He Hongli, Liu Ling, Chen Qihong, Liu Airan, Cai Shixia, Yang Yi, Lu Xiaomin, Qiu Haibo
Department of Critical Care Medicine, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, P. R. China.
Cell Transplant. 2015;24(9):1699-715. doi: 10.3727/096368914X685087. Epub 2014 Oct 6.
Bone marrow-derived mesenchymal stem cells (MSCs), which have beneficial effects in acute lung injury (ALI), can serve as a vehicle for gene therapy. Angiotensin-converting enzyme 2 (ACE2), a counterregulatory enzyme of ACE that degrades angiotensin (Ang) II into Ang 1-7, has a protective role against ALI. Because ACE2 expression is severely reduced in the injured lung, a therapy targeted to improve ACE2 expression in lung might attenuate ALI. We hypothesized that MSCs overexpressing ACE2 would have further benefits in lipopolysaccharide (LPS)-induced ALI mice, when compared with MSCs alone. MSCs were transduced with ACE2 gene (MSC-ACE2) by a lentiviral vector and then infused into wild-type (WT) and ACE2 knockout (ACE2(-/y)) mice following an LPS-induced intratracheal lung injury. The results demonstrated that the lung injury of ALI mice was alleviated at 24 and 72 h after MSC-ACE2 transplantation. MSC-ACE2 improved the lung histopathology and had additional anti-inflammatory effects when compared with MSCs alone in both WT and ACE2(-/y) ALI mice. MSC-ACE2 administration also reduced pulmonary vascular permeability, improved endothelial barrier integrity, and normalized lung eNOS expression relative to the MSC group. The beneficial effects of MSC-ACE2 could be attributed to its recruitment into the injured lung and enhanced local expression of ACE2 protein without changing the serum ACE2 levels after MSC-ACE2 transplantation. The biological activity of the increased ACE2 protein decreased the Ang II amount and increased the Ang 1-7 level in the lung when compared with the ALI and MSC-only groups, thereby inhibiting the detrimental effects of accumulating Ang II. Therefore, compared to MSCs alone, the administration of MSCs overexpressing ACE2 resulted in a further improvement in the inflammatory response and pulmonary endothelial function of LPS-induced ALI mice. These additional benefits could be due to the degradation of Ang II that accompanies the targeted overexpression of ACE2 in the lung.
骨髓间充质干细胞（MSCs）对急性肺损伤（ALI）具有有益作用，可作为基因治疗的载体。血管紧张素转换酶2（ACE2）是ACE的一种反调节酶，可将血管紧张素（Ang）II降解为Ang 1-7，对ALI具有保护作用。由于ACE2在受损肺组织中的表达严重降低，因此旨在提高肺组织中ACE2表达的治疗可能会减轻ALI。我们假设，与单独使用MSCs相比，过表达ACE2的MSCs对脂多糖（LPS）诱导的ALI小鼠具有更大的益处。通过慢病毒载体将ACE2基因转导至MSCs（MSC-ACE2），然后在LPS诱导气管内肺损伤后将其注入野生型（WT）和ACE2基因敲除（ACE2（-/-））小鼠体内。结果表明，在移植MSC-ACE2后24小时和72小时，ALI小鼠的肺损伤得到缓解。与单独使用MSCs相比，在WT和ACE2（-/-）ALI小鼠中，MSC-ACE2均改善了肺组织病理学，并具有额外的抗炎作用。与MSC组相比，给予MSC-ACE2还降低了肺血管通透性，改善了内皮屏障完整性，并使肺组织eNOS表达恢复正常。MSC-ACE2的有益作用可能归因于其被募集到受损肺组织中，并增强了ACE2蛋白的局部表达，而在移植MSC-ACE2后血清ACE2水平未发生变化。与ALI组和仅使用MSCs组相比，增加的ACE2蛋白的生物学活性降低了肺组织中Ang II的量并提高了Ang 1-7水平，从而抑制了Ang II积累的有害作用。因此，与单独使用MSCs相比，给予过表达ACE2的MSCs可进一步改善LPS诱导的ALI小鼠的炎症反应和肺内皮功能。这些额外的益处可能是由于肺组织中ACE2靶向过表达伴随的Ang II降解所致。
