Kupffer cell-dependent TNF-α signaling mediates injury in the arterialized small-for-size liver transplantation in the mouse

Abstract

Implantation of small liver grafts causes liver injury and defective regeneration leading to graft failure. We investigated whether Kupffer cell-dependent TNF-␣ signaling contributes to this poor outcome. Partial 30% liver transplantation was performed in C57BL͞6 wild-type mice (control group), and in three groups with down-regulation of the TNF-␣ pathway: (i) TNF receptor 1 knockout [TNFR-1(؊͞؊)] mice, and mice pretreated with (ii) gadolinium chloride or (iii) pentoxifylline (PTX). Fifty-percent partial liver transplantation, a model associated with full recovery, and transplantation in IL-6 knockout [IL-6(؊͞؊)] mice were performed in some experiments. Graft injury, regeneration, portal flow, liver microcirculation, leukocyte adhesion, and animal survival were assessed. Animal survival rates were 14% in the control group vs. 43% in the gadolinium chloride group, 57% for the TNFR-1(؊͞؊) group, and 86% in the PTX group (P < 0.001). Markers of liver injury were reduced in all treated groups when compared with controls. Each treated group disclosed better portal flow and sinusoid perfusion, decreased leukocyte adherence, particularly in the PTX group. Liver regeneration occurred only in the treated groups. IL-6 and IL-10 levels were dramatically up-regulated (50؋) in the PTX group, and at lower levels in other experimental groups. The protective effect of PTX was lost in IL-6(؊͞؊) mice and protection was restored by a single dose of r-IL-6. In conclusion, interruption of TNF-␣ signaling or depletion of Kupffer cells improves survival after 30% liver transplantation, reduces liver injury, and enhances regeneration. The superior effects of PTX are mediated by IL-6.

Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration

“…After resection the remaining liver can regenerate to a fully functional organ [1][2][3] . Tissue damage due to the surgical process further decreases the amount of healthy remnant liver tissue leading to an additional reduction in functional liver capacity in the postoperative period [4,5] . This situation can lead to liver insufficiency and, ultimately, to liver failure and death [6][7][8] .…”

“…In particular, the role of proregenerative cytokines (e.g. IL-6 and TNF-a) and the role of transcription factors such as NF-κB are ambiguous [5,[20][21][22] .…”

Pentoxifylline improves liver regeneration through down-regulation of TNF-α synthesis and TGF-β1 gene expression

“…It has also been demonstrated that PTX administration increases the production of anti-inflammatory and growth promoting factors (IL-6 and IL-10) in a small-for-size liver transplantation in mice [13] . It was concluded that these effects were related to inhibition of the TNF-α signaling pathway [13] .…”

“…It has also been demonstrated that PTX administration increases the production of anti-inflammatory and growth promoting factors (IL-6 and IL-10) in a small-for-size liver transplantation in mice [13] . It was concluded that these effects were related to inhibition of the TNF-α signaling pathway [13] . However, in the present study we did not find a reduction in TNF-α levels in liver tissue following the administration of PTX, suggesting that the production of TNF-α in the liver tissue follows a different signaling pathway from that of macrophages.…”

“…Its excessive production after 90% hepatectomy has been associated with adverse effects on the hepatic microcirculation and liver regeneration [11] . It has also been recently demonstrated that pentoxifylline (PTX), an inhibitor of TNF-α production [12] , reduces liver injury and improves liver regeneration in a model of small-for-size liver transplantation through a mechanism thought to be related to interruption of TNF-α signaling [13] . Indeed a recent randomized controlled trial demonstrated the beneficial effects of PTX in major liver resections [14] .…”