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(Circulation. 2001;104:2107.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Ultrasound Assessment of Inflammation and Renal Tissue Injury With Microbubbles Targeted to P-Selectin

Jonathan R. Lindner, MD; Ji Song, PhD; Jonathan Christiansen, MB ChB; Alexander L. Klibanov, PhD; Fang Xu, MD; Klaus Ley, MD

From the Cardiovascular Division (J.R.L., J.S., J.C., F.X.) and the Department of Biomedical Engineering (J.S., K.L.), University of Virginia School of Medicine, Charlottesville, and Mallinckrodt Medical, Inc, St Louis, Mo (A.L.K.).

Correspondence to Jonathan R. Lindner, MD, Box 158, Cardiovascular Division, University of Virginia Medical Center, Charlottesville, VA 22908. E-mail jlindner{at}virginia.edu

Background— Routine methods capable of assessing tissue inflammation noninvasively are currently not available. We hypothesized that tissue retention of microbubbles targeted to the endothelial cell adhesion molecule P-selectin would provide a means to assess inflammation with ultrasound imaging.

Methods and Results— Phospholipid microbubbles targeted to P-selectin (MB_p) were created by conjugating monoclonal antibodies against murine P-selectin to the lipid shell. The microvascular behaviors of MB_p and control microbubbles without antibody (MB) or with isotype control antibody (MB_iso) were assessed by intravital microscopy of cremasteric venules of control and tumor necrosis factor (TNF)-–stimulated wild-type mice. Retention of all microbubbles increased (P<0.05) with TNF- treatment because of increased attachment to activated leukocytes. Extensive attachment of MB_p directly to the venular endothelium or to adherent platelet-leukocyte aggregates was observed in TNF-–stimulated mice, resulting in 4-fold greater (P<0.01) retention of MB_p than either MB_iso or MB. Enhanced retention of MB_p was completely abolished in TNF-–stimulated P-selectin–deficient mice. The ultrasound signal from microbubbles retained in inflamed tissue was assessed by contrast-enhanced renal ultrasound imaging of the kidneys of mice undergoing ischemia-reperfusion injury. In wild-type mice, this signal was significantly higher (P<0.05) for MB_p (12±2 U) than either MB_iso (6±3 U) or MB (5±3 U). In P-selectin–deficient mice, the signal for MB_p was equivalent to that from control microbubbles.

Conclusions— Microvascular retention of microbubbles targeted to P-selectin produces strong signal enhancement on ultrasound imaging of inflamed tissue. These results suggest that site-targeted microbubbles may be used to assess inflammation, tissue injury, and other endothelial responses noninvasively with ultrasound.

Key Words: contrast media • cell adhesion molecules • echocardiography • inflammation

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