALI 模型，然后通过尾静脉注射 hPMSCs。hPMSCs 治疗可改善肺组织病理学损伤，降低肺损伤评分，减少支气管肺泡灌洗液（BALF）中的白细胞计数和蛋白水平，保护受损的肺泡上皮屏障，并逆转 LPS 诱导的促炎因子白细胞介素 6（IL-6）和肿瘤坏死因子-α（TNF-α）在 BALF 中的上调和抗炎因子白细胞介素 10（IL-10）的下调。此外，hPMSCs 的给药抑制血管紧张素（Ang）II 的激活，并促进 ACE2 和 Ang（1-7）在 ALI 小鼠中的表达水平。在 ACE2 基因缺失后，ALI 小鼠的病理损伤、炎症水平和肺泡上皮屏障的破坏增加，肾素血管紧张素系统（RAS）失衡加剧。hPMSCs 在 ACE2 KO 小鼠中的治疗效果显著降低。我们的研究结果表明，ACE2 在 hPMSCs 修复肺泡上皮屏障以防止 ALI 中发挥关键作用，为 ALI 的临床治疗奠定了新的基础。
