Breckwoldt Michael O, Chen John W, Stangenberg Lars, Aikawa Elena, Rodriguez Elisenda, Qiu Shumei, Moskowitz Michael A, Weissleder Ralph
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, CNY-149, 13th Street, Charlestown, MA 02129, USA.
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18584-9. doi: 10.1073/pnas.0803945105. Epub 2008 Nov 14.
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. Myeloperoxidase (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.
在实验动物模型中，炎症可扩大缺血性脑损伤并对预后产生不利影响。将动物研究转化为人体研究的一个关键难点在于缺乏一种在体内确认和追踪脑部炎症的确定性方法。髓过氧化物酶（MPO）是活化的中性粒细胞以及巨噬细胞/小胶质细胞分泌的一种关键炎症酶，可产生高活性氧物质，在脑缺血中造成额外损伤。我们在此报告，一种功能性、酶可激活的磁共振成像（MRI）剂能够在活体动物中风模型中无创地准确追踪MPO的氧化活性。我们发现，MPO广泛分布于缺血组织中，与梗死灶大小呈正相关，甚至在梗死3周后仍可检测到。通过体内激活MPO传感剂确定并经MPO活性和定量逆转录聚合酶链反应（RT-PCR）测定法确认，MPO活性的峰值出现在缺血后第3天。中性粒细胞和巨噬细胞/小胶质细胞均参与缺血性脑内MPO的分泌，不过中性粒细胞峰值出现较早（第1 - 3天），而巨噬细胞/小胶质细胞在后期（第3 - 7天）最为丰富。与报告血脑屏障破坏情况的传统MRI剂二乙烯三胺五乙酸钆不同，MPO成像能够在体内额外追踪MPO活性并在分子水平确认炎症，而此前这些信息只能通过离体脑切片获取，无法在活体人类患者中进行评估。我们的研究结果可实现针对炎症的治疗方法的高效无创系列筛查，并将MPO成像用作一种成像生物标志物对患者进行风险分层。
