Reversibility of experimental rabbit liver cirrhosis by portal collagenase administration

Jin, Bo; Alter, Harvey J.; Zhang, Zhicheng; Shih, Johanna; Esteban, Juan M; Sun, Tao; Yang, Yunsheng; Qiu, Qi; Liu, Xiaolin; Lin, Yao; Wang, Haidong; Cheng, Longzhen

doi:10.1038/labinvest.3700304

Cited by 19 publications

(6 citation statements)

References 35 publications

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“…In conclusion, data obtained during the present study: (1) demonstrate that the loss of SECs during CI‐WR has no effect on the overall function of cirrhotic rat livers; and (2) strongly suggest that collagenization is more important than capillarization in the reduced exchange between sinusoids and hepatocytes in these cirrhotic rat livers. It is therefore tempting to hypothesize than use of matrix metalloproteinase or collagenase, while administered through the portal vein, may well retard cirrhosis development or even induce regression of established cirrhosis, as it has been shown in preliminary experimental studies 32, 33. These provocative findings should be first confirmed in additional animal studies before a potential application to human cirrhosis treatment, but they are further supported by the present data showing a preponderant role for the hepatic collagenization.…”

Section: Discussionsupporting

confidence: 72%

Effect of cold ischemia–warm reperfusion on the cirrhotic rat liver

Huet¹,

Giroux²,

Laurens³

et al. 2008

Liver Transpl

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Cirrhosis is known to induce capillarization of the sinusoidal endothelial cells (SECs) and collagenization of the space of Disse, resulting in a reduced access of plasma and plasma-dissolved substances to hepatocytes due to their limited diffusion in the extravascular space. The aim of the present study was to use a well known effect of cold ischemia-warm reperfusion (CI-WR) on liver SECs, that is, their retraction and detachment, progressing to a denudation of the SEC lining. The disappearance of the capillarized SEC lining would improve the access of plasma and plasma-dissolved substances to the hepatocytes and consequently might improve the metabolic function of cirrhotic livers. This study was performed using the isolated perfused rat liver model subjected to 24-hour CI followed by a 60-minute WR in thioacetamide-induced cirrhosis. Liver microcirculation was evaluated using the multiple indicator dilution curve (MIDC) technique. Hepatocyte, SEC, and Kupffer cell functions were evaluated using specific elimination processes. As occurs in normal livers, CI-WR induced extensive SEC necrosis with a marked reduction of the hyaluronic acid elimination. By contrast, the hepatic microcirculation was not modified: vascular, extravascular, and the cellular spaces were similar before and following CI-WR. In addition, the hepatic metabolic functions, as evaluated by propranolol and taurocholate hepatic uptake, were neither improved nor decreased, as were Kupffer cell functions. The present data strongly suggest that capillarization of SECs plays a lesser role than collagenization of the space of Disse in the reduced exchange between sinusoids and hepatocytes in thioacetamide-induced cirrhotic rat livers, which appear to be quite resistant to CI-WR. Liver Transpl 14:486-493, 2008. © 2008 AASLD. Received July 14, 2007; accepted October 11, 2007.Within the normal hepatic acinus, sinusoids have a unique structure to the liver that allows maximum contact between the hepatocytes and blood perfusing the liver. The endothelial cells lining the sinusoids, the sinusoidal endothelial cells (SECs), are perforated by a multitude of fenestrae 50 to 200 nm in diameter, but there is no continuous basement membrane.1 A large extravascular space (the space of Disse) lies behind the endothelial lining and is continuous with the extracellular space up to the tight junction of hepatocytes, which separate the extravascular space from bile canaliculi. Under normal conditions, a few collagen bundles can be found within the space of Disse. The entire space is therefore freely accessible to all large molecules contained in plasma, but red blood cells (RBC) larger than the fenestrae do not have access to the space of Disse. This arrangement is unique, since in no other organ do substances carried in the plasma have such direct access to the membrane where the uptake process occurs.In the presence of chronic liver diseases, 3 types of alterations of the liver microcirculation have been reported: (1) Capillarization of the sinusoids with disappear...

