34
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Significance

          Pulsed focused ultrasound (pFUS) with systemic microbubble (MB) infusion is a noninvasive technique that opens the blood–brain barrier (BBB) and is currently advocated for increasing drug or gene delivery in neurological diseases. The opening of the BBB by pFUS+MB resulted in immediate damage-associated molecular patterns that led to a sterile inflammation response within the parenchyma that lasted 24 h. Currently, pFUS+MB exposure is under consideration as an adjuvant in the treatment in malignancy or neurodegenerative disease. These results demonstrate that pFUS+MB induces a sterile inflammatory response compatible with ischemia or mild traumatic brain injury. Further investigation will be required before translation to clinical trials.

          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.

          Related collections

          Author and article information

          Journal
          Proc Natl Acad Sci U S A
          Proc. Natl. Acad. Sci. U.S.A
          pnas
          pnas
          PNAS
          Proceedings of the National Academy of Sciences of the United States of America
          National Academy of Sciences
          0027-8424
          1091-6490
          3 January 2017
          19 December 2016
          : 114
          : 1
          : E75-E84
          Affiliations
          [1] aFrank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health , Bethesda, MD 20892;
          [2] bNational Institute of Biomedical Imaging and Bioengineering, National Institutes of Health , Bethesda, MD 20892
          Author notes
          1To whom correspondence may be addressed. Email: jf5z@ 123456nih.gov or zsofia.kovacs@ 123456nih.gov .

          Edited by Kevin J. Tracey, Feinstein Institute for Medical Research, Manhasset, NY, and accepted by Editorial Board Member Carl F. Nathan, November 23, 2016 (received for review September 5, 2016)

          Author contributions: Z.I.K., S.K., and J.A.F. designed research; Z.I.K., S.K., N.J., F.Q., B.M., B.K.L., and M.B. performed research; Z.I.K., S.K., N.J., F.Q., B.M., B.K.L., M.B., S.R.B., and J.A.F. analyzed data; and Z.I.K., S.K., S.R.B., and J.A.F. wrote the paper.

          Article
          PMC5224365 PMC5224365 5224365 201614777
          10.1073/pnas.1614777114
          5224365
          27994152
          dfe82c44-caf0-46f1-bf7e-dadb8e0fa712
          History
          Page count
          Pages: 10
          Funding
          Funded by: HHS | National Institutes of Health (NIH) 100000002
          Award ID: ZIA CL040014-08
          Categories
          PNAS Plus
          Biological Sciences
          Medical Sciences
          From the Cover
          PNAS Plus

          magnetic resonance imaging,sterile inflammation,blood-brain barrier,microbubbles,pulsed focused ultrasound

          Comments

          Comment on this article