Stokes K Y, Clanton E C, Russell J M, Ross C R, Granger D N
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Circ Res. 2001 Mar 16;88(5):499-505. doi: 10.1161/01.res.88.5.499.
Experimental animals placed on a high-cholesterol diet for 2 or more weeks exhibit an inflammatory response in postcapillary venules. The aims of this study were to determine (1) whether superoxide mediates the hypercholesterolemia-induced inflammatory response and (2) whether leukocyte and/or vessel wall NAD(P)H oxidase contributes to this response. Intravital videomicroscopy was used to quantify leukocyte-endothelial cell adhesion in cremasteric postcapillary venules of wild-type (WT) mice, CuZn-superoxide dismutase transgenic (SOD TgN) mice, and mice heterozygous (p47(phox)+/-) or homozygous (p47(phox)-/-) for NAD(P)H oxidase placed on either a normal diet or high-cholesterol diet (HCD) for 2 weeks. The number of adherent and emigrated leukocytes in postcapillary venules of WT HCD mice was significantly higher than that detected in venules of their normal-diet counterparts. However, the HCD-induced recruitment of adherent and emigrated leukocytes was not observed in SOD TgN mice. Whereas hypercholesterolemic p47(phox)+/- and WT mice exhibited similar inflammatory responses, p47(phox)-/- mice did not. Bone marrow chimeras were developed to selectively delete p47(phox) from either the vessel wall or circulating leukocytes. Whereas WT marrow transplanted into WT mice produced a normal inflammatory response of venules to HCD, chimeric mice with p47(phox) deficiency in either the vessel wall or leukocytes exhibited an attenuated inflammatory response to HCD that was comparable with that observed in p47(phox)-/- HCD mice. Our findings indicate that enhanced superoxide production is a critical event that initiates the leukocyte-endothelial cell adhesion in postcapillary venules of HCD mice. NAD(P)H oxidase appears to be an important source of this superoxide.
将实验动物置于高胆固醇饮食2周或更长时间后，其毛细血管后微静脉会出现炎症反应。本研究的目的是确定：（1）超氧化物是否介导高胆固醇血症诱导的炎症反应；（2）白细胞和/或血管壁NAD（P）H氧化酶是否参与此反应。采用活体视频显微镜技术，对野生型（WT）小鼠、铜锌超氧化物歧化酶转基因（SOD TgN）小鼠，以及NAD（P）H氧化酶杂合（p47（phox）+/-）或纯合（p47（phox）-/-）的小鼠的提睾肌毛细血管后微静脉中白细胞与内皮细胞的黏附进行定量分析。这些小鼠分别给予正常饮食或高胆固醇饮食（HCD）2周。WT HCD小鼠毛细血管后微静脉中黏附和游出的白细胞数量显著高于正常饮食组的对应小鼠微静脉中的数量。然而，在SOD TgN小鼠中未观察到HCD诱导的黏附和游出白细胞募集现象。高胆固醇血症的p47（phox）+/-小鼠和WT小鼠表现出相似的炎症反应，而p47（phox）-/-小鼠则没有。构建骨髓嵌合体以选择性地从血管壁或循环白细胞中删除p47（phox）。将WT骨髓移植到WT小鼠中，会产生微静脉对HCD的正常炎症反应，而血管壁或白细胞中缺乏p47（phox）的嵌合小鼠对HCD的炎症反应减弱，这与p47（phox）-/- HCD小鼠中观察到的情况相当。我们的研究结果表明，超氧化物生成增加是引发HCD小鼠毛细血管后微静脉中白细胞与内皮细胞黏附的关键事件。NAD（P）H氧化酶似乎是这种超氧化物的重要来源。
