Molecular and histological effects of MR-guided pulsed focused ultrasound to the rat heart

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s12967-017-1361-y) contains supplementary material, which is available to authorized users.

MR‐guided pulsed focused ultrasound improves mesenchymal stromal cell homing to the myocardium

“…Under MR guidance, the left ventricle was sonicated with 3 MPa of PNP, which is approximately 1.6 MPa intramyocardially (equivalent to a MI = 1.7) as a result of attenuation at rat chest wall. 22 Following pFUS treatment, no macroscopic and microscopic evidence of pulmonary damage was observed as has been previously reported at sonications at PNP = 6 MPa. 22…”

Boiling Histotripsy Ablation of Renal Cell Carcinoma in the Eker Rat Promotes a Systemic Inflammatory Response

“…In those studies tumor-infiltrating lymphocytes were not examined, but the increase in the number of activated, tumor antigen-specific dendritic cells in the draining lymph nodes was observed within 1–3 days following ablation. Similarly, in a study of molecular changes in healthy rat cardiac tissue following milder mechanical disruption by pulsed FUS (Jang et al 2017), infiltrating macrophages and neutrophils were observed within the myocardium 24 hours post treatment, but were undetectable by 48 hours.…”

Pulsed focused ultrasound enhances the therapeutic effect of mesenchymal stromal cell-derived extracellular vesicles in acute kidney injury

“…The homing process for MSCs is well-characterized: in order to travel from circulation into a target tissue, they must undergo (1) tethering by selectins, (2) activation by chemokines, (3) arrest by integrins, (4) transmigration or diapedesis across the endothelial layer, and (5) extravascular migration to the target tissue mediated by cytokines [49]. pFUS at certain parameters can enhance this process by upregulating homing molecules at the target tissue, especially chemokines like SDF-1 and cell adhesion molecules like VCAM-1 [31][32][33][34]. Many studies have demonstrated increased MSC homing following pFUS [30,32,34,35], but whether the same effect would be true of EVs was unknown.…”

“…Previous studies have shown that pFUS can enhance MSC therapy for AKI [ 29 , 30 ], but different mechanisms have been proposed for this effect. The homing hypothesis posits that sound waves transiently upregulate local inflammatory and chemoattractive signals [ 31 – 33 ]. This local gradient of cytokines, chemokines, and trophic factors has been shown to promote the homing of MSCs to various tissues including the skeletal muscle [ 34 , 35 ] and the kidney [ 29 , 30 , 32 , 36 ].…”