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Am J Physiol Gastrointest Liver Physiol (February 12, 2003). doi:10.1152/ajpgi.00526.2002
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Submitted on December 19, 2002
Accepted on February 5, 2003

EMBOLIZATION BY SINUSOIDAL LINING CELLS OBSTRUCTS THE MICROCIRCULATION IN RAT SINUSOIDAL OBSTRUCTION SYNDROME (HEPATIC VENOOCCLUSIVE DISEASE)

Laurie D. DeLeve1*, Yoshiya Ito2, Nancy W. Bethea2, Margaret K. McCuskey2, Xiangdong Wang1, and Robert S. McCuskey2

1 Division of Gastrointestinal and Liver Disease and the Research Center for Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
2 Department of Cell Biology and Anatomy, University of Arizona, Tucson, AZ, USA

* To whom correspondence should be addressed. E-mail: deleve{at}usc.edu.

The mechanisms leading to the obstruction of the microcirculation in sinusoidal obstruction syndrome (SOS) have been unclear. Since this occurs at the onset of disease, this is a potential key target for therapeutic intervention. Rats were treated with monocrotaline ± continuous intraportal infusion of glutathione and were studied at 0.5, 1, 2, 4, 6 and 10 days after monocrotaline treatment using in vivo microscopy and transmission electron microscopy. Results: Sinusoidal perfusion decreased from day 1 through 10 with a nadir on day 4. At 12 hours numerous swollen sinusoidal endothelial cells (SECs) could be observed. Subsequently, red blood cells penetrated into the space of Disse through gaps between and through swollen SEC and dissected the sinusoidal lining away from the parenchymal cells. Sinusoidal blood flow was obstructed by an embolism of aggregates of sinusoidal lining cells, red blood cells, and adherent monocytes. All changes were prevented by glutathione infusion, notably the initial swelling of SEC. Conclusions: SOS is initiated by changes in SEC. Microcirculatory obstruction is due to dissection of the sinusoidal lining, followed by embolization of the sinusoid by sinusoidal lining cells, compounded by aggregates of monocytes adherent in the sinusoids. Glutathione prevents SOS by preserving an intact sinusoidal barrier.




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