The Role of Prostaglandins in Liver Ischemia-Reperfusion Injury

Abstract

Ischemia reperfusion (IR) of the liver is a multifactorial process that, at least in part, is responsible for the morbidity associated with major liver surgery under occlusion of the portal triad with the Pringle maneuver, total vascular exclusion or after liver transplantation. Surgeons are confronted with IR injury (IRI) more often than they anticipate. Although the human body has its own defense system, understanding the pathophysiology of IRI is essential for the surgeon in preventing and/or treating the reperfusion injury in common clinical practice. Several endogenous mechanisms exist to overcome IRI and a large number of pharmacological agents have also been found to confer protection against ischemic injury in the liver. They either blocked the injurious pathways directly or they subjected the liver to preconditioning. Prostaglandins (PGs) are a group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase (COX) pathway. They are short-lived, hormone-like chemicals that regulate cellular activities on a moment-to-moment basis and are produced in most tissues of the body, although the liver has emerged as the major organ participating in the synthesis, degradation and elimination of arachidonate products of systemic origin. PGs are released through the prostaglandin transporter on the cell's plasma membrane. During the last decade intensive work on the cytoprotective effects of PGs on livers suffering from IRI have been well documented. Prostaglandins confer their protective effects on IR-injured livers mainly by inhibiting the generation of reactive oxygen species, preventing leukocyte migration, reducing the synthesis or production of membrane degradation products, improving hepatic insulin and lipid metabolism, and regulating the production of inflammatory cytokines and cell adhesion molecules. Production of PGs have been found essential also soon after partial hepatectomy for hepatocyte proliferation.

Induction of Hepatobiliary Efflux Transporters in Acetaminophen-Induced Acute Liver Failure Cases

“…Alternatively, the exported compounds may function as paracrine signaling molecules to adjacent hepatocytes and nonparenchymal cells to facilitate the recovery process. As mentioned previously, MRP4 is capable of exporting prostaglandins, which have been documented to play an important role in hepatocyte proliferation after partial hepatectomy and to be hepatoprotective during liver ischemia-reperfusion injury (Rudnick et al, 2001;Hossain et al, 2006). In addition, cyclic nucleotides are substrates of both MRP4 and MRP5, which have also been shown to be important signaling molecules during hepatocyte proliferation and have been suggested to be a potential paracrine signaling pathway in the liver (Schlosser et al, 1996;Della Fazia et al, 1997).…”

Treprostinil, a Prostacyclin Analog, Ameliorates Ischemia-Reperfusion Injury in Rat Orthotopic Liver Transplantation

“…TNF-a, tumor necrosis factor-a; IL, interleukin-1b, −6 and −10; IFN-c , Interferon-c ; * p < 0.05, * * p < 0.01 versus placebo, n = 3 per group. decrease expression of cell adhesion molecules and leukocyte activation, inhibit the production of TNF-a and other proinflammatory cytokines, suppress neutrophil activation and adhesion to the vascular endothelium, and counteract the activity of vasoconstrictors and platelet aggregation (11,14). This is the first study to evaluate the effect of treprostinil, a commercially available PGI 2 analog, for its protection against IRI in a rat OLT model.…”

“…PGs (PGE 1 and PGI 2 ) play a critical role in maintaining vascular homeostasis of microcirculation, which contributes to its wide range of protective effects against I/R-induced liver injury (11)(12)(13). Different PG analogs have been reported to maintain blood flow, inhibit local vascular thrombosis, Treprostinil Ameliorates I/R Injury in Rat OLT Figure 3: Pro-inflammatory cytokine upregulation attenuated by treprostinil.…”

Omega 3 – Omega 6: What is right for the liver?

“…For instance, leukotriene B4 (LTB4) is known to be associated with liver injury like hepatitis and cirrhosis [75]. However, there are only a few studies about its role in hepatic ischemia/reperfusion injury.…”