Cytoprotective effect of prostacyclin on hepatic ischemia-reperfusion injury

Table 1 Overproduced molecules and its consequences in hepatic ischemia-reperfusion injury

Number	Molecule	Effect
1	Tumor necrosis factor α	Central mediator with multifactorial effect
2	Interleukin-1α	Mediator of neutrophil infiltration
3	Interleukin-1β	Induction of prostaglandin synthesis, enhancement of T-cell and neutrophil activation and cytokine production
4	Interleukin-12	Induction and development of hepatic ischemia-reperfusion injury
5	Interferon-γ	Increases or reduces neutrophil accumulation in a dose-depend manner
6	Damage-associated molecular patterns	Pro- and anti-inflammatory mediators that promote tissue damage
7	Intercellular adhesion molecule 1	Promotes neutrophil accumulation
8	Vascular cell adhesion molecule 1	Mediates inflammation and promotes neutrophil migration
9	P-selectin	Promotes neutrophil and platelets adhesion
10	Transforming growth factor-β	Promotes vessel wall inflammation and increase vascular permeability
11	Vascular endothelial growth factor	Promotes T lymphocyte, macrophage and neutrophil accumulation
12	Plasminogen activator inhibitor 1	Promotes neutrophil accumulation and suppresses fibrinolysis
13	Nitric oxide	Prevents or promotes cell damage depending on NO synthesis processes
14	Endothelin-1	Vasoconstriction
15	Combination of released factors	Heart-kidney damage, systematic inflammatory response syndrome SIRS, multiple organ dysfunction, death

Table 2 Prostacyclin effects (IP receptors)

Number	Prostacyclin effects
1	Inhibition of platelets aggregation
2	Vasodilation
3	Inhibition of platelets adhesion
4	Angiogenesis
5	Reduction of myo-vascular remodelling
6	Inhibition of proliferation
7	Reduction of fibroblast migration
8	Reduction of cytokine release
9	Reduction of lipid peroxidation
10	Downregulation of adhesion molecules and growth factors
11	Inhibition of apoptosis
12	Reinforcement of endothelial cell function
13	Regulation of lipid metabolism

Table 3 Summarizing the main characteristics of the studies before 2000 regarding effects of prostacyclin analogs on hepatic ischemia-reperfusion injury

Ref.	Prostacyclin analog	Dose	Intervention	Species	Study size	Outcome
Monden et al[152], 1982	PGI2	100 μg	Liver preservation for orthotopic liver transplantation	Mongrel dogs	6	100% 48 hours survival
Sikujara et al[155], 1983	PGI2	350 ng/kg/min i.v	75 min Hepatic ischemia	Wistar rats	31	67% one-week survival
Tanaka et al[186], 1990	aPGI2	350 ng/kg/min for 60 min i.v	90 min Hepatic ischemia	Rats		No effect alone
Sanchez-Urdazpal et al[172], 1991	Iloprost	200 μl/L storage solution. 3 μg/kg/min bolus administration through the aortic patch	Liver graft preservation	Lewis rats	12	91% survival
Goto et al[154], 1992	OP-41483	500 ng/kg/min i.v	Liver transplantation	Wistar rats	7	86% one-week survival
Abe et al[176], 1993	OP-41483	400 ng/kg/min	40 min normothermic liver ischemia	Wistar rats	8	Improved microcirculation and increased effective hepatic blood flow
Kim et al[156], 1994	OP-2507	2 pg/kg/min for 30 min, intraportal infusion 200 μg/l	Liver donor pretreatment, graft preservation. Dissolution in preservation solution	Mongrel pigs	6	Improved 5-day survival
Kim et al[157], 1994	OP-2507	2 pg/kg/min for 30 min via mesenteric vein administration	1 hour complete hepatic vascular exclusion	Mongrel pigs	7	86% 5-day survival
Anthuber et al[170], 1996	Epoprostenol	50 μg/ml solution	Liver donor bolus pretreatment	Lewis rats	8	Improved perfusion of liver sinusoids, reduced leukocyte adherence, increased bile production
Klein et al[195], 1999	Epoprostenol	500 μg	Orthotopic liver transplantation	Human	57	Reduced ischemia-reperfusion injury

PGI₂: Prostacyclin.

Table 4 Summarizing the main characteristics of the studies after 2000 regarding effects of prostacyclin analogs on hepatic ischemia-reperfusion injury

Ref.	Prostacyclin analog	Dose	Intervention	Species	Study size	Outcome
Neumann et al[171], 2000	Epoprostenol	4 ng/kg/min i.v for 7 days	Continuous infusion after liver transplantation	Human	15	Improvement of hepatic-splanchnic oxygenation
Chen et al[180], 2001	OP-2507	1 μg/kg/min, 0.1 μg/kg/min	Hepatic ischemia	Sprague-Dawley rats	24	Ameliorated ischemia-reperfusion of the liver
Zardi et al[174], 2006	Iloprost	2 ng/kg/min, 6 h/day for 5 days	Portal flow velocity evaluation	Human	15	Improved hepatic perfusion
Gedik et al[188], 2009	Iloprost	10 μg/kg	45 min hepatic ischemia followed by reperfusion	Sprague-Dawley rats	10	Hepatoprotective effects
Ghonem et al[191], 2012	Treprostinil	100 ng/kg/min	Donor and recipient treatment prior liver transplantation	Lewis rats	58	Ameliorated hepatic injury reduced cytokines expression and improved CYP450 activity
Deng et al[28], 2018	Beraprost sodium	50-100 μg/kg	Hepatic ischemia-reperfusion	Mice	36	Ameliorated hepatic IR injury by suppressing inflammation, apoptosis, and autophagy
Almazroo et al[193], 2022	Treprostinil	20 ng/mL of storage solution	Hepatic ischemia-reperfusion	Sprague-Dawley rats	8	Reduced liver injury