Hematoma Resolution as a Therapeutic Target The Role of Microglia/Macrophages
Hematoma Resolution as a Therapeutic Target The Role of Microglia/Macrophages
复制标题
DOI：
10.1161/strokeaha.108.533158
复制
发表时间：
2009-03-01
期刊：
影响因子：
8.3
通讯作者：
Aronowski, Jaroslaw
中科院分区：
文献类型：
--
作者：
Zhao, Xiurong;Grotta, James;Aronowski, Jaroslaw
目前尚无有效的疗法可用于治疗脑出血（ICH）。 ICH后脑损伤的几个关键因素之一是血液制品的神经毒性。 ICH后数小时至数天内，血肿中外渗的红细胞发生裂解，释放细胞毒性血红蛋白、血红素和铁，从而启动二次过程，对血肿周围细胞的活力产生负面影响。为了抵消这一过程，吞噬细胞（包括大脑的小胶质细胞和血源性巨噬细胞）会吞噬并处理渗出的红细胞，然后发生裂解和随后的毒性。因此，我们假设刺激吞噬作用的治疗将导致更快地从受 ICH 影响的大脑中清除血液，从而限制/防止溶血的发生。 CD36 是一种公认的完整小胶质细胞/巨噬细胞细胞膜蛋白，已知可介导受损、凋亡或衰老细胞（包括红细胞）的吞噬作用。 CD36 和过氧化氢酶的表达受过氧化物酶体增殖物激活受体-γ 激动剂（例如罗格列酮）的调节。我们证明，过氧化物酶体增殖物激活受体-γ 激动剂诱导巨噬细胞中 CD36 的上调增强了小胶质细胞吞噬红细胞的能力（体外测定），有助于改善血肿消退，并减少 ICH 小鼠模型中 ICH 诱导的缺陷。还讨论了过氧化物酶体增殖物激活受体γ诱导的过氧化氢酶表达在吞噬作用中的有益作用。邻近体增殖物激活受体-γ 激动剂可能代表脑出血治疗的潜在治疗策略。 （行程。2009 年；40[增补 1]：S92-S94。）
No effective therapy is available for treating intracerebral hemorrhage (ICH). One of several key components of brain damage after ICH is the neurotoxicity of blood products. Within hours to days after ICH, extravasated erythrocytes in the hematoma undergo lysis, releasing cytotoxic hemoglobin, heme, and iron, thereby initiating secondary processes, which negatively influence the viability of cells surrounding the hematoma. To offset this process, phagocytic cells, including the brain's microglia and hematogenous macrophages, phagocytose and then process extravasated erythrocytes before lysis and subsequent toxicity occurs. Therefore, we hypothesize that a treatment that stimulates phagocytosis will lead to faster removal of blood from the ICH-affected brain, thus limiting/preventing hemolysis from occurring. CD36 is a well-recognized integral microglia/macrophage cell membrane protein known to mediate phagocytosis of damaged, apoptotic, or senescent cells, including erythrocytes. CD36 and catalase expression are regulated by peroxisome proliferator activated receptor-gamma agonists (eg, rosiglitazone). We demonstrate that peroxisome proliferator activated receptor-gamma agonist-induced upregulation of CD36 in macrophages enhances the ability of microglia to phagocytose red blood cells (in vitro assay), helps to improve hematoma resolution, and reduces ICH-induced deficit in a mouse model of ICH. The beneficial role of peroxisome proliferator activated receptor-gamma-induced catalase expression in the context of phagocytosis is also discussed. Proxisome proliferator activated receptor-gamma agonists could represent a potential treatment strategy for treatment of ICH. (Stroke. 2009; 40[suppl 1]: S92-S94.)