title: Investigation of cellular and molecular responses to pulsed focused ultrasound in a mouse model.
abstract: Continuous focused ultrasound (cFUS) has been widely used for thermal ablation of tissues, relying on continuous exposures to generate temperatures necessary to induce coagulative necrosis. Pulsed FUS (pFUS) employs non-continuous exposures that lower the rate of energy deposition and allow cooling to occur between pulses, thereby minimizing thermal effects and emphasizing effects created by non-thermal mechanisms of FUS (i.e., acoustic radiation forces and acoustic cavitation). pFUS has shown promise for a variety of applications including drug and nanoparticle delivery; however, little is understood about the effects these exposures have on tissue, especially with regard to cellular pro-homing factors (growth factors, cytokines, and cell adhesion molecules). We examined changes in murine hamstring muscle following pFUS or cFUS and demonstrate that pFUS, unlike cFUS, has little effect on the histological integrity of muscle and does not induce cell death. Infiltration of macrophages was observed 3 and 8 days following pFUS or cFUS exposures. pFUS increased expression of several cytokines (e.g., IL-1α, IL-1β, TNFα, INFγ, MIP-1α, MCP-1, and GMCSF) creating a local cytokine gradient on days 0 and 1 post-pFUS that returns to baseline levels by day 3 post-pFUS. pFUS exposures induced upregulation of other signaling molecules (e.g., VEGF, FGF, PlGF, HGF, and SDF-1α) and cell adhesion molecules (e.g., ICAM-1 and VCAM-1) on muscle vasculature. The observed molecular changes in muscle following pFUS may be utilized to target cellular therapies by increasing homing to areas of pathology.
authors.affiliation: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, United States of America. scott.burks@nih.gov
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burks
authors.forename: Ali
authors.initials: A
authors.lastname: Ziadloo
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Hancock
authors.forename: Aneeka
authors.initials: A
authors.lastname: Chaudhry
authors.forename: Dana D
authors.initials: DD
authors.lastname: Dean
authors.forename: Bobbi K
authors.initials: BK
authors.lastname: Lewis
authors.forename: Victor
authors.initials: V
authors.lastname: Frenkel
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Frank
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D054405:Chemokine CCL3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D057086:High-Intensity Focused Ultrasound Ablation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages; D008279:Magnetic Resonance Imaging; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D054405:Chemokine CCL3; D016207:Cytokines; D007375:Interleukin-1; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1