Beyond Preconditioning: Postconditioning as an Alternative Technique in the Prevention of Liver Ischemia-Reperfusion Injury

Table 1

Summary of outcome of studies on ischemic postconditioning of the liver.

Study group	Year	Species	Hepatic ischemia	Ischemia time	Reperfusion time	IPostC technique	Parameters assessed	Outcome of IPostC (IPostC versus control)	Proposed mechanism
Sun et al. [37]	2004	Rat	Warm and partial	60 min	120 min	2/3/5/7 min R +; 2 min I	MDA, SOD, CAT, GSH-, Bcl-2 protein, apoptotic index, and mitochondrial ultrastructure	(i) MDA and apoptotic index; (ii) SOD, CAT, GSH- and Bcl-2 protein, and improved mitochondrial ultrastructure	Modulation of apoptosis cascade and maintenance of integrity of mitochondrial membrane
Wu et al. [65]	2007	Rat	Warm and partial				ALT, AST, MDA, GSH, SOD, GSH-, MPO, and one-week survival	(i) ALT, AST, MDA, and MPO; (ii) GSH, SOD, GSH-, and improved animal survival	Not addressed
Wang et al. [66]	2008	Rat	Warm, total, and cold (transplantation)	30 min of warm ischemia; 2 h of cold ischemia	3 h	(30 sec R + 30 sec I) × 3	ALT, AST, bile γGT, bile glucose, histopathology, hepatocyte apoptotic activity, apoptotic-related protein Fas, and one-week survival	(i) ALT, AST, apoptotic activity, and Fas; (ii) bile γGT, and bile glucose; (iii) inflammation and necrosis on histopathology and improved animal survival	Inhibition of apoptosis
Wang et al. [45]	2009	Rat	Cold (transplantation)	24 h	6 h	(30 sec R + 30 sec I) × 3 or 6	ALT, AST, LDH, MDA, SOD, GSH-, MPO, TNF-α expression, MIP-2 expression, histopathology, NO, i-NOS expression, and e-NOS expression	(i) ALT, AST, and LDH; (ii) MDA and MPO; (iii) TNF-α and MIP-2 expression; (iv) SOD, GSH-, and; improved hepatic morphology; (v) NO and i-NOS and e-NOS expression	Inhibition of neutrophil recruitment and activation,; i-NOS and e-NOS-mediated NO production
Zhang et al. [38]	2009	Rat	Warm and partial	60 min	120 min	2/3/5/7 min R +; 2 min I	ALT, AST, NF-κB p65 expression, SOD, apoptotic index, and light and electron microscopy	(i) ALT and AST; (ii) NF-κB p65 expression and apoptotic index; (iii) SOD; (iv) Lower degree of sinusoid congestion and neutrophilic infiltration, lower degree of disruption of nuclear and mitochondrial membranes, and lower degree of degranulation of endoplasmic reticulum	Modulation of apoptotic cascade and maintenance of mitochondrial ultrastructure and function
Teixeira et al. [40]	2009	Rat	Warm and partial	60 min	120 min	(5 sec R + 5 sec I) × 5	MDA and GST-α3	(i) MDA; (ii) Nonsignificant increase in expression of GST-α3	Not addressed
Dos Santos et al. [41]	2010	Rat	Warm and total	30 min	60 min	(30 sec R + 30 sec I) × 3	ALT, AST, and histopathology	(i) ALT and AST; (ii) Decreased congestion and hepatocyte degeneration	Not addressed
Zeng et al. [46]	2010	Rat	Cold (transplantation)	24 h	6 h	(60 sec R + 60 sec I) × 6	ALT, AST, MDA, SOD, HO-1 expression, and histopathology	(i) ALT, AST, and MDA; (ii) SOD and HO-1 expression; (iii) Decreased vacuolization, sinusoidal congestion, and hepatocyte necrosis	Upregulation of HO-1 expression
Knudsen et al. [71]	2010	Rat	Warm and total	30 min	30 min	(30 sec R + 30 sec I) × 3	ALT and gene expression analysis after RNA extraction	(i) ALT not different from control and upregulation of genes involved in angiogenesis	Not addressed
Guo et al. [83]	2011	Mouse	Warm and partial	60 min	2/4/12 h	(10 sec R + 10 sec I) × 3	ALT, MDA, SOD, NO, e-NOS, TNF-α, ICAM-1, HIF-1α, PI3K-Akt, and histopathology	(i) ALT, MDA, TNF-α, and ICAM-1; (ii) SOD, NO, and e-NOS; (iii) HIF-1α and PI3K-Akt; (iv) Lower scores of cytoplasmic vacuolization, sinusoidal congestion, and hepatocyte necrosis	Suppression of proinflammatory mediators and adhesion molecules, e-NOS-mediated NO production through PI3K-Akt, and upregulation of HIF-1α through NO
Knudsen et al. [70]	2011	Rat	Warm and total	30 min	30 min	(30 sec R + 30 sec I) × 3	ALT, HIF-1α, and VEGF	(i) ALT not different from control and lack of upregulation of HIF-1α and VEGF	Not addressed
