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PubMed1996

The effect of oxygen transport resistances on the viability and functions of isolated rat hepatocytes.

The treatment of fulminant hepatic failure with a bioartificial liver support device relies on the possibility of replacing the detoxification and synthetic functions of the injured liver for as long as needed for patient recovery. In spite of progress in cell culture techniques, the effective use of isolated hepatocytes in liver support devices is currently hampered by a lack of information on the metabolic factors limiting long term hepatocyte culture. In this paper, we report our investigation on the effects of oxygen transport resistances on the viability and functions of isolated rat hepatocytes cultured on collagen coated Petri dishes. Detoxification and synthetic functions of the hepatocytes were studied with respect to ammonia and phenolsulphonphthalein elimination and urea synthesis. Lower resistances to oxygen transport favored hepatocyte survival. The isolated hepatocytes synthesized urea at rates that decreased as the resistance to oxygen transport increased. The rate at which urea was synthesized also decreased during the culture. Neither PSP, nor ammonia elimination rate was greatly affected by increasing oxygen transport resistances and remained rather constant up to a week of culture.

Ammonia↗
PubMedDate not supplied

A hybrid bioartificial liver composed of multiplated hepatocyte monolayers.

Monolayer cultures of hepatocytes were shown to have good function when compared with suspended cells. The authors manufactured a new hybrid artificial liver containing hepatocyte monolayers and evaluated its function. Hepatocytes isolated from an adult dog liver were cultured on collagen coated borosilicated glass (10 X 20 X 0.04 cm). A long-stroke artificial liver module was constructed by stacking 200 glass plates bearing hepatocytes, which were viable and functioned well during 4 weeks in perfusion culture; glyconeogenesis = 110 ng/micrograms DNA/min, urea synthesis = 3.6 ng/micrograms DNA/min and albumin synthesis = 29 micrograms/10(6) cells/day at the 5th day of perfusion. The levels were maintained for 2 weeks. The new device was applied to anhepatic dogs (Group 3) and compared with untreated (Group 1) and plasma exchange dogs (Group 2). The survival times were 21.3 +/- 5.6 hours in Group 1 (N = 6), 27.8 +/- 4.0 hours in Group 2 (N = 3), and 55.0 +/- 10.3 hours in