Mesenchymal Stem Cells Overexpressing Angiotensin-Converting Enzyme 2 Rescue Lipopolysaccharide-Induced Lung Injury
Mesenchymal Stem Cells Overexpressing Angiotensin-Converting Enzyme 2 Rescue Lipopolysaccharide-Induced Lung Injury
复制标题
过度表达血管紧张素转换酶 2 的间充质干细胞可挽救脂多糖诱导的肺损伤。
DOI：
10.3727/096368914x685087
复制
发表时间：
2015-01-01
影响因子：
3.3
通讯作者：
Qiu, Haibo
中科院分区：
文献类型：
--
作者：
He, Hongli;Liu, Ling;Qiu, Haibo
骨髓间充质干细胞（MSCs）在急性肺损伤（ALI）中具有有益作用，可作为基因治疗的载体。血管紧张素转换酶2（ACE 2）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ACE 2表达在损伤的肺中严重降低，靶向改善肺中ACE 2表达的治疗可能减轻ALI。我们假设，与单独的MSC相比，过表达ACE 2的MSC在脂多糖（LPS）诱导的ALI小鼠中具有进一步的益处。通过慢病毒载体将ACE 2基因（MSC-ACE 2）转导到MSC中，然后在LPS诱导的肺内损伤后将MSC输注到野生型（WT）和ACE 2敲除（ACE 2-/y）小鼠中。结果表明，MSC-ACE 2移植后24 h和72 h肺损伤明显减轻。在WT和ACE 2-/y ALI小鼠中，与单独使用MSC相比，MSC-ACE 2改善了肺组织病理学，并具有额外的抗炎作用。与MSC组相比，MSC-ACE 2给药还降低了肺血管通透性，改善了内皮屏障完整性，并使肺eNOS表达正常化。MSC-ACE 2的有益作用可能是由于其向损伤肺的募集和增强局部ACE 2蛋白的表达而不改变MSC-ACE 2移植后血清ACE 2水平。与ALI和仅MSC组相比，增加的ACE 2蛋白的生物活性降低了肺中的Ang II量并增加了Ang 1-7水平，从而抑制了积聚Ang II的有害作用。因此，与单独的MSC相比，施用过表达ACE 2的MSC导致LPS诱导的ALI小鼠的炎症反应和肺内皮功能的进一步改善。这些额外的益处可能是由于伴随肺中ACE 2靶向过表达的Ang II降解。
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.