Molecular mechanisms of leukocyte recruitment in postischemic liver microcirculation

Abstract

Evidence shows that leukocyte recruitment into inflamed liver sinusoids does not require selectins, with one notable exception: ischemia-reperfusion (I/R). We used intravital microscopy to directly visualize the liver microcirculation during I/R and localized endotoxemia (liver superfused with lipopolysaccharide). General anti-selectin therapy (fucoidan) or anti-adhesion therapy with an antithrombin inhibitor (hirudin) was also used. Many neutrophils rolled and adhered in postsinusoidal vessels and sequestered in the sinusoids during I/R and local endotoxin superfusion. Although fucoidan blocked rolling in both forms of inflammation, leukocyte recruitment into sinusoids was only blocked in I/R. Adhesion was also inhibited in postischemic sinusoids with a second anti-adhesive agent (hirudin). Because liver I/R inevitably induces ischemia upstream in the intestine, anti-selectin therapy may prevent intestinal injury, which could prevent downstream liver inflammation. To test this hypothesis, we completely removed the intestine and rerouted blood flow from the superior mesenteric artery to the superior mesenteric vein. I/R was induced in the liver microcirculation, and many leukocytes rolled and adhered in postsinusoidal venules and adhered in sinusoids. Although fucoidan significantly reduced the rolling in postsinusoidal vessels, adhesion persisted in the sinusoids. Our data suggest that anti-adhesion therapy is effective in liver I/R in the sinusoids and postsinusoidal venules, perhaps in part due to its beneficial effect on the intestine.

Hepatic reticuloendothelial system dysfunction after ischemia-reperfusion: Role of P-selectin-mediated neutrophil accumulation

“…A recent report by Kubes et al 16 provided an explanation for these contradictions. They convincingly showed that reduced neutrophil accumulation and tissue protection induced by P-selectin interventions in I-R models are secondary effects caused by gut protection, rather than directly related to mechanisms in the liver.…”

II. Modulating leukocyte recruitment to splanchnic organs to reduce inflammation

“…When ischemia-reperfusion was performed exclusively in the liver (intestine was removed), the results suggested that the liver was quite resistant to this insult. Only a small amount of leukocyte recruitment was noted in postischemic liver, and antiselectin therapy had minimal effects in sinusoids (17).…”

“…By contrast, an important role for selectins in liver in ischemia-reperfusion has been reported, and substantial numbers of leukocytes adhere in both the postsinusoidal and the sinusoidal venules (17). Because the majority of blood that perfuses the liver initially drains the intestine, ischemia-reperfusion of the liver would also have induced ischemia-reperfusion in the intestine.…”

Ischemia-Reperfusion Injury Associated with Liver Transplantation in 2011: Past and Future

“…However, during I/R, a number of interventions directed against selectins reduced hepatic neutrophil accumulation and cell injury . Because these findings cannot be explained by the prevention of P-selectin-dependent rolling in sinusoids, it has been suggested that most liver I/R models include some degree of intestinal ischemia, which leads to neutrophil accumulation in remote organs including the liver Kubes et al, 2002). Thus the lower number of neutrophils in the liver when selectins are blocked may be a secondary effect due to the protection of antiselectin therapy against intestinal reperfusion injury ( Kubes et al, 2002).…”