Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice
Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice
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DOI：
10.4049/jimmunol.179.3.1855
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发表时间：
2007-08-01
影响因子：
4.4
通讯作者：
Matthay, Michael A.
中科院分区：
文献类型：
--
作者：
Gupta, Naveen;Su, Xiao;Matthay, Michael A.
最近的体内和体外工作表明间充质干细胞（MSC）具有抗炎特性。在这项研究中，我们测试了在大肠杆菌内毒素（5 mg/kg）内肺内给药后4小时直接将MSC直接施用到肺空间的作用。与PBS处理的对照小鼠48小时相比，MSC提高了生存率（80 vs 42％； P <0.01）。多余的肺水也有显着降低，这是肺水肿的量度（145 +/- 50 vs 87 +/- 20 mu l; p <0.01）和支气管肺泡灌洗蛋白，这是内皮和肺泡上皮性渗透性的量度（ 3.1 +/- 0.4 vs 2.2 +/- 0.8 mg/ml；老鼠。这些保护效应不会通过使用包括成纤维细胞和凋亡MSC在内的进一步控件来复制。 MSC的有益作用与细胞在肺中植入的能力无关，与MSC的内毒素清除无关。 MSC给药介导了对内毒素的促炎反应的下调（减少了支气管肺泡灌洗和血浆中的TNF-Alpha和MIP-2），同时增加了抗炎细胞因子IL-100。 MSC与肺泡巨噬细胞的体外共培养研究提供了证据，表明抗炎作用是旁分泌，而不是细胞接触。总之，用肺内MSC的治疗显着降低了内毒素诱导的急性肺损伤的严重程度，并改善了小鼠的存活率。
Recent in vivo and in vitro work suggests that mesenchymal stem cells (MSC) have anti-inflammatory properties. In this study, we tested the effect of administering MSC directly into the airspaces of the lung 4 h after the intrapulmonary administration of Escherichia coli endotoxin (5 mg/kg). MSC increased survival compared with PBS-treated control mice at 48 h (80 vs 42%; p < 0.01). There was also a significant decrease in excess lung water, a measure of pulmonary edema (145 +/- 50 vs 87 +/- 20 mu l; p < 0.01), and bronchoalveolar lavage protein, a measure of endothelial and alveolar epithelial permeability (3.1 +/- 0.4 vs 2.2 +/- 0.8 mg/ml; p < 0.01), in the MSC-treated mice. These protective effects were not replicated by the use of further controls including fibroblasts and apoptotic MSC. The beneficial effect of MSC was independent of the ability of the cells to engraft in the lung and was not related to clearance of the endotoxin by the MSC. MSC administration mediated a down-regulation of proinflammatory responses to endotoxin (reducing TNF-alpha and MIP-2 in the bronchoalveolar lavage and plasma) while increasing the anti-inflammatory cytokine IL-10. In vitro coculture studies of MSC with alveolar macrophages provided evidence that the anti-inflammatory effect was paracrine and was not cell contact dependent. In conclusion, treatment with intrapulmonary MSC markedly decreases the severity of endotoxin-induced acute lung injury and improves survival in mice.