Németh Krisztián, Leelahavanichkul Asada, Yuen Peter S T, Mayer Balázs, Parmelee Alissa, Doi Kent, Robey Pamela G, Leelahavanichkul Kantima, Koller Beverly H, Brown Jared M, Hu Xuzhen, Jelinek Ivett, Star Robert A, Mezey Eva
National Institute of Dental and Craniofacial Research (NIDCR), Craniofacial and Skeletal Diseases Branch, NIH, Bethesda, MD 20892, USA.
Nat Med. 2009 Jan;15(1):42-9. doi: 10.1038/nm.1905. Epub 2008 Nov 21.
Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCs -- also known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF) receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-alpha) reprogram macrophages by releasing prostaglandin E(2) that acts on the macrophages through the prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups.
在美国，脓毒症每年导致超过20万人死亡；迫切需要更好的治疗方法。在通过盲肠结扎和穿刺诱导小鼠脓毒症之前或之后不久给予骨髓基质细胞（BMSCs，也称为间充质干细胞），可降低死亡率并改善器官功能。巨噬细胞耗竭或用白细胞介素10（IL-10）或IL-10受体特异性抗体预处理可消除BMSCs的有益作用。与未处理的小鼠相比，从用BMSCs处理的小鼠制备的脓毒症肺中的单核细胞和/或巨噬细胞产生更多的IL-10。用BMSCs培养时，脂多糖（LPS）刺激的巨噬细胞产生更多的IL-10，但如果BMSCs缺乏编码Toll样受体4、髓样分化初级反应基因-88、肿瘤坏死因子（TNF）受体-1a或环氧化酶-2的基因，则这种作用会消除。我们的结果表明，BMSCs（由LPS或TNF-α激活）通过释放前列腺素E2来重新编程巨噬细胞，前列腺素E2通过前列腺素EP2和EP受体作用于巨噬细胞。由于BMSCs已成功应用于人类，并且易于培养，可能无需进行人类白细胞抗原匹配即可使用，我们建议培养的、储存的人BMSCs可能对治疗高危患者群体的脓毒症有效。
