Chimeric SOD2/3 inhibits at the endothelial-neutrophil interface to limit vascular dysfunction in ischemia-reperfusion

被引:14
作者
Bonder, CS
Knight, D
Hernandez-Saavedra, D
McCord, JM
Kubes, P
机构
[1] Univ Calgary, Fac Med, Dept Physiol & Biophys, Immunol Res Grp, Calgary, AB T2N 4N1, Canada
[2] Univ Colorado, Hlth Sci Ctr, Webb Waring Inst Biomed Res, Denver, CO 80262 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY | 2004年 / 287卷 / 03期
关键词
superoxide dismutase; in vivo; endothelium;
D O I
10.1152/ajpgi.00049.2004
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
After an ischemic episode, reperfusion causes profound oxidative stress in the vasculature of the afflicted tissue/ organ. The dysregulated accumulation of reactive oxygen species (ROS), such as superoxide, has been closely linked to the production and release of proinflammatory mediators, a profound increase in adhesion molecule expression by the vascular endothelium, and infiltration of neutrophils during ischemia-reperfusion (I/R). Superoxide dismutase (SOD) has been shown to protect tissues and organs against I/R-induced injury; however, the drug had to be continuously per-fused or kidneys had to be occluded to prevent clearance. We used intravital microscopy, a system that allowed us to visualize neutrophil-endothelial interactions within the mesenteric posteapillary venules of cats subjected to I/R and tested the hypothesis that I/R-induced neutrophil recruitment was inhibited by treatment with SOD2/3. SOD2/3 is a chimeric fusion gene product that contains the mature SOD2 as well as the COON-terminal "tail" of SODS and, unlike the three naturally occurring SODS (SOD1, SOD2, and SOD3), which bear a net negative charge at pH 7.4, SOD2/3 is positively charged and physiologically stable. Our results suggest that not only does SOD2/3 have a much greater efficacy in vivo than the native human SOD2, but its administration prevents I/R-induced neutrophil-endothelial cell interactions and microvascular dysfunction. Moreover, our data support the hypothesis that reactive oxidants mediate I/R-induced injury and that the chimeric recombinant SOD2/3 has the potential to be a therapeutic agent against this debilitating illness.
引用
收藏
页码:G676 / G684
页数:9
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