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Section: Discussionsupporting

confidence: 72%

Effect of cold ischemia–warm reperfusion on the cirrhotic rat liver

Huet¹,

Giroux²,

Laurens³

et al. 2008

Liver Transpl

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“…The continuing progress in biotechnological and medical research is uncovering an ever-growing number of possible applications for clostridial collagenases, in particular ColG and H (Antonioli et al 2007; Chu 1987; Jin et al 2005; Jordan 2008; Ku et al 1993; Kuriyama et al 2001; Segev et al 2005; Wang et al 2004). There are various commercial preparations available, but these usually contain several collagenase isoforms and even other proteases (e.g., clostripain).…”

Section: Discussionmentioning

confidence: 99%

A universal strategy for high-yield production of soluble and functional clostridial collagenases in E. coli

Ducka

Eckhard

Schönauer

et al. 2009

Appl Microbiol Biotechnol

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Clostridial collagenases are foe and friend: on the one hand, these enzymes enable host infiltration and colonization by pathogenic clostridia, and on the other hand, they are valuable biotechnological tools due to their capacity to degrade various types of collagen and gelatine. However, the demand for high-grade preparations exceeds supply due to their pathogenic origin and the intricate purification of homogeneous isoforms. We present the establishment of an Escherichia coli expression system for a variety of constructs of collagenase G (ColG) and H (ColH) from Clostridium histolyticum and collagenase T (ColT) from Clostridium tetani, mimicking the isoforms in vivo. Based on a setup of five different expression strains and two expression vectors, 12 different constructs were expressed, and a flexible purification platform was established, consisting of various orthogonal chromatography steps adaptable to the individual needs of the respective variant. This fast, cost-effective, and easy-to-establish platform enabled us to obtain at least 10 mg of highly pure mono-isoformic protein per liter of culture, ideally suited for numerous sophisticated downstream applications. This production and purification platform paves the way for systematic screenings of recombinant collagenases to enlighten the biochemical function and to identify key residues and motifs in collagenolysis.

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“…Hepatic fibrosis is successfully induced in rabbits by subcutaneous injection of CCl 4 [9]. To test the pharmacodynamic effects of mivacurium following the severity of liver dysfunction in an experimental model, we examined dose-response relationships and the duration of neuromuscular blockade and confirmed the relationship between recovery indices and plasma cholinesterase.…”

Section: Introductionmentioning

confidence: 99%

The pharmacodynamics of mivacurium in the rabbit with carbon tetrachloride-induced liver disease

Cheong

Kim

Lee

2007

European Journal of Anaesthesiology

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Background and objective: Neuromuscular blocking effects according to the severity of liver dysfunction have not been evaluated. We assessed the neuromuscular effects of mivacurium in carbon tetrachloride (CCl 4 )-treated rabbits with toxic hepatitis in vivo. Methods: We compared the dose-response relationships and the neuromuscular blocking effects of mivacurium in 66 rabbits randomly treated with 0.3 mL kg 21 of corn oil, 0.3 mL kg 21 of CCl 4 or 0.6 mL kg 21 of CCl 4 for 11 weeks, respectively. Train-of-four stimuli were applied every 10 s to the common peroneal nerve and the force of contraction of the tibialis anterior muscle was measured. Results: Severe hepatitis was associated with a rightward shift of the mivacurium dose-response curves, but mild hepatitis had no effect. The calculated ED 50 values for the control, mild and severe hepatitis were 17.1 6 2.6, 18.2 6 2.7 and 31.8 6 3.2 mg kg 21 , respectively. Rabbits with severe hepatitis had a significantly prolonged recovery time from neuromuscular blockade compared with other rabbits. Cholinesterase activity had a negative correlation with recovery indices of mivacurium even in severe hepatic injury. Severe hepatitis induced a prolongation of action duration of repeated doses, but maintained the constant intervals. Conclusions: The dose-response and the time course of neuromuscular blockade of mivacurium differ in mild hepatitis compared with severe hepatitis, but required no adjustments of different doses for repeated injection after the desired depth of neuromuscular block, and had a negative correlation with the activity of plasma cholinesterase in both hepatic injuries.

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Reversibility of experimental rabbit liver cirrhosis by portal collagenase administration

Cited by 19 publications

References 35 publications

Effect of cold ischemia–warm reperfusion on the cirrhotic rat liver

Effect of cold ischemia–warm reperfusion on the cirrhotic rat liver

A universal strategy for high-yield production of soluble and functional clostridial collagenases in E. coli

The pharmacodynamics of mivacurium in the rabbit with carbon tetrachloride-induced liver disease

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