In Vivo Fluorescence-mediated Tomography for Quantification of Urokinase Receptor-dependent Leukocyte Trafficking in Inflammation
In Vivo Fluorescence-mediated Tomography for Quantification of Urokinase Receptor-dependent Leukocyte Trafficking in Inflammation
复制标题
DOI：
10.1097/aln.0b013e3181e99bfc
复制
发表时间：
2010-09-01
期刊：
影响因子：
8.8
通讯作者：
Theilmeier, Gregor
中科院分区：
文献类型：
--
作者：
Larmann, Jan;Frenzel, Tim;Theilmeier, Gregor
背景：炎症的特征是白细胞募集。巨噬细胞和中性粒细胞导致组织损伤和器官功能障碍。调节白细胞侵入可以保护免受这些不利影响。白细胞募集主要依赖于尿激酶型纤溶酶原激活物受体（u-PAR）。在这里，我们使用一种新的技术来纵向量化细胞贩运的炎症模型在live animal.Methods：近红外荧光团标记的白细胞过继转移到小鼠巯基乙酸盐腹膜炎，研究白细胞贩运的炎症部位。巨噬细胞和中性粒细胞的运输与三维荧光介导的断层扫描。通过交叉过继细胞转移研究u-PAR-/-和野生型巨噬细胞募集，以阐明白细胞相对于在其他细胞上表达的u-PAR的作用。结果：腹膜炎小鼠巨噬细胞（315%，n = 9-10）或中性粒细胞（194%，n = 6，P <0.05）的聚集明显增强，肺组织中u-PARs的平均荧光强度明显增强。放射性介导的断层扫描发现，与对照小鼠（基线的335%，n = 8-9，P < 0.05）相比，u-PAR-/-小鼠腹膜炎模型中的巨噬细胞募集缺陷（基线的147%）。当u-PAR-/-巨噬细胞转移到野生型小鼠时，荧光强度增加到145%，而野生型巨噬细胞转移到u-PAR-/-中导致与基线相比增加192%（n = 6，P < 0.05）。减少中性粒细胞招聘在肺部炎症中的u-PAR-/-小鼠是伴随着改善肺部气体exchang.Conclusion：使用非侵入性体内荧光介导的断层成像白细胞招聘炎症小鼠模型，我们描述了一种新的巨噬细胞招聘缺陷u-PAR-/-小鼠。靶向u-PAR以调节白细胞募集是改善白细胞诱导的组织损伤的有希望的治疗策略。
Background: Inflammation is characterized by leukocyte recruitment. Macrophages and neutrophils contribute to tissue damage and organ dysfunction. Modulating leukocyte invasion can protect from these adverse effects. Leukocyte recruitment critically depends on the urokinase-type plasminogen activator receptor (u-PAR). We here use a novel technique to longitudinally quantify cell trafficking in inflammatory models in live animals.Methods: Near-infrared fluorophore-labeled leukocytes were adoptively transferred to mice with thioglycollate peritonitis to study leukocyte trafficking to sites of inflammation. Macrophage and neutrophil trafficking was followed with three-dimensional fluorescence-mediated-tomography. u-PAR-/- and wild-type macrophage recruitment was studied by cross-over adoptive cell transfer to elucidate the role of leukocytic versus u-PAR expressed on other cells. Endotoxic shock-induced pulmonary inflammation was used to study u-PARs role for pulmonary neutrophil recruitment.Results: Mice experiencing peritonitis showed a significant increase in mean fluorescence intensity because of enhanced macro-phage (315%, n = 9-10), P < 0.05) or neutrophil (194%, n = 6, P < 0.02) recruitment. Fluorescence-mediated-tomography uncovered a macrophage recruitment defect in the peritonitis model for u-PAR-/- mice (147% of baseline) compared with control mice (335% of baseline, n = 8-9, P < 0.05). When u-PAR-/- macrophages were transferred to wild-type mice fluorescence intensity increased to 145% while wild-type macrophage transfer into u-PAR-/- resulted in 192% increase compared with baseline (n = 6, P < 0.05). Reduced neutrophil recruitment in pulmonary inflammation in u-PAR-/- mice was accompanied by improved pulmonary gas exchange.Conclusion: Using noninvasive in vivo fluorescence-mediated tomography to image leukocyte recruitment in inflammatory mouse models, we describe a novel macrophage recruitment defect in u-PAR-/- mice. Targeting u-PAR for modulation of leukocyte recruitment is a promising therapeutic strategy to ameliorate leukocyte induced tissue damage.