Blood-Brain Barrier Disruption and Oxidative Stress in Guinea Pig after Systemic Exposure to Modified Cell-Free Hemoglobin
Blood-Brain Barrier Disruption and Oxidative Stress in Guinea Pig after Systemic Exposure to Modified Cell-Free Hemoglobin
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DOI：
10.1016/j.ajpath.2010.12.006
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发表时间：
2011-03-01
影响因子：
6
通讯作者：
D'Agnillo, Felice
中科院分区：
文献类型：
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作者：
Butt, Omer I.;Buehler, Paul W.;D'Agnillo, Felice
溶血后全身暴露于无细胞血红蛋白（Hb）或其分解产物或使用基于Hb的氧治疗剂可能会改变血脑屏障的功能和完整性。使用豚鼠交换输血模型，我们研究了聚合的无细胞血红蛋白（HbG）对内皮紧密连接蛋白（闭锁小带1，claudin-5和occludin），星形胶质细胞活化，IgG外渗，血红素加氧酶（HO），铁沉积，氧化终产物（4-羟基壬烯醛加合物和8-羟基脱氧鸟苷）和细胞凋亡（裂解半胱天冬酶3）的表达的影响。通过Western印迹和共聚焦显微镜观察到HbG输注后闭合小带1表达减少。Claudin-5分布在小型至中型血管中发生改变。然而，claudin-5和occludin的总表达保持不变，除了在HbG输注后72小时occludin显著增加。输注HbG的动物在72小时后也显示星形胶质细胞胶质细胞酸性蛋白表达增加和IgG外渗。HO活性和HO-1表达增加，在表达CD 163的血管周围细胞和浸润的单核细胞/巨噬细胞中HO-1免疫反应性显著增强。与氧化应激一致，HbG增加铁沉积，4-羟基壬烯醛和8-羟基脱氧鸟苷免疫反应性，并裂解caspase-3的表达。全身暴露于细胞外Hb会触发血脑屏障破坏和氧化应激，这可能对使用基于Hb的治疗方法具有重要意义，并可能间接了解与过度溶血相关的中枢神经系统血管病变。(Am J Pathol 2011，178：1316-1328; DOI：10.1016/j.ajpath.2010.12.006）
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)