Microbubble persistence in the microcirculation during ischemia/reperfusion and inflammation is caused by integrin- and complement- mediated adherence to activated leukocytes

Jonathan R. Lindner, Matthew P. Coggins, Sanjiv Kaul, Alexander L. Klibanov, Gary H. Brandenburger, Klaus Ley

Research output: Contribution to journalArticlepeer-review

197 Scopus citations

Abstract

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-α (TNF-α) 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 an anionic lipid microbubbles, respectively, due to their attachment to leukocytes adherent to the venular endothelium. TNF-α 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 β2-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-α-induced inflammation is due to their β2-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.

Original languageEnglish (US)
Pages (from-to)668-675
Number of pages8
JournalCirculation
Volume101
Issue number6
DOIs
StatePublished - Feb 15 2000
Externally publishedYes

Keywords

  • Echocardiography
  • Ischemia
  • Leukocytes
  • Microcirculation
  • Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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