Research reviewFactors in the Pathophysiology of the Liver Ischemia-Reperfusion Injury
Introduction
Interruption of an organ's blood flow, with its subsequent lack of oxygen and nutrient supply, is an inherent phenomenon during diverse surgical procedures. In liver surgery, there are clinical situations in which the ischemic periods can be particularly long, such as during the resection of large hepatic tumors, management of hepatic trauma of diverse origins, vascular reconstructions, and liver procurement for transplantation [1, 2, 3]. Once the blood flow and oxygen supply are reestablished, reperfusion enhances the injury caused by the ischemic period, aggravating the damage caused at the cellular level [4, 5]. This phenomenon, known as ischemia-reperfusion (IR) injury, impacts directly on liver viability, especially during transplantation and liver surgery [3, 6]. During an ischemic period, several functional changes occur at the cellular level that promote cell injury. A decrease in oxidative phosphorylation results in adenosine triphosphate (ATP) depletion and derangements in calcium homeostasis [7].
The deleterious effects of ATP catabolism modification are further enhanced by the production of several substances, including reactive oxygen species (ROS), cytokines, adhesion molecules, and vasoactive agents (endothelin and thromboxane-A2). These alterations are accompanied by a decrease of cytoprotective substances including nitric oxide, prostacyclin, and others [8]. Hepatic cell death occurs due to both necrosis and apoptosis [9].
Section snippets
Microcirculatory Failure
During the ischemic period, the lack of energetic substrate interferes with active transmembrane transport, producing edema in Kupffer cells (KC) and endothelial cells (EC) [10]. Loss of the delicate equilibrium between nitric oxide (NO) and endothelin (ET) induces vasoconstriction and narrowing of the sinusoidal lumen, compromising leukocyte flow and bringing them in close contact with the capillary wall [11]. The increase in contact between leukocytes and EC promotes leukotaxis, and although
KC
During the initial stages of reperfusion, KC are activated, producing morphological changes that cause them to protrude into the sinusoids, contributing to the reduction of blood flow within the sinusoidal lumen [18, 37]. Activated KC release a large amount of both proinflammatory (TNF-α, IL-6, IL-1, and prostaglandins) and anti-inflammatory mediators (IL-10, IL-13), as well as ROS [22, 23]. Some studies show that IR injury can be attenuated or aggravated by the suppression or potentiation of
Conclusion
The cell signaling pathways and mediators of hepatic ischemia reperfusion are summarized in Fig. 1. In vitro and preclinical animal studies have led to an overall better understanding of liver anatomy, physiology, and the complex signaling events during IR injury [106].
Application of pharmacologic, genetic, and surgical approaches to reduce hepatic IR injury have been applied and are increasingly being used. Therapeutic approaches include pharmacologic use of N-acetylcysteine, prostaglandins,
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