Mecanismos moleculares en el daño por isquemia-reperfusión hepática y en el preacondicionamiento isquémico

Abstract

Ischemia-reperfusion (IR) liver injury is associated with temporary clamping of hepatoduodenal ligament during liver surgery, hypoperfusion shock and graft failure after liver transplantation. Mechanisms of IR liver injury include: i) loss of calcium homeostasis, ii) reactive oxygen and nitrogen species generation, iii) changes in microcirculation, iv) Kupffer cell activation, and (v) complement activation. Pre-exposure of the liver to transient ischemia increases the tolerance to IR injury, a phenomenon known as hepatic ischemic preconditioning (IP). IP involves: i) recovery of the energy supply and calcium, sodium and pH homeostasis, ii) enhancement in the antioxidant potential, and iii) expression of multiple stress-response proteins, including acute phase proteins, heat shock proteins, and heme oxygenase. These observations and preliminary studies in humans give a rationale for the assessment of IP in minimizing or preventing IR injury during surgery and non surgical conditions of tissue hypoperfusion.

Cytoprotective and suicidal signaling in oxidative stress

“…In general terms, IR injury refers to tissue damage produced by blood perfusion to the previously ischemic organ, which in the liver is associated with the clinical settings of hepatic resection, transplantation, low-blood pressure states, and abdominal surgery requiring hepatic vascular occlusion (Romanque et al, 2005;Casillas-Ramírez et al, 2006). IR liver injury assessed in a model involving 1 hour of partial ischemia induced by vascular clamping followed by reperfusion for 20 h elicited substantial liver damage, concomitantly with (i) a drastic increase in the oxidative stress status of the liver and TNF-α response; (ii) loss in the DNA binding of NF-κB and STAT3 implying loss of cytoprotective potential; and (iii) enhancement in the hepatic AP-1 DNA binding activity, which may constitute a major determinant of hepatotoxicity under conditions of reduced NF-κB activation and TNF-α response (Fernández et al, 2007b;2008).…”

“…The moderate increase in ROS and reactive nitrogen species (RNS) in a defined time window can elicit an imbalance capable of redox regulation, as found for L-3,3 , ,5triiodothyronine (T 3 )-induced oxidative stress (Varela et al, 2006), which may involve important signals regulating either protein function, via reversible oxidation or nitrosation of protein sulfhydryls, and/or gene expression, through modulation of specific kinases, phosphatases, and redoxsensitive transcription factors (Dröge, 2002;Poli et al, 2004). However, in the case of organs subjected to ischemiareperfusion (IR) (Romanque et al, 2005) or in obesity (Videla, 2008), large levels of ROS are attained, which may induce loss of cell viability and death. The relevance of oxidative stress on human pathology is manifold.…”

Avaliação da lesão após isquemia e reperfusão hepática em modelos experimentais com camundongos knockout heterozigotos para expressão da conexina 43

“…Após as primeiras horas de reperfusão, as citocinas pró-inflamatórias, principalmente, o fator de necrose tumoral (TNF-alfa) e interleucinas (IL-6 e IL-1) recrutam e ativam células CD4+ (Linfócitos-T), as quais produzem GM-CSF (fator estimulador de colônias de granulócitos-macrófagos, interferon-gama (IFN-gama) e fator de necrose tumoral-alfa (TNF-alfa). Estas citocinas participam facilitando a migração, a ativação e a adesão de neutrófilos aos sinusoides hepáticos (Lentsch et al, 2000;Romanque et al, 2005;Massip-Salcedo et al, 2007). A interação entre neutrófilos e as células endoteliais sinusoidais é pré-requisito para o desenvolvimento da lesão da microvascularização.…”

“…A interação entre neutrófilos e as células endoteliais sinusoidais é pré-requisito para o desenvolvimento da lesão da microvascularização. A adesão e a migração do sneutrófilos ativados através do endotélio leva à destruição de tecidos pela liberação de radicais livres, enzimas proteolíticas e peroxidase, mediados pelas ações do fator ativador de plaquetas (PAF) e de leucotrieno B4 (Miranda et al, 2004;Romanque et al, 2005).…”

Pré e pós-condicionamento isquêmico em músculo esquelético de ratos

“…O oxido nítrico (NO) é produzido por diversos tipos de células (endotélio, neurônios, macrófagos, epitélio) a partir do L-arginina, por ação da enzima NO sintetase (NOS) incluindo uma isoforma indutível que se expressa principalmente em condições patológicas (iNOS ou NOS-2) e duas constitutivas: a eNOS (NOS-3) e a nNOS (NOS-1) que se expressam no endotélio e no sistema nervoso respectivamente. A NOS é ativada pelo influxo de Ca 2+ no interior das células (CAMPOS et al, 2004 ROMANQUE;URIBE;VIDELA, 2005;TZENG et al, 1994).…”