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Effect of Pulsed Focused Ultrasound on the Native Pancreas.

ABSTRACT: Pulsed focused ultrasound (pFUS) utilizes short cycles of sound waves to mechanically shake cells within tissues which, in turn, causes transient local increases in cytokines, growth factors and cell adhesion molecules. Although the effect of pFUS has been investigated in several different organs including the kidney, muscle and heart, its effect on the pancreas has not been investigated. In the present work, we applied pFUS to the rodent pancreas with the following parameters: 1.1-MHz frequency, 5-Hz pulse repetition frequency, 5% duty cycle, 10-ms pulse length, 160-s duration. Low-intensity pFUS had a spatial average temporal average intensity of 11.5 W/cm² and a negative peak pressure of 3 MPa; high-intensity pFUS had a spatial average temporal average intensity of 18.5 W/cm² and negative peak pressure of 4 MPa. Here we found that pFUS changed the expression of several cytokines while having no effect on the underlying tissue histology or health of pancreatic cells (as reflected by no significant change in plasma levels of amylase and lipase). Furthermore, we found that this effect on cytokine expression in the pancreas was acoustic intensity dependent; while pFUS at low intensities turned off the expression of several cytokines, at high intensities it had the opposite effect and turned on the expression of these cytokines. The ability to non-invasively manipulate the microenvironment of the pancreas using sound waves could have profound implications for priming and modulating this organ for the application of cellular therapies in the context of both regenerative medicine (i.e., diabetes and pancreatitis) and oncology (i.e., pancreatic cancer).

SUBMITTER: Razavi M

PROVIDER: S-EPMC7010559 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Effect of Pulsed Focused Ultrasound on the Native Pancreas.

Razavi Mehdi M Zheng Fengyang F Telichko Arsenii A Ullah Mujib M Dahl Jeremy J Thakor Avnesh S AS

Ultrasound in medicine & biology 20191224 3

Pulsed focused ultrasound (pFUS) utilizes short cycles of sound waves to mechanically shake cells within tissues which, in turn, causes transient local increases in cytokines, growth factors and cell adhesion molecules. Although the effect of pFUS has been investigated in several different organs including the kidney, muscle and heart, its effect on the pancreas has not been investigated. In the present work, we applied pFUS to the rodent pancreas with the following parameters: 1.1-MHz frequency ...[more]

PMID: 31882169

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Project description:BackgroundImage-guided high intensity focused ultrasound has been used as an extracorporeal cardiac pacing tool and to enhance homing of stem cells to targeted tissues. However, molecular changes in the myocardium after sonication have not been widely investigated. Magnetic-resonance (MR)-guided pulsed focused ultrasound (pFUS) was targeted to the rat myocardium over a range of pressures and the microenvironmental and histological effects were evaluated over time.MethodsEight-to-ten-week-old Sprague-Dawley rats received T2-weighted MR images to target pFUS to the left ventricular and septum without cardiac or respiratory gating. Rats were sonicated through the thoracic wall at peak negative pressures (PNP) from 1 to 8 MPa at a center frequency of 1 MHz, 10 ms pulse duration and 1 Hz pulse repetition frequency for 100 pulses per focal target. Following pFUS, myocardium was harvested over 24 h and subjected to imaging, proteomic, and histological measurements.ResultspFUS to the myocardium increased expression of cytokines, chemokines, and trophic factors characterized by an initial increase in tumor necrosis factor (TNF)-α followed by increases in pro- and anti-inflammatory factors that returned to baseline by 24 h. Immediately after pFUS, there was a transient (< 1 h) increase in N-terminal pro b-type natriuretic peptide (NT-proBNP) without elevation of other cardiac injury markers. A relationship between PNP and expression of TNF-α and NT-proBNP was observed with significant changes (p < 0.05 ANOVA) ≥ 4 MPa compared to untreated controls. Contrast-enhanced ex vivo T1-weighted MRI revealed vascular leakage in sonicated myocardium that was accompanied by the presence of albumin upon immunohistochemistry. Histology revealed infiltration of neutrophils and macrophages without morphological myofibril changes in sonicated tissue accompanied by pulmonary hemorrhage at PNP > 4 MPa.ConclusionsMR-guided pFUS to myocardium induced transient proteomic and histological changes. The temporal proteomic changes in the myocardium indicate a short-lived sterile inflammatory response consistent with ischemia or contusion. Further study of myocardial function and strain is needed to determine if pFUS could be developed as an experimental model of cardiac injury and chest trauma.

