Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA.
Huck Institutes of the Life Sciences, Pennsylvania State University; University Park, PA, 16802, USA.
Theranostics. 2023 May 8;13(9):2843-2862. doi: 10.7150/thno.83942. eCollection 2023.
Trauma, surgery, and infection can cause severe inflammation. Both dysregulated inflammation intensity and duration can lead to significant tissue injuries, organ dysfunction, mortality, and morbidity. Anti-inflammatory drugs such as steroids and immunosuppressants can dampen inflammation intensity, but they derail inflammation resolution, compromise normal immunity, and have significant adverse effects. The natural inflammation regulator mesenchymal stromal cells (MSCs) have high therapeutic potential because of their unique capabilities to mitigate inflammation intensity, enhance normal immunity, and accelerate inflammation resolution and tissue healing. Furthermore, clinical studies have shown that MSCs are safe and effective. However, they are not potent enough, alone, to completely resolve severe inflammation and injuries. One approach to boost the potency of MSCs is to combine them with synergistic agents. We hypothesized that alpha-1 antitrypsin (A1AT), a plasma protein used clinically and has an excellent safety profile, was a promising candidate for synergism. This investigation examined the efficacy and synergy of MSCs and A1AT to mitigate inflammation and promote resolution, using inflammatory assay and mouse acute lung injury model. The assay measured cytokine releases, inflammatory pathways, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs) production by neutrophils and phagocytosis in different immune cell lines. The model monitored inflammation resolution, tissue healing, and animal survival. We found that the combination of MSCs and A1AT was much more effective than each component alone in i) modulating cytokine releases and inflammatory pathways, ii) inhibiting ROS and NETs production by neutrophils, iii) enhancing phagocytosis and, iv) promoting inflammation resolution, tissue healing, and animal survival. These results support the combined use of MSCs, and A1AT is a promising approach for managing severe, acute inflammation.
创伤、手术和感染会导致严重的炎症。炎症强度和持续时间的失调都可能导致严重的组织损伤、器官功能障碍、死亡率和发病率。抗炎药物，如类固醇和免疫抑制剂，可以抑制炎症强度，但它们会破坏炎症的解决，损害正常的免疫功能，并产生显著的不良反应。间充质基质细胞（MSCs）是天然的炎症调节因子，具有减轻炎症强度、增强正常免疫和加速炎症解决和组织愈合的独特能力，因此具有很高的治疗潜力。此外，临床研究表明 MSCs 是安全有效的。然而，它们单独使用时，不足以完全解决严重的炎症和损伤。增强 MSCs 效力的一种方法是将它们与协同剂结合使用。我们假设α-1 抗胰蛋白酶（A1AT），一种临床上使用的血浆蛋白，具有极好的安全性，是协同作用的有前途的候选物。本研究使用炎症测定和小鼠急性肺损伤模型，研究了 MSCs 和 A1AT 减轻炎症和促进解决的功效和协同作用。该测定法测量了不同免疫细胞系中细胞因子的释放、炎症途径、活性氧（ROS）和中性粒细胞胞外陷阱（NETs）的产生以及中性粒细胞和吞噬细胞的吞噬作用。该模型监测炎症解决、组织愈合和动物存活情况。我们发现，与单独使用每种成分相比，MSCs 和 A1AT 的组合在以下方面更为有效：i）调节细胞因子的释放和炎症途径，ii）抑制中性粒细胞产生的 ROS 和 NETs，iii）增强吞噬作用，iv）促进炎症解决、组织愈合和动物存活。这些结果支持 MSCs 和 A1AT 的联合使用，这是一种管理严重急性炎症的有前途的方法。
