Blood-Brain Barrier Disruption and Oxidative Stress in Guinea Pig after Systemic Exposure to Modified Cell-Free Hemoglobin

被引:68
作者
Butt, Omer I. [1 ]
Buehler, Paul W. [1 ]
D'Agnillo, Felice [1 ]
机构
[1] US FDA, Lab Biochem & Vasc Biol, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA
关键词
EXPERIMENTAL INTRACEREBRAL HEMORRHAGE; EXPERIMENTAL SUBARACHNOID HEMORRHAGE; HEME OXYGENASE-1; ENDOTHELIAL-CELLS; CLINICAL-ASPECTS; CARBON-MONOXIDE; IN-VIVO; INJURY; PROTEIN; RAT;
D O I
10.1016/j.ajpath.2010.12.006
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Systemic exposure to cell-free hemoglobin (Hb) or its breakdown products after hemolysis or with the use of Hb-based oxygen therapeutics may alter the function and integrity of the blood-brain barrier. Using a guinea pig exchange transfusion model, we investigated the effect of a polymerized cell-free Hb (HbG) on the expression of endothelial tight junction proteins (zonula occludens 1, claudin-5, and occludin), astrocyte activation, IgG extravasation, heme oxygenase (HO), iron deposition, oxidative end products (4-hydroxynonenal adducts and 8-hydroxydeoxyguanosine), and apoptosis (cleaved caspase 3). Reduced zonula occludens 1 expression was observed after HbG transfusion as evidenced by Western blot and confocal microscopy. Claudin-5 distribution was altered in small- to medium-sized vessels. However, total expression of claudin-5 and occludin remained unchanged except for a notable increase in occludin 72 hours after HbG transfusion. HbG-transfused animals also showed increased astrocytic glial fibrillary acidic protein expression and IgG extravasation after 72 hours. Increased HO activity and HO-1 expression with prominent enhancement of HO-1 immunoreactivity in CD163-expressing perivascular cells and infiltrating monocytes/macrophages were also observed. Consistent with oxidative stress, HbG increased iron deposition, 4-hydroxynonenal and 8-hydroxydeoxyguanosine immunoreactivity, and cleaved caspase-3 expression. Systemic exposure to an extracellular Hb triggers blood-brain barrier disruption and oxidative stress, which may have important implications for the use of Hb-based therapeutics and may provide indirect insight on the central nervous system vasculopathies associated with excessive hemolysis. (Am J Pathol 2011, 178:1316-1328; DOI: 10.1016/j.ajpath.2010.12.006)
引用
收藏
页码:1316 / 1328
页数:13
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