Project description:Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound (pFUS) combined with microbubbles (MB) contrast agent infusion has been shown to transiently disrupt the blood-brain barrier (BBBD), increasing the delivery of neurotherapeutics to treat central nervous system (CNS) diseases. pFUS interaction with the intravascular MB results in acoustic cavitation forces passing through the neurovascular unit (NVU), inducing BBBD detected on contrast-enhanced MRI. Multiple pFUS+MB exposures in Alzheimer's disease (AD) models are being investigated as a method to clear amyloid plaques by activated microglia or infiltrating immune cells. Since it has been reported that pFUS+MB can induce a sterile inflammatory response (SIR) [1-5] in the rat, the goal of this study was to investigate the potential long-term effects of SIR in the brain following single and six weekly sonications by serial high-resolution MRI and pathology. Methods: Female Sprague Dawley rats weighing 217±16.6 g prior to sonication received bromo-deoxyuridine (BrdU) to tag proliferating cells in the brain. pFUS was performed at 548 kHz, ultrasound burst 10 ms and initial peak negative pressure of 0.3 MPa (in water) for 120 s coupled with a slow infusion of ~460 µL/kg (5-8×107 MB) that started 30 s before and 30 s during sonication. Nine 2 mm focal regions in the left cortex and four regions over the right hippocampus were treated with pFUS+MB. Serial high-resolution brain MRIs at 3 T and 9.4 T were obtained following a single or during the course of six weekly pFUS+MB resulting in BBBD in the left cortex and the right hippocampus. Animals were monitored over 7 to 13 weeks and imaging results were compared to histology. Results: Fewer than half of the rats receiving a single pFUS+MB exposure displayed hypointense voxels on T2*-weighted (w) MRI at week 7 or 13 in the cortex or hippocampus without differences compared to the contralateral side on histograms of T2* maps. Single sonicated rats had evidence of limited microglia activation on pathology compared to the contralateral hemisphere. Six weekly pFUS+MB treatments resulted in pathological changes on T2*w images with multiple hypointense regions, cortical atrophy, along with 50% of rats having persistent BBBD and astrogliosis by MRI. Pathologic analysis of the multiple sonicated animals demonstrated the presence of metallophagocytic Prussian blue-positive cells in the parenchyma with significantly (p<0.05) increased areas of activated astrocytes and microglia, and high numbers of systemic infiltrating CD68+ macrophages along with BrdU+ cells compared to contralateral brain. In addition, multiple treatments caused an increase in the number of hyperphosphorylated Tau (pTau)-positive neurons containing neurofibrillary tangles (NFT) in the sonicated cortex but not in the hippocampus when compared to contralateral brain, which was confirmed by Western blot (WB) (p<0.04). Conclusions: The repeated SIR following multiple pFUS+MB treatments could contribute to changes on MR imaging including persistent BBBD, cortical atrophy, and hypointense voxels on T2w and T2*w images consistent with pathological injury. Moreover, areas of astrogliosis, activated microglia, along with higher numbers of CD68+ infiltrating macrophages and BrdU+ cells were detected in multiple sonicated areas of the cortex and hippocampus. Elevations in pTau and NFT were detected in neurons of the multiple sonicated cortex. Minimal changes on MRI and histology were observed in single pFUS+MB-treated rats at 7 and 13 weeks post sonication. In comparison, animals that received 6 weekly sonications demonstrated evidence on MRI and histology of vascular damage, inflammation and neurodegeneration associated with the NVU commonly observed in trauma. Further investigation is recommended of the long-term effects of multiple pFUS+MB in clinical trials.

Dataset Information

Effect of Pulsed Focused Ultrasound on the Native Pancreas.

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Effect of Pulsed Focused Ultrasound on the Native Pancreas.

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