Liver ischemia and reperfusion injury. Pathophysiology and new horizons in preconditioning and therapy

It is well known that during hepatic operative procedures, it is often critical that the irrigation is interrupted to avoid possible bleeding, blood transfusions, variable intensities, and their short and long-term consequences. It was believed in the past that the flow interruption should not exceed 20 minutes, which limited the use of this maneuver. However, it has been postulated that ischemia could be maintained for more than 60 minutes in healthy livers. The present paper review includes: 1) A brief introduction to justify the rationale of the review design; 2) Aspects of the pathophysiology of the three stages of the liver ischemia-reperfusion injury; 3) The innate and acquired immunity; 4) Oxidative stress; 5) Apoptosis and autophagy, Some essential biomarkers (Tumor Necrosis Factor-α, nitric oxide, metalloproteinases); and, finally; 6) Preventive (“cheating”) strategies, non-pharmacological and pharmacological options to treat the liver IR injury.

Key words:
Liver; Ischemia; Reperfusion Injury

Authorship

Paula Carolina Grande Nakazato

Medical student, Surgery and Anatomy Department, Medical School, Universidade de São Paulo (USP), Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study; acquisition, analysis and interpretation of data.Universidade de São PauloBrazilRibeirao Preto, SP, BrazilMedical student, Surgery and Anatomy Department, Medical School, Universidade de São Paulo (USP), Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study; acquisition, analysis and interpretation of data.

João Paulo Victorino

BScN, USP, College of Nursing, PAHO/WHO Collaborating Centre for Nursing Research Development, Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study, manuscript preparation.USPBrazilRibeirao Preto, SP, BrazilBScN, USP, College of Nursing, PAHO/WHO Collaborating Centre for Nursing Research Development, Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study, manuscript preparation.

Clarice Fleury Fina

Laboratory Specialist, Surgery and Anatomy Department, Medical School, USP, Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study.USPBrazilRibeirao Preto, SP, BrazilLaboratory Specialist, Surgery and Anatomy Department, Medical School, USP, Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study.

Karina Dal Sasso Mendes

PhD, General and Specialized Nursing Department, USP, College of Nursing, PAHO/WHO Collaborating Centre for Nursing Research Development, Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study.USPBrazilRibeirao Preto, SP, BrazilPhD, General and Specialized Nursing Department, USP, College of Nursing, PAHO/WHO Collaborating Centre for Nursing Research Development, Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study.

Maria Cecília Jordani Gomes

Paulo Roberto Barbosa Evora

Full Professor, Surgery and Anatomy Department, Medical School, USP, Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study.USPBrazilRibeirao Preto, SP, BrazilFull Professor, Surgery and Anatomy Department, Medical School, USP, Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study.

Luiz Augusto Carneiro D’Albuquerque

Full Professor, Department of Gastroenterology, Medical School, USP, Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study.USPBrazilRibeirao Preto, SP, BrazilFull Professor, Department of Gastroenterology, Medical School, USP, Ribeirao Preto-SP, Brazil. Scientific and intellectual content of the study.

Orlando Castro-e-Silva

Full Professor, Surgery and Anatomy Department, and Department of Gastroenterology, Medical School, USP, Ribeirao Preto-SP, Brazil. Scientific, intellectual, conception and design of the study; acquisition, analysis and interpretation of data; manuscript writing; critical revision; final approval.USPBrazilRibeirao Preto, SP, BrazilFull Professor, Surgery and Anatomy Department, and Department of Gastroenterology, Medical School, USP, Ribeirao Preto-SP, Brazil. Scientific, intellectual, conception and design of the study; acquisition, analysis and interpretation of data; manuscript writing; critical revision; final approval.

Correspondence: Orlando Castro-e-Silva Departamento de Cirurgia e Anatomia, USP orlando@fmrp.usp.br

Conflict of interest:

none

SCIMAGO INSTITUTIONS RANKINGS

Figures | Tables

Figures (3)
Tables (1)

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Figure 1
Simplified scheme of cellular bioenergetic processes involved in ischemic injury. The oxygen depletion caused by the inhibition of the mechanisms of electron transport in the respiratory chain leads to a decrease in the cellular levels of ATP, originating Na+/K+ failure and generating depolarization of the cell membrane with consequent intracellular accumulation of Ca⁺², activating proteases, lipases, phospholipases and ATPases. At the same time, the change from aerobic to anaerobic metabolism causes lactic acidosis which also activates intracellular proteases that cause cell dysfunction. In relation to the mitochondria, the increase of Ca⁺² influx to the organelle, associated to the accumulation of ADP, AMP and phosphate, leads to the transition of membrane permeability and mitochondrial dysfunction. These events can lead to cell death.

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Figure 2
Processes involved during the reperfusion Injury. Restoration of blood flow associated with increased intracellular Ca2+ concentration leads to the disordered increase of ROS by several pathways. This increase leads to cellular and mitochondrial changes that are often irreversible, leading to cell death.

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Figure 3
Inflammatory process involved during the IR Injury, showing the consequences of endothelial loss function and activation of Kupffer cells and neutrophils in the liver.

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Chart 1
Liver ischemia and reperfusion injury and its pathophysiology aspects in relation to the preconditioning: a simplified overview of the past, present and future.

Figure 1 Simplified scheme of cellular bioenergetic processes involved in ischemic injury. The oxygen depletion caused by the inhibition of the mechanisms of electron transport in the respiratory chain leads to a decrease in the cellular levels of ATP, originating Na+/K+ failure and generating depolarization of the cell membrane with consequent intracellular accumulation of Ca⁺², activating proteases, lipases, phospholipases and ATPases. At the same time, the change from aerobic to anaerobic metabolism causes lactic acidosis which also activates intracellular proteases that cause cell dysfunction. In relation to the mitochondria, the increase of Ca⁺² influx to the organelle, associated to the accumulation of ADP, AMP and phosphate, leads to the transition of membrane permeability and mitochondrial dysfunction. These events can lead to cell death.

Figure 2 Processes involved during the reperfusion Injury. Restoration of blood flow associated with increased intracellular Ca2+ concentration leads to the disordered increase of ROS by several pathways. This increase leads to cellular and mitochondrial changes that are often irreversible, leading to cell death.

Figure 3 Inflammatory process involved during the IR Injury, showing the consequences of endothelial loss function and activation of Kupffer cells and neutrophils in the liver.

Chart 1 Liver ischemia and reperfusion injury and its pathophysiology aspects in relation to the preconditioning: a simplified overview of the past, present and future.

It was believed in the past that the flow interruption should not exceed 20 minutes, which limited the use of this maneuver. However, in subsequent studies, it has been postulated that ischemia could be maintained for more than 60 minutes in healthy livers.

The pathophysiology liver IR includes three stages of the liver ischemia-reperfusion injury and an innate and acquired immunity.

Oxidative stress, apoptosis and autophagy are detrimental injury mechanisms.

Some important biomarkers (Tumor Necrosis Factor-α, nitric oxide, metalloproteinases) have pivotal role.

Preventive (“cheating”) strategies, non-pharmacological and pharmacological options to treat the liver IR injury.

To mitigate the lesion caused and prevent organ loss, various strategies have been studied, from surgical interventions, pharmacological agents to gene therapy.

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