Zeng et al. [47]	2011	Rat	Cold (transplantation)	24 h	6 h	(60 sec R + 60 sec I) × 6	ALT, AST, MDA, SOD, HO-1 expression, histopathology, and electron microscopic examination	(i) ALT, AST, and MDA; (ii) SOD and HO-1 expression; (iii) Decreased vacuolization, sinusoidal congestion and hepatocyte necrosis, and decreased evidence of chromatin damage and mitochondrial disruption	Upregulation of HO-1 expression
Lin et al. [42]	2012	Rat	Warm and partial	45 min	4 h	(60 sec R + 60 sec I) × 3	ALT, apoptotic index, 4-HNE modified protein, cytochrome c release from mitochondria, and change of mitochondrial membrane potential	(i) ALT, apoptotic count, and 4-HNE modified protein; (ii) Attenuated cytochrome c release from mitochondria and preservation of mitochondrial membrane potential	Inhibition of mitochondrial permeability transition pore opening, preservation of the electrochemical gradient across the inner mitochondrial membrane, and inhibition of release of proapoptotic solutes like cytochrome c
Song et al. [67]	2012	Mouse	Warm and partial	30 min	60 min	(30 sec R + 30 sec I) × 3	ALT, AST, TNF-α, IL-1β, T-AOC, MDA, SOD, CAT, GSH-, T-NOS, i-NOS, HIF-1α, and VEGF	(i) ALT, AST, TNF-α, IL-1β, and MDA; (ii) T-AOC, SOD, CAT, GSH-, T-NOS, i-NOS, HIF-1α, and VEGF	Induction of hepatic own defensive mechanism for tissue adaptation in oxygen-deficient environments
Knudsen et al. [74]	2012	Rat	Warm and total	30 min	30 min	(30 sec R + 30 sec I) × 3	ALT, gene expression analysis after RNA extraction, and quantitative real-time PCR	(i) ALT not different from control; (ii) Upregulation of genes involved in DNA binding and transcription, cellular membrane function, and apoptosis and metabolic processes	Not addressed
Knudsen et al. [43]	2013	Rat	Warm and partial	60 min	4/24 h	(30 sec R + 30 sec I) × 3	ALT, TNF-α, IL-6, NVR, and apoptotic cell number	(i) ALT not different from control, variable kinetics of IL-6, and TNF-α below detection limit at all time points; (ii) NVR; (iii) apoptotic cell profiles (insignificantly)
Young et al. [75]	2014	Prepubertal rat	Warm and total	30 min	24 h	(30 sec R + 30 sec I) × 2	ALT, AST, PCNA, and regenerated liver mass	(i) AST and ALT; (ii) Improved liver regeneration	Not addressed
Yoon et al. [39]	2015	Rat	Warm and partial	60 min	120 min	2/3/5/7 min R +; 2 min I	ALT, AST, MDA, and survivin	(i) No significant difference in ALT, AST, and MDA; (ii) Increased expression of survivin	Inhibition of apoptosis
Ricca et al. [48]	2015	Man	Cold (transplantation)	Not standard	120 min for reperfusion biopsies	(60 sec R + 60 sec I) × 3 at arterial reperfusion	AST (peak postop levels), EGD, histopathology, evidence of apoptosis or autophagy, postop morbidity and mortality, and one-year patient and graft survival	(i) Less severe injury on histology; (ii) Increased autophagy; (iii) No difference in median postop AST, EGD, apoptosis, postop morbidity and mortality, and one-year patient and graft survival	Not addressed

R: reperfusion; I: ischemia; IPostC; ischemic postconditioning; MDA: malondialdehyde; SOD: superoxide dismutase; CAT: catalase; GSH-: glutathione peroxidase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; MPO: myeloperoxidase; γGT: gamma-glutamyltransferase; LDH: lactate dehydrogenase; TNF-α: tumor necrosis factor-alpha; MIP-2: macrophage inflammatory protein-2; NO: nitric oxide; i-NOS: inducible NO synthase; e-NOS: endothelial NO synthase; NF-κB: nuclear factor-kappa B; GST-α3: glutathione-s-transferase-α-3; ICAM-1: intercellular adhesion molecule-1; HIF-1α: hypoxia inducible factor 1-alpha; PI3K-Akt: phosphatidylinositol 3-kinase; VEGF: vascular endothelial growth factor; 4-HNE: 4-hydroxy-2-nonenal; T-AOC: total antioxidant capacity; T-NOS: total NOS; PCR: polymerase chain reaction; NVR: necrotic volume ratio; PCNA: proliferating cell nuclear antigen; EGD: early graft dysfunction.