AJP - Gastrointestinal and Liver Physiology, Vol 272, Issue 4 727-G731, Copyright © 1997 by American Physiological Society
Interleukin-2-induced hepatic injury involves temporal patterns of cell adhesion in the microcirculation
A. B. Lentsch, F. N. Miller and M. J. Edwards
Center for Applied Microcirculatory Research, Department of Physiology, University of Louisville, Kentucky 40292, USA.
The treatment of metastatic cancer with interleukin-2 (IL-2) is limited by
systemic toxicities, including hepatic dysfunction. The objective of this
study was to determine the cellular mechanisms of IL-2-induced hepatic
injury. Intravital microscopy was used for the direct observation of the
murine hepatic microcirculation after 2 h, 2 days, and 4 days of IL-2
treatment. At each interval, leukocyte- and platelet-endothelial adherence
were observed and quantitated. Simultaneously, sinusoidal perfusion, serum
levels of glutamate pyruvate transaminase, and edema were measured as
indexes of hepatic toxicity. IL-2 increased neutrophil adhesion acutely in
association with decreased sinusoidal perfusion. Leukocyte adhesion
subsided at 2 days, but platelet-endothelial interactions were enhanced and
40% of mice receiving IL-2 had microvascular thrombi. These effects
occurred in conjunction with decreased sinusoidal perfusion and the
development of hepatic edema. After 4 days of IL-2, maximal hepatic edema,
hypoperfusion, and increased serum levels of glutamate pyruvate
transaminase were associated with increased lymphocyte adhesion and
microvascular thrombosis. These data suggest coordinated, temporal roles of
leukocytes and platelets in the generation of IL-2-induced hepatic injury.
