title: Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation.
abstract: 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.
authors.affiliation: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892; jf5z@nih.gov zsofia.kovacs@nih.gov.
authors.forename: Zsofia I
authors.initials: ZI
authors.lastname: Kovacs
authors.affiliation: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Saejeong
authors.initials: S
authors.lastname: Kim
authors.affiliation: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Neekita
authors.initials: N
authors.lastname: Jikaria
authors.affiliation: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Farhan
authors.initials: F
authors.lastname: Qureshi
authors.affiliation: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Blerta
authors.initials: B
authors.lastname: Milo
authors.affiliation: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Bobbi K
authors.initials: BK
authors.lastname: Lewis
authors.affiliation: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Michele
authors.initials: M
authors.lastname: Bresler
authors.affiliation: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burks
authors.affiliation: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892; jf5z@nih.gov zsofia.kovacs@nih.gov.|National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Frank
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D018014:Gene Transfer Techniques; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D017628:Microglia / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000628:therapy; D000072356:Parenchymal Tissue / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013010:Sonication / Q000379:methods*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014463:Ultrasonography / Q000379:methods*
chemical_list: D015815:Cell Adhesion Molecules; D018840:HSP70 Heat-Shock Proteins; D007375:Interleukin-1; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha
keywords: blood-brain barrier; magnetic resonance imaging; microbubbles; pulsed focused ultrasound; sterile inflammation