Zhao Xiurong, Grotta James, Gonzales Nicole, Aronowski Jaroslaw
Professor of Neurology, Director of Stroke Research, Department of Neurology, University of Texas-Houston Medical School, Houston, TX 77030, USA.
Stroke. 2009 Mar;40(3 Suppl):S92-4. doi: 10.1161/STROKEAHA.108.533158. Epub 2008 Dec 8.
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.
目前尚无有效的疗法可用于治疗脑出血（ICH）。脑出血后脑损伤的几个关键因素之一是血液成分的神经毒性。在脑出血后的数小时至数天内，血肿中渗出的红细胞发生裂解，释放出具有细胞毒性的血红蛋白、血红素和铁，从而引发一系列继发性过程，对血肿周围细胞的活力产生负面影响。为了抵消这一过程，包括脑内小胶质细胞和血源性巨噬细胞在内的吞噬细胞会在红细胞裂解及后续毒性发生之前吞噬并处理渗出的红细胞。因此，我们推测，一种能刺激吞噬作用的治疗方法将促使脑出血损伤的大脑更快地清除血液，从而限制/防止溶血的发生。CD36是一种广为人知的小胶质细胞/巨噬细胞膜整合蛋白，已知其可介导对受损、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（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上调，可增强小胶质细胞吞噬红细胞的能力（体外试验），有助于改善血肿的消退，并减轻脑出血小鼠模型中脑出血引起的功能缺陷。我们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。过氧化物酶体增殖物激活受体γ激动剂可能代表一种治疗脑出血的潜在策略。
