Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase
Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase
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DOI：
10.1073/pnas.0803945105
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发表时间：
2008-11-25
影响因子：
11.1
通讯作者：
Weissleder, Ralph
中科院分区：
文献类型：
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作者：
Breckwoldt, Michael O.;Chen, John W.;Weissleder, Ralph
在实验动物模型中，炎症会加重缺血性脑损伤并对结果产生不利影响。将动物研究成果转化到人类身上的一个关键困难在于，缺乏一种确定的方法在体内确认和追踪大脑中的炎症。髓过氧化物酶（MPO）是一种由活化的中性粒细胞以及巨噬细胞/小胶质细胞分泌的关键炎症酶，它能产生高活性氧物质，在脑缺血中造成额外损伤。我们在此报告，一种功能性的、酶可激活的磁共振成像（MRI）试剂能够在活体动物的中风模型中非侵入性地准确追踪MPO的氧化活性。我们发现MPO广泛分布于缺血组织中，与梗死面积呈正相关，甚至在梗死3周后仍能被检测到。通过体内MPO传感试剂的激活确定，并由MPO活性和定量逆转录聚合酶链反应（RT - PCR）测定所证实，MPO活性的峰值出现在缺血后的第3天。中性粒细胞和巨噬细胞/小胶质细胞都参与了缺血大脑中MPO的分泌，不过中性粒细胞的峰值出现得更早（第1 - 3天），而巨噬细胞/小胶质细胞在后期（第3 - 7天）数量最多。与报告血脑屏障破坏的常规MRI试剂二乙烯三胺五乙酸钆不同，MPO成像能够在体内分子水平上额外追踪MPO活性并确认炎症，这些信息以前只能从离体脑切片中获取，而无法在活体人类患者中进行评估。我们的研究结果可能允许对针对炎症的治疗进行有效的非侵入性系列筛查，并将MPO成像用作一种成像生物标志物来对患者进行风险分层。
Inflammation can extend ischemic brain injury and adversely affect outcome in experimental animal models. A key difficulty in translating animal studies to humans is the lack of a definitive method to confirm and track inflammation in the brain in vivo. Myeloper-oxidase (MPO), a key inflammatory enzyme secreted by activated neutrophils and macrophages/microglia, can generate highly reactive oxygen species to cause additional damage in cerebral ischemia. We report here that a functional, enzyme-activatable MRI agent can accurately track the oxidative activity of MPO noninvasively in stroke in living animals. We found that MPO is widely distributed in ischemic tissues, correlates positively with infarct size, and is detected even 3 weeks postinfarction. The peak level of MPO activity, determined by activation of the MPO-sensing agent in vivo and confirmed by MPO activity and quantitative RT-PCR assays, occurred on day 3 after ischemia. Both neutrophils and macrophages/microglia contribute to secrete MPO in the ischemic brain, although neutrophils peak earlier (days 1-3) whereas macrophages/microglia are most abundant later (days 3-7). In contrast to the conventional MRI agent diethylenetriamine-pentatacetate gadolinium, which reports blood-brain barrier disruption, MPO imaging is able to additionally track MPO activity and confirm inflammation on the molecular level in vivo, information that was previously only possible to obtain on ex vivo brain sections and impossible to assess in living human patients. Our findings could allow efficient noninvasive serial screening of therapies targeting inflammation and the use of MPO imaging as an imaging biomarker to risk-stratify patients.