Interaction of Kupffer Cells and Platelets Determines the Severity of Ischemia-Reperfusion Injury in Steatosis

Abstract

Liver steatosis increases the risk of postoperative complications following major liver resection, since the steatotic liver is susceptible to ischemia-reperfusion (IR) injury. However, it is unclear how IR injury changes in relation to the degree of hepatic steatosis. Previously, we reported that interaction between Kupffer cells (KCs) and platelets induced hepatic IR injury. The aim of our present study was to evaluate the relationship between the degree of liver steatosis and IR injury by focusing on the interaction of KCs and platelets. Mild and moderate steatotic liver models were generated in Wistar rats by feeding a cholinedeficient diet for 2 and 4 weeks, respectively. The intensity of steatosis was defined based on the proportion of hepatocytes with fatty infiltration: normal (less than 5%), a mild steatosis (5-30%), and moderate steatosis (30-60%). All groups were subjected to 20 min of warm ischemia followed by 120 min of reperfusion. The number of adhesion of KCs to platelets in sinusoids was observed by intravital microscopy. IR injury was evaluated with serum alanine aminotransferase levels, histological findings, and sinusoidal perfusion. Compared to the normal liver, mild steatosis reduced the adhesion of KCs to platelets, inducing the attenuation of IR injury. In contrast, moderate steatosis increased the adhesion of KCs to platelets, aggravating IR injury relative to the normal liver. IR injury in the steatotic liver was not simply proportional to the degree of steatosis. Mild steatosis ameliorates IR injury compared to the normal liver, whereas moderate steatosis increases IR injury.

Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

“…128 In hepatic I/R injury, the KC-platelet interaction contributes to exacerbation of liver injury, especially in steatotic livers. 129,130 Moreover, the KC-platelet interaction is critical for firstline defense against bacterial infection. In mice infected by bacteria, such as Bacillus cereus and methicillin-resistant Staphylococcus aureus (MRSA), it has been observed that platelets switch from a transient "touch-and-go" interaction with KCs to sustained GPIIb/IIIa-mediated adhesion to KCs via von Willebrand factor (VWF).…”

Platelets: No longer bystanders in liver disease

“…During the early period of an ischemic insult, platelets sequester in the liver, with most adhering to Kupffer cells, most likely through the interactions between platelet CLEC‐2 and macrophage podoplanin, which is up‐regulated under inflammatory conditions . The interaction between platelets and Kupffer cells provides bidirectional signals which together drive tissue injury; reducing platelet‐Kupffer cell binding ameliorates hepatic inflammation in steatotic livers of rodents . During ischemia‐reperfusion injury platelet‐Kupffer cell interaction precedes and initiates leukocyte accumulation, sinusoidal dysfunction, and the iterative inflammation which eventually results in liver failure …”

“…(43,44) The interaction between platelets and Kupffer cells provides bidirectional signals which together drive tissue injury; reducing platelet-Kupffer cell binding ameliorates hepatic inflammation in steatotic livers of rodents. (45) During ischemia-reperfusion injury platelet-Kupffer cell interaction precedes and initiates leukocyte accumulation, sinusoidal dysfunction, and the iterative inflammation which eventually results in liver failure. (46)…”