Adoptive Transfer of Ex Vivo HO-1 Modified Bone Marrow-derived Macrophages Prevents Liver Ischemia and Reperfusion Injury
Adoptive Transfer of Ex Vivo HO-1 Modified Bone Marrow-derived Macrophages Prevents Liver Ischemia and Reperfusion Injury
复制标题
DOI：
10.1038/mt.2009.285
复制
发表时间：
2010-05-01
影响因子：
12.4
通讯作者：
Kupiec-Weglinski, Jerzy W.
中科院分区：
文献类型：
--
作者：
Ke, Bibo;Shen, Xiu-Da;Kupiec-Weglinski, Jerzy W.
巨噬细胞在肝脏缺血再灌注损伤（IRI）的病理生理过程中起重要作用。然而，过表达抗氧化剂血红素氧合酶-1（HO-1）的巨噬细胞可能发挥深刻的抗炎功能。本研究探讨了离体修饰的HO-1表达的骨髓源性巨噬细胞（BMDM）在明确定义的小鼠肝脏热缺血再灌注模型中的细胞保护作用及其机制。Ad-HO-1转导的巨噬细胞的连续转移防止了IR诱导的肝细胞损伤，与Ad-beta-gal对照相比，血清谷草转氨酶（sGOT）水平降低和肝脏组织学（Suzuki评分）保持不变证明了这一点。这种有益作用在用HO-1 siRNA伴随治疗后逆转。与对照组相比，Ad-HO-1转染的巨噬细胞显著降低了局部中性粒细胞聚集、TNF-α/IL-1 β、IFN-γ/E-选择素和IP-10/MCP-1表达、caspase-3活性和凋亡细胞的频率。与对照组不同，Ad-HO-1转染的巨噬细胞显著增加了抗凋亡Bcl-2/Bcl-xl的肝脏表达，并抑制了caspase-3活性。这些结果建立了一个新的研究工具的先例，并提供了一个临床上有吸引力的新策略，其中天然巨噬细胞可以转染离体细胞保护HO-1，然后输注，如果需要的话，暴露于肝IR介导的局部炎症，如在肝移植，切除术，或创伤的预期收件人的基本原理。
Macrophages play a critical role in the pathophysiology of liver ischemia and reperfusion (IR) injury (IRI). However, macrophages that overexpress antioxidant heme oxygenase-1 (HO-1) may exert profound anti inflammatory functions. This study explores the cytoprotective effects and mechanisms of ex vivo modified HO-1-expressing bone marrow-derived macrophages (BMDMs) in well-defined mouse model of liver warm ischemia followed by reperfusion. Adoptive transfer of Ad-HO-1-transduced macrophages prevented IR-induced hepatocellular damage, as evidenced by depressed serum glutamic-oxaloacetic transaminase (sGOT) levels and preserved liver histology (Suzuki scores), compared to Ad-beta-gal controls. This beneficial effect was reversed following concomitant treatment with HO-1 siRNA. Ad-HO-1-transfected macrophages significantly decreased local neutrophil accumulation, TNF-alpha/IL-1 beta, IFN-gamma/E-selectin, and IP-10/MCP-1 expression, caspase-3 activity, and the frequency of apoptotic cells, as compared with controls. Unlike in controls, Ad-HO-1-transfected macrophages markedly increased hepatic expression of antiapoptotic Bcl-2/Bcl-xl and depressed caspase-3 activity. These results establish the precedent for a novel investigative tool and provide the rationale for a clinically attractive new strategy in which native macrophages can be transfected ex vivo with cytoprotective HO-1 and then infused, if needed, to prospective recipients exposed to hepatic IR-mediated local inflammation, such as during liver transplantation, resection, or trauma.