(Circulation. 2000;101:668.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Microbubble Persistence in the Microcirculation During Ischemia/Reperfusion and Inflammation Is Caused by Integrin- and Complement-Mediated Adherence to Activated Leukocytes
From the Cardiovascular Division (J.R.L., M.P.C., S.K.) and the Department of Biomedical Engineering (S.K., K.L.), University of Virginia School of Medicine, Charlottesville, Va; and Mallinckrodt Medical, Inc (A.L.K., G.H.B.), St Louis, Mo.
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—Albumin microbubbles that are used for contrast echocardiography persist within the myocardial microcirculation after ischemia/reperfusion (I-R). The mechanism responsible for this phenomenon is unknown.
Methods and Results—Intravital microscopy of the microcirculation
of exteriorized cremaster muscle was performed in 12 wild-type mice
during intravenous injections of
fluorescein-labeled microbubbles composed of
albumin, anionic lipids, or cationic lipids. Injections were
performed at baseline and after 30 to 90 minutes of I-R in 8 mice and 2
hours after intrascrotal tumor necrosis factor-
(TNF-) in 4 mice.
Microbubble adherence at baseline was uncommon (<2/50
high-power fields). After I-R, adherence increased
(P<0.05) to 9±5 and 5±4 per 50 high-power fields for
albumin and anionic lipid microbubbles, respectively, due to
their attachment to leukocytes adherent to the venular
endothelium. TNF- produced even greater microbubble
binding, regardless of the microbubble shell composition. The degree of
microbubble attachment correlated (r=0.84 to 0.91) with
the number of adhered leukocytes. Flow cytometry revealed that
microbubbles preferentially attached to activated leukocytes.
Albumin microbubble attachment was inhibited by blocking the
leukocyte ß2-integrin Mac-1, whereas lipid microbubble
binding was inhibited when incubations were performed in
complement-depleted or heat-inactivated serum rather than
control serum.
Conclusions—Microvascular attachment of albumin and lipid
microbubbles in the setting of I-R and TNF-–induced inflammation is
due to their ß2-integrin– and complement-mediated
binding to activated leukocytes adherent to the venular wall.
Thus, microbubble persistence on contrast ultrasonography may be useful
for the detection and monitoring of leukocyte adhesion in inflammatory
diseases.
Key Words: microcirculation • echocardiography • leukocytes • ischemia • reperfusion
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