The Molecular Mechanisms of Leukocyte Recruitment in Post Ischemic Liver Microcirculation

There is a growing body of evidence that leukocyte recruitment into inflamed liver sinusoids does not require selectins, with one notable exception being ischemia/reperfusion. In this study we used intravital microscopy to directly visualize the liver microcirculation during ischemia/reperfusion and during localized endotoxemia (LPS superfused on liver). In additional experiments, general anti-selectin therapy (fucoidan) or anti-adhesion therapy with the antithrombin inhibitor (hirudin) were used. The data reveal that many neutrophils rolled and adhered in postsinusoidal vessels and sequestered in the sinusoids during both ischemia/reperfusion as well as local endotoxin superfusion. Although fucoidan blocked rolling in both forms of inflammation, leukocyte recruitment into sinusoids was only blocked during ischemia/reperfusion. The inhibition of adhesion in post-ischemic sinusoids was also observed with a second anti-adhesive agent hirudin. Since ischemia/reperfusion of the liver inevitably also induces ischemia upstream in the intestine, it is possible that the anti-selectin therapy may prevent intestinal injury which could prevent downstream liver inflammation. To test this hypothesis, the intestine was removed in its entirety and blood flow was re-routed from the superior mesenteric artery to the superior mesenteric vein. Ischemia/reperfusion was induced in the liver microcirculation and many leukocytes rolled and adhered in postsinusoidal venules and adhered in sinusoids. Although fucoidan reduced a significant amount of the rolling in postsinusoidal vessels, adhesion still persisted in the sinusoids. Our data suggest that anti-adhesion therapy is effective in ischemia/reperfusion of the liver in both the sinusoids and post-sinusoidal venules perhaps in part due to its beneficial impact on the intestine.