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Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppresses renal injury in mouse Goodpasture syndrome.
转基因骨髓持续供应抗炎细胞并抑制小鼠 Goodpasture 综合征的肾损伤。

摘要

In chronic inflammation, macrophages and neutrophils, which are derived from bone marrow, play a pivotal role. Therefore, reconstitution of bone marrow with anti-inflammatory stem cells may modify inflammation. In this study, transplantation-based gene therapy was applied to glomerular inflammation for a long-lasting suppression of the glomerular damage seen in chronic nephritis. Bone marrow cells were harvested from male donor mice, which had received 5-fluorouracil 3 days previously, and transduced with an interleukin 1 (IL-1) receptor antagonist (IL-1Ra) or a mock gene using a retrovirus vector. After confirmation that transduced cells possessed the transgene at approximately 0.7 copies per cell and secreted recombinant IL-1Ra, these cells were infused into sublethally irradiated (6 Gy) female recipients once daily for 4 consecutive days. These female recipient mice had the male Y antigen in bone marrow, liver, and spleen, and 10% to 20% of their spleen cells possessed the transgene even 8 weeks after transplantation. Glomerulonephritis was then induced in these mice. Renal function and histology were retarded in the mice whose bone marrow was reconstituted with IL-1Ra-producing cells compared with mock transduced cells. In situ hybridization using a Y painting probe revealed that transplanted donor cells were recruited into the glomerulus upon induction of nephritis, suggesting therapeutic effects were channeled through the secretion of IL-1Ra from these cells. Furthermore, the survival rate after a second challenge with nephrotoxic antibody was significantly improved in the IL-1Ra chimera. These results suggest that reconstitution of bone marrow for continuous supply of anti-inflammatory cells may be a useful strategy for the treatment of chronic inflammation.

译文

在慢性炎症中,来源于骨髓的巨噬细胞和中性粒细胞发挥着关键作用。因此,用抗炎干细胞重建骨髓可能会改变炎症。在这项研究中,基于移植的基因疗法被应用于肾小球炎症,以长期抑制慢性肾炎中肾小球损伤。骨髓细胞是从三天前接受 5-氟尿嘧啶的雄性供体小鼠中获取的,并用白细胞介素 1 (IL-1) 受体拮抗剂 (IL-1Ra) 转导或者使用逆转录病毒载体的模拟基因。在确认转导细胞拥有转基因,每个细胞约 0.7 个拷贝,并分泌重组 IL-1Ra 后,这些细胞被注入亚致死性辐射 (6 Gy) 女性受体中,每天一次,连续 4 天。这些雌性受体小鼠的骨髓、肝脏和脾脏中含有雄性 Y 抗原,甚至在移植后 8 周,它们 10% 到 20% 的脾细胞也具有转基因。然后在这些小鼠中诱导肾小球肾炎。与模拟转导细胞相比,骨髓用 IL-1Ra-producing 细胞重组的小鼠的肾功能和组织学迟钝。使用 Y 涂层探针的原位杂交显示,移植的供体细胞在肾炎诱导时被招募到肾小球,这表明治疗效果是通过从这些细胞分泌 IL-1Ra 来实现的。此外,在 IL-1Ra 嵌合体中,肾毒性抗体第二次激发后的存活率显著提高。这些结果表明,重建骨髓以持续供应抗炎细胞可能是治疗慢性炎症的有效策略。

Goodpasture syndrome

呼吸 自身免疫性疾病 疾病
概述  :  

肺出血肾炎综合征是以突发性肺出血伴有其他肺部症状,同时合并进行性肾小球肾炎和贫血以致发生尿毒症和呼吸功能衰竭为特征的病症,好发于青中年男性。 病因 肺出血肾炎综合征可能是由于多种病因引起的一种自身免疫性疾病,如吸入某种化学物质,或肺部病毒感染,使机体同时产生抗肺泡、脊小球基底膜抗体(抗GBM抗体),循环抗GBM抗体与肺泡基底膜上暴露的Ⅳ型胶原α3链羧基端球形非胶原区的位点结合,激活补体链接反应,引起多形核白细胞和和单核细胞浸润。动物实验证

Goodpasture   /ɡʊdˈpæstʃər/

释    义   肾炎综合征

例    句   To discuss the clinical manifestations and imaging features of Goodpasture syndrome. 探讨肺出血肾炎综合症的临床表现和影像学特征。

 

Syndrome   英 /ˈsɪndrəʊm/   美 /ˈsɪndroʊm/

释    义   n. [临床] 综合症状;并发症状;校验子

例    句   Why cancer and metabolic syndrome might be connected is not yet clear. 还不清楚为什么癌症和新陈代谢综合症有联系。

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