Blockage of CX3CL1 Attenuates Platelet and Leukocyte Recruitment in Murine Hepatic I/R

Abstract

Background. The chemokine fractalkine (CX3CL1) is critically involved in the pathophysiology of different inflammatory diseases and myocardial ischemia-reperfusion (I/R). This study aims to analyze the role of fractalkine in the activation of platelets and leukocytes during hepatic I/R. Methods. Under inhalation anesthesia, C57BL6 mice were subjected to warm hepatic I/R (90min/240min). The animals were pretreated either with a function-blocking anti-mouse CX3CL1 antibody or IgG control administered systemically before ischemia. Sham-operated animals served as controls (n=7 each group). The inflammatory response and sinusoidal perfusion failure were evaluated by intravital microscopy. Hepatic transaminases plasma levels and histopathological tissue damage were determined as markers of hepatocellular injury. Results. Sinusoidal perfusion failure, leukocyte recruitment to the liver, and transaminase activities were sharply increased upon I/R compared to sham-operated mice. Firm adhesion of platelets and concordantly leukocytes to endothelial cells is reduced significantly by a function-blocking anti-fractalkine antibody. We demonstrate that inhibition of fractalkine signaling attenuates leukocyte adhesion in the postischemic liver but does not significantly ameliorate overall perfusion failure and hepatocellular injury. Discussion/Conclusion. Our in vivo data demonstrate a mild attenuating effect of CX3CL1 blockade on platelet and leukocyte, but not CD4+ T cell accumulation and activation in hepatic I/R injury. We report a significant effect of blocking chemokine fractalkine on sinusoidal perfusion failure without considerably improving overall hepatocellular injury during early reperfusion.

The roles of liver sinusoidal endothelial cells in liver ischemia/reperfusion injury

“…69 The latest research indicates that blocking the expression of the chemokine CX3CL1 reduces platelet and neutrophil adhesion to endothelial cells in mouse liver I/R but does not significantly mitigate overall liver injury during early reperfusion. 70 To date, no clinical drugs have been approved for use to protect against liver damage caused by IRI. Further studies on drug pretreatment or treatment may lead to novel research ideas for protecting the liver and treating liver IRI.…”

“…A study showed that liver‐selective MMP‐9 inhibitors exerted a significant protective effect on IRI by enhancing liver VEGF‐mesenchymal cell‐derived factor 1 (SDF1) signal transduction and promoting LSEC bone marrow progenitor cell (BM) production, even in rats with severe steatosis 69 . The latest research indicates that blocking the expression of the chemokine CX3CL1 reduces platelet and neutrophil adhesion to endothelial cells in mouse liver I/R but does not significantly mitigate overall liver injury during early reperfusion 70 . To date, no clinical drugs have been approved for use to protect against liver damage caused by IRI.…”