Macrophage Migration Inhibitory Factor Enzymatic Activity, Lung Inflammation, and Cystic Fibrosis
Macrophage Migration Inhibitory Factor Enzymatic Activity, Lung Inflammation, and Cystic Fibrosis
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DOI：
10.1164/rccm.201110-1864oc
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发表时间：
2012-07-15
影响因子：
24.7
通讯作者：
Donnelly, Seamas C.
中科院分区：
文献类型：
--
作者：
Adamali, Huzaifa;Armstrong, Michelle E.;Donnelly, Seamas C.
基本原理：巨噬细胞移动抑制因子（MIF）是一种促炎介质，具有独特的互变异构酶酶活性;确切的功能尚未明确定义。我们以前证明，囊性纤维化（CF）谁是遗传倾向于高MIF生产者发展加速终末器官injury.Objectives的个别患者：为了表征的MIF-CATT多态性在CF患者离体的影响。目的：探讨巨噬细胞移动抑制因子（MIF）的互变异构酶活性在铜绿假单胞菌感染小鼠模型中的作用。方法：采用ELISA法检测血浆或外周血单个核细胞（PBMC）培养上清中MIF和肿瘤坏死因子（TNF）-α蛋白水平。在MIF野生型小鼠（mif（+/+））和互变异构酶缺失的MIF基因敲入小鼠（mif（P1 G/P1 G））中使用慢性假单胞菌感染的鼠肺模型。测量和主要结果：测量了来自患有CF的5-和6-CATT患者的血浆和PBMC中的MIF蛋白;还评估了LPS诱导的来自PBMC的TNF-α产生。在PBMC中研究了MIF-互变异构酶活性的特异性抑制剂ISO-1的作用。在鼠感染模型中，测量总重量损失、分类细胞计数、细菌负荷和腺泡内空气空间/组织体积。与5-CATT CF患者相比，6-CATT患者的MIF和TNF-α水平升高。LPS诱导的PBMC产生TNF-α在ISO-1存在下减弱。在假单胞菌感染的小鼠模型中，显着减少肺部炎症和细菌负荷，观察到在mif（P1 G/P1 G）与mif（+/+）mice.Conclusions：MIF-互变异构酶活性可能提供一种新的治疗靶点，在慢性炎症性疾病，如CF患者，特别是那些谁是遗传倾向于产生这种细胞因子的水平增加。
Rationale: Macrophage migration inhibitory factor (MIF) is a proinflammatory mediator with unique tautomerase enzymatic activity; the precise function has not been clearly defined. We previously demonstrated that individual patients with cystic fibrosis (CF) who are genetically predisposed to be high MIF producers develop accelerated end-organ injury.Objectives: To characterize the effects of the MIF-CATT polymorphism in patients with CF ex vivo. To investigate the role of MIF's tautomerase activity in a murine model of Pseudomonas aeruginosa infection.Methods: MIF and tumor necrosis factor (TNF)-alpha protein levels were assessed in plasma or peripheral blood mononuclear cell (PBMC) supernatants by ELISA. A murine pulmonary model of chronic Pseudomonas infection was used in MIF wild-type mice (mif(+/+)) and in tautomerase-null, MIF gene knockin mice (mif(P1G/P1G)).Measurements and Main Results: M IF protein was measured in plasma and PBMCs from 5- and 6-CATT patients with CF; LPS-induced TNF-alpha production from PBMCs was also assessed. The effect of a specific inhibitor of MIF-tautomerase activity, ISO-1, was investigated in PBMCs. In the murine infection model, total weight loss, differential cell counts, bacterial load, and intraacinar airspace/tissue volume were measured. MIF and TNF-alpha levels were increased in 6-CATT compared with 5-CATT patients with CF. LPS-induced TNF-alpha production from PBMCs was attenuated in the presence of ISO-1. In a murine model of Pseudomonas infection, significantly less pulmonary inflammation and bacterial load was observed in mif(P1G/P1G) compared with mif(+/+) mice.Conclusions: MIF-tautomerase activity may provide a novel therapeutic target in patients with chronic inflammatory diseases such as CF, particularly those patients who are genetically predisposed to produce increased levels of this cytokine.