(Circulation. 2000;102:531.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Noninvasive Imaging of Inflammation by Ultrasound Detection of Phagocytosed Microbubbles
From the Cardiovascular Division (J.R.L., M.P.C., S.K.) and the Department of Biomedical Engineering (P.A.D., K.L., J.S., S.K., K.F.), University of Virginia School of Medicine, Charlottesville.
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—We have previously shown that microbubbles adhere to leukocytes in regions of inflammation. We hypothesized that these microbubbles are phagocytosed by neutrophils and monocytes and remain acoustically active, permitting their detection in inflamed tissue.
Methods and Results—In vitro studies were performed in which
activated leukocytes were incubated with albumin or
lipid microbubbles and observed under microscopy. Microbubbles attached
to the surface of activated neutrophils and monocytes, were
phagocytosed, and remained intact for up to 30 minutes. The rate of
destruction of the phagocytosed microbubbles on exposure to ultrasound
was less (P
0.05) than that of free microbubbles at all
acoustic pressures applied. Intravital microscopy and
simultaneous ultrasound imaging of the cremaster muscle was
performed in 6 mice to determine whether phagocytosed microbubbles
could be detected in vivo. Fifteen minutes after
intravenous injection of fluorescein-labeled
microbubbles, when the blood-pool concentration was negligible, the
number of phagocytosed/attached microbubbles within venules was 7-fold
greater in tumor necrosis factor-
(TNF-)–treated animals than in
control animals (P<0.01). This increase in retained
microbubbles resulted in a 5- to 6-fold-greater
(P<0.01) degree of ultrasound contrast enhancement than
in controls.
Conclusions—After attaching to activated neutrophils and monocytes, microbubbles are phagocytosed intact. Despite viscoelastic damping, phagocytosed microbubbles remain responsive to ultrasound and can be detected by ultrasound in vivo after clearance of freely circulating microbubbles from the blood pool. Thus, contrast ultrasound has potential for imaging sites of inflammation.
Key Words: imaging • inflammation • ultrasonics • leukocytes
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