A reproducible model of acute hepatic failure by transient ischemia in the pig

Groot, Gerrit H. de; Reuvers, Cees B.; Schalm, Solko W.; Boks, Anton L.; Terpstra, Onno T.; Jeekel, Hans; Kate, F. W. J. Ten; Bruinvels, J.

doi:10.1016/0022-4804(87)90070-9

Cited by 47 publications

(38 citation statements)

References 6 publications

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“…the organ is made watertight) for a brief interval of time (<10 min) through vascular ligation in vivo. This procedure does not pose a risk for the animals, as evidenced by other authors [22,23] who studied liver ischemia for longer periods of time. The technique is invasive (laparotomy) but also easy and rapid (<1 h), and proves harmless for the pigs.…”

Section: Discussionmentioning

confidence: 71%

A Surgical Model for Isolating the Pig Liver in vivo for Gene Therapy

et al. 2013

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Several studies report results that suggest the need of vascularization blocking for efficient gene transfer to the liver, especially in nonviral gene therapy. In this study, we describe a surgical strategy for in vivo isolation of the pig liver, resulting in a vascular watertight organ that allows the evaluation of several gene injection conditions. The hepatic artery and portal, suprahepatic and infrahepatic cava veins were dissected. Then, liver vascularization was excluded for 5-7 min. In that time, we first injected 200 ml saline solution containing the p3c-eGFP plasmid (20 µg/ml) simultaneously through two different catheters placed in the portal and cava veins, respectively. Vital constants were monitored during the surgery to assess the safety of the procedure. Basal systolic/diastolic blood pressures were 92.8/63.2 mm Hg and dropped to 40.7/31.3 mm Hg at the end of vascular exclusion; the mean basal heart rate was 58 bpm, reaching 95 bpm when the blood pressure was low. Oxygen saturation was maintained above 98% during the intervention, and no relevant changes were observed in the ECG tracing. Peak plasma AST (aspartate aminotransferase) and ALT (alanine aminotransferase) levels were observed after 24 h (151 and 57 IU, respectively). These values were higher, but not relevant, in 60 ml/s injection than in 20 ml/s injection. Efficiency of gene transfer was studied with simultaneous (cava and portal veins) injection of eGFP gene at flow rates of 20 and 60 ml/s. Liver tissue samples were collected 24 h after injection and qPCR was carried out on each lobe sample. The results confirmed the efficiency of the procedure. Gene delivery differed between 20 ml/s (9.9-31.0 eGFP DNA copies/100 pg of total DNA) and 60 ml/s injections (0.6-1.1 eGFP DNA copies/100 pg of total DNA). Gene transcription showed no significant differences between 20 ml/s (15,701.8-21,475.8 eGFP RNA copies/100 ng of total RNA) and 60 ml/s (12,014-36,371 eGFP RNA copies/100 ng of total RNA). The procedure is not harmful for animals and it offers a wide range of gene delivery options because it allows different perfusion ways (anterograde and retrograde) and different flow rates to determine the optimal conditions of gene transfer. This strategy permits the use of cell therapy and viral or non-viral liver gene therapy, especially appropriated to a wide variety of inherited or acquired diseases because of the liver's ability to produce and deliver proteins to the bloodstream.

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Section: Discussionmentioning

confidence: 71%

A Surgical Model for Isolating the Pig Liver in vivo for Gene Therapy

et al. 2013

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“…This limits the pathophysiological study of certain systemic features of acute liver failure. This is overcome to a certain extent by ischemic models of FHF used by Olafsson et al 13 and de Groot et al 18 This leads, however, to the disadvantage that the greater the complexity of the surgical procedure, the greater the need for expert surgical help.…”

Section: Resultsmentioning

confidence: 99%

Animal models of fulminant hepatic failure: A critical evaluation

et al. 2000

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Few conditions in medicine are more dramatic or more devastating than acute liver failure. Our understanding and treatment of this condition have been limited by the lack of satisfactory animal models. The most widely used models consist of surgical anhepatic and devascularization procedures and hepatotoxins, such as galactosamine and acetaminophen. Potential disadvantages with surgical models are their inability to recreate the inflammatory milieu that exists in acute liver failure and their reliance on surgical expertise. Models using hepatotoxins are free of such constraints. Galactosamine-induced hepatotoxicity is more predictable than acetaminophen, but its cost and lack of a human equivalent clinical syndrome has restricted its use. Acetaminophen-based models offer the greatest potential but have proven the most difficult to develop because of difficulties with reproducibility and refractory anemia. Although progress has been made, research must continue in this area to establish an animal model with minimal disadvantages that would accurately reflect the clinical syndrome seen in humans.

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“…De Groot et al [10] reported a group of 15 pigs with PCA and temporary hepatic artery compression. Among the 13 animals which died within an interval of 15-20 h, ALF was the cause of death in only 8 of them.…”

Section: Resultsmentioning

confidence: 99%

“…This basic procedure is modified by the technique of HAL. ALF's irreversibility can be avoided by compression of the hepatic artery for only a short period of time [10]. No blood loss occurs in the event of liver devascularization and PCA.…”

Section: Introductionmentioning

confidence: 99%

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Devascularization Surgical Model of Acute Liver Failure in Minipigs

et al. 2004

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Aim: The study was designed to develop a readily reproducible model of acute liver failure (ALF) in the minipig, to gain an 8-hour therapeutic window to mimic, as closely as possible, acute liver failure in man. Method: We used reversible devascularization model of ALF in the minipig involving hepatic artery ligation and establish an end-to-side portocaval anastomosis. Standard laboratory monitoring was complemented with intracranial pressure (ICP) measurement. Material: Twenty minipigs (weight 25–30 kg) were used for the experiment. The animals were divided into 3 groups: I: 10 animals in an experimental group with ALF; II: 5 animals in an experimental group with ALF and ICP measurement, and III: 5 animals in a control group without ALF. Results: Laboratory testing has shown the significant changes in levels of AST (33.44 ± 39.96 vs. 1.56 ± 0.50 mmol/l), lactate (2.97 ± 1.16 vs. 1.18 ± 0.61 mmol/l), and ammonia (264.3 ± 93.05 vs. 42.5 ± 12.98 mmol/l) between ALF groups and controls (p < 001) 6 h after the operative procedure, and significant changes in hypoglycemia and intracranial pressure were found 4 h after the operative procedure. The difference in Quick values (67.4 ± 17.03 vs. 75.2 ± 2.68) was not significant. We assume that the therapeutic window starts 4 h after the beginning of the experiment. Conclusion: Our devascularization model of ALF is simple and readily reproducible. The therapeutic window occurring shortly after surgery and persisting for a mean 9 h is suitable to evaluate bioartificial liver devices.

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A reproducible model of acute hepatic failure by transient ischemia in the pig

Cited by 47 publications

References 6 publications

A Surgical Model for Isolating the Pig Liver in vivo for Gene Therapy

A Surgical Model for Isolating the Pig Liver in vivo for Gene Therapy

Animal models of fulminant hepatic failure: A critical evaluation

Devascularization Surgical Model of Acute Liver Failure in Minipigs

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