Interleukin-10 Delivery via Mesenchymal Stem Cells: A Novel Gene Therapy Approach to Prevent Lung Ischemia–Reperfusion Injury

间充质干细胞 医学 移植 生理盐水 再灌注损伤 肺移植 干细胞 充氧 骨髓 缺血 内科学 病理 生物 遗传学
作者
Eddie W. Manning,Si M. Pham,Sen Li,Roberto I. Vázquez-Padrón,James M. Mathew,Phillip Ruiz,Shashikumar K. Salgar
出处
期刊:Human Gene Therapy [Mary Ann Liebert, Inc.]
卷期号:21 (6): 713-727 被引量:80
标识
DOI:10.1089/hum.2009.147
摘要

Ischemia reperfusion (IR)-induced lung injury is a major cause of primary graft failure after lung transplantation. In this study, Manning and colleagues examine whether bone-marrow derived mesenchymal stem cells engineered to secrete IL-10 can prevent lung IR injury in a rat model. Ischemia–reperfusion (IR) injury is an important cause of primary graft failure in lung transplantation. In this study, viral interleukin-10 (vIL-10)-engineered mesenchymal stem cells (MSCs) were tested for their ability to prevent lung IR injury. Bone marrow-derived MSCs were transduced with rvIL-10-retrovirus. After 120 min of warm left lung ischemia, rats received ∼15 × 106 vIL-10-engineered MSCs (MSC-vIL-10), empty vector-engineered MSCs (MSC-vec), or saline intravenously. Mean blood oxygenation (PaO2/FiO2 ratio, mmHg) was measured at 4 hr, 24 hr, 72 hr, and 7 days. As early as 4 hr post-IR injury with MSC-vIL-10 treatment, blood oxygenation was significantly (p < 0.05) improved (319 ± 94; n = 7) compared with untreated (saline) controls (63 ± 19; n = 6). At 24 hr post-IR injury, in the MSC-vIL-10-treated group there was a further increase in blood oxygenation (353 ± 105; n = 10) compared with the MSC-vec group (138 ± 86; n = 9) and saline group (87 ± 39; n = 10). By 72 hr, oxygenation reached normal (475 ± 55; n = 9) in the MSC-vIL-10-treated group but not in the saline-treated and MSC-vec-treated groups. At 4 hr after IR injury, lungs with MSC-vIL10 treatment had a lower (p < 0.05) injury score (0.9 ± 0.4) compared with lungs of the untreated (saline) group (2.5 ± 1.4) or MSC-vec-treated group (2 ± 0.4). Lung microvascular permeability and wet-to-dry weight ratios were markedly lower in the MSC-vIL10 group compared with untreated (saline) controls. ISOL (in situ oligonucleotide ligation for DNA fragmentation detection) and caspase-3 staining demonstrated significantly (p < 0.05) fewer apoptotic cells in MSC-vIL10-treated lungs. Animals that received MSC-vIL10 therapy had fewer (p < 0.05) CD4+ and CD8+ T cells in bronchoalveolar lavage fluid compared with untreated control animals. A therapeutic strategy using vIL-10-engineered MSCs to prevent IR injury in lung transplantation seems promising.

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