Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog

Table 1 Hepatic ischemia-reperfusion injury mechanisms

Primary mechanisms	Subsequent reactions	Final outcomes
Metabolism disorders		Systemic inflammatory response syndrome, multiple organ dysfunction syndrome
Anaerobic glycolysis	Mitochondria dysfunction
ATP production	Cellular immunity
Lactic acid and toxic acidic metabolites	Cell injury
Reactive oxygen species	Programmed cell death and apoptosis
Intracellular calcium overload	Microcirculatory dysfunction
Microcirculatory system disorders
Vasoconstriction
Obstruction	Microcirculatory dysfunction
Apoptosis of sinusoidal endothelial cells	Vascular permeability
Expression of adhesion molecules	Endothelial cells oedema
	Ischemic injury
	Neutrophil accumulation
Immune system disorders
Kupffer cells activation
Neutrophils activation
Production of pro- and anti-inflammatory cytokines	Excessive inflammatory process
Accumulation of circulating lymphocytes, platelets and monocytes	Anti-inflammatory response
	Recruitment of CD4+ T lymphocytes
Gene expression
Imbalance in mRNAs expression	Cell damage
Programmed cell death	Necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis

Table 2 Treprostinil mechanisms of action

Effect	Mechanism of action	Cellular response
Vessel tone	cAMP increased. Endothelin 1 decreased. Potassium decreased	Vasodilation. Improvement of microcirculation dysfunction
Antiproliferative	PPARs increased. cAMP increased. VEGF-A increased	Angiogenesis. Regulation of vascular homeostasis
Antithrombotic	Thromboxane A2 decreased. PDGF decreased	Inhibition of platelets aggregation. Platelets adherence decreased
Anti-inflammatory	P38 and JNK cascades decreased. IL-1, IL-6, TNF-α decreased. IL-10 increased. Reactive oxygen species decreased. TLR 9 decreased	Attenuation of inflammatory cascade. Apoptosis rate increased
Energy balance	Pgc-1α mRNA expression decreased. Cytochrome c decreased. Caspase 3 activation decreased	ATP production increased. Mitochondrial biogenesis increased

cAMP: Cyclic adenosine monophosphate; PPARs: Peroxisome proliferator-activated receptors; VEGF: Vascular endothelial-derived growth factor; JNK: c-Jun N-terminal kinase; IL: Interleukin; TNF: Tumor necrosis factor; TLR: Toll-like-receptor; ATP: Adenosine triphosphate.