Dual Effect of Hepatic Macrophages on Liver Ischemia and Reperfusion Injury during Liver Transplantation

Abstract

Ischemia-reperfusion injury (IRI) is a major complication in liver transplantation (LT) and it is closely related to the recovery of grafts' function. Researches has verified that both innate and adaptive immune system are involved in the development of IRI and Kupffer cell (KC), the resident macrophages in the liver, play a pivotal role both in triggering and sustaining the sterile inflammation. Damage-associated molecular patterns (DAMPs), released by the initial dead cell because of the ischemia insult, firstly activate the KC through pattern recognition receptors (PRRs) such as toll-like receptors. Activated KCs is the dominant players in the IRI as it can secret various pro-inflammatory cytokines to exacerbate the injury and recruit other types of immune cells from the circulation. On the other hand, KCs can also serve in a contrary way to ameliorate IRI by upregulating the anti-inflammatory factors. Moreover, new standpoint has been put forward that KCs and macrophages from the circulation may function in different way to influence the inflammation. Managements towards KCs are expected to be the effective way to improve the IRI.

Rivastigmine prevents injury induced by ischemia and reperfusion in rat liver

“…The tissue MDA, which indicates the degree of oxidative stress, increased in the I/R group, but this increment was not statistically significant. Although not statistically significant, this increment of MDA suggests that tissue concentrations of ROS are higher in livers exposed to I/R, which may lead to activation of KCs 11 . At the same time, the inflammatory response resulting from KCs activation may lead to increased ROS generation and further aggravate local oxidative stress 26 .…”

“…However, for this action to occur, the AChE inhibition must be established in the ischemia phase. It should be noted that in this phase the first cellular lesions occur, with the release of DAMPs 11 . Apparently, early modulation upon KCs, already in the ischemia phase, is more likely to protect hepatic cells submitted to I/R.…”

“…It has been proposed that the reduction of tissue oxygenation due to ischemia interrupts the respiratory chain in the internal mitochondrial membrane, leading to the production of ROS, mainly when the blood flow is reestablished during reperfusion 11 . In fact, high concentrations of ROS in tissues exposed to I/R lead to peroxidation of lipid cellular structures 26 .…”

“…high concentration of ROS, there is involvement of local inflammatory response. Damageassociated molecular patterns (DAMPs) that are released by hepatic tissue injured in the ischemia, act on Toll-like receptors present on cells of the immune system, mainly in the Kupffer cells (KCs), thereby releasing of several pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interferon-gamma (INF-γ), among others 10,11 . High concentrations of reactive oxygen species can also activate the KCs 11,12 .…”

A review of pig liver xenotransplantation: Current problems and recent progress

“…32 Kupffer cells in the pig liver and circulating macrophages release proinflammatory and procoagulant factors that augment graft injury. 33 Pig Kupffer cells destroy human erythrocytes through a sialic acid-dependent mechanism 34,35 and also recognize desialylated β-glucans (specifically…”