Byrnes Declan, Masterson Claire, Brady Jack, Horie Shahd, McCarthy Sean D, Gonzalez Hector, O'Toole Daniel, Laffey John
Anaesthesia, School of Medicine, Clinical Sciences Institute, University of Galway, Galway, Ireland.
Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, Galway, Ireland.
Front Med (Lausanne). 2023 Jul 3;10:1132749. doi: 10.3389/fmed.2023.1132749. eCollection 2023.
Mesenchymal stromal cells (MSC) are a promising therapeutic for pneumonia-induced sepsis. Here we sought to determine the efficacy of delayed administration of naïve and activated bone marrow (BM), adipose (AD), and umbilical cord (UC) derived MSCs in organized antibiotic resistant pneumosepsis.
Human BM-, AD-, and UC-MSCs were isolated and expanded and used either in the naïve state or following cytokine pre-activation. The effect of MSC tissue source and activation status was assessed first . Subsequent experiments assessed therapeutic potential as a delayed therapy at 48 h post infection of rodents with , with efficacy assessed at 120 h.
BM-, AD-, and UC-MSCs accelerated epithelial healing, increased phagocytosis, and reduced ROS-induced epithelial injury , with AD-MSCs less effective, and naïve MSCs more effective than pre-activated MSCs. Delayed MSC administration in pre-clinical organized pneumosepsis had no effect on physiologic indices, but enhanced resolution of structural lung injury. Delayed therapy with pre-activated MSCs reduced mRNA concentrations of fibrotic factors. Naïve MSC treatment reduced key circulating cell proportions and increased bacterial killing capacity in the lungs whereas pre-activated MSCs enhanced the phagocytic index of pulmonary white cells.
Delayed MSC therapy enhanced resolution of lung injury induced by antibiotic resistant infection and favorably modulated immune cell profile. Overall, AD-MSCs were less effective than either UC- or BM-MSCs, while naïve MSCs had a more favorable effect profile compared to pre-activated MSCs.
间充质基质细胞（MSC）是治疗肺炎诱导性脓毒症的一种有前景的疗法。在此，我们试图确定未激活和激活的骨髓（BM）、脂肪（AD）和脐带（UC）来源的间充质基质细胞延迟给药对有组织的抗生素耐药性肺脓毒症的疗效。
分离并扩增人骨髓、脂肪和脐带间充质基质细胞，以未激活状态或细胞因子预激活后使用。首先评估间充质基质细胞组织来源和激活状态的影响。随后的实验评估在啮齿动物感染后48小时作为延迟疗法的治疗潜力，在120小时评估疗效。
骨髓、脂肪和脐带间充质基质细胞加速上皮愈合，增加吞噬作用，并减少活性氧诱导的上皮损伤，脂肪间充质基质细胞效果较差，未激活的间充质基质细胞比预激活的间充质基质细胞更有效。在临床前有组织的肺脓毒症中间充质基质细胞延迟给药对生理指标无影响，但增强了肺结构损伤的消退。预激活的间充质基质细胞延迟治疗降低了纤维化因子的mRNA浓度。未激活的间充质基质细胞治疗降低了关键循环细胞比例，并增加了肺部细菌杀伤能力，而预激活的间充质基质细胞增强了肺白细胞的吞噬指数。
间充质基质细胞延迟治疗增强了抗生素耐药性感染诱导的肺损伤的消退，并有利地调节了免疫细胞谱。总体而言，脂肪间充质基质细胞比脐带或骨髓间充质基质细胞效果差，而未激活的间充质基质细胞与预激活的间充质基质细胞相比具有更有利的效应谱。
