Kovacs Zsofia I, Kim Saejeong, Jikaria Neekita, Qureshi Farhan, Milo Blerta, Lewis Bobbi K, Bresler Michele, Burks Scott R, Frank Joseph A
Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892;
Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2017 Jan 3;114(1):E75-E84. doi: 10.1073/pnas.1614777114. Epub 2016 Dec 19.
MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.
磁共振成像引导的脉冲聚焦超声（pFUS）联合全身注射超声造影剂微泡（MB）可导致局部血脑屏障（BBB）破坏，目前这一方法被提倡用于增加神经疾病中的药物或基因递送。如对比增强磁共振成像所证实，低强度pFUS+MB打开血脑屏障的机械性声空化效应导致了即时的损伤相关分子模式（DAMP）反应，包括热休克蛋白70、白细胞介素-1、白细胞介素-18和肿瘤坏死因子α升高，表明实质内存在无菌性炎症反应（SIR）。与DAMP表现同时，检测到促炎、抗炎和营养因子以及神经营养和神经发生因子显著升高；这些升高持续24小时。对超声处理的脑组织进行转录组分析支持了蛋白质组学研究结果，并表明通过诱导NFκB途径促进了无菌性炎症反应。组织学评估显示实质内白蛋白增加，24小时后清除，同时伴有TUNEL神经元、活化的星形胶质细胞、小胶质细胞以及血管中细胞粘附分子增加。在pFUS+MB处理前3天注入荧光珠显示，超声处理后6天CD68巨噬细胞浸润，这与先天免疫反应一致。pFUS+MB正被视为恶性肿瘤或神经退行性疾病非侵入性辅助治疗的一部分。这些结果表明，pFUS+MB诱导了与缺血或轻度创伤性脑损伤相容的无菌性炎症反应。在该方法能够在临床试验中广泛应用之前，还需要进一步研究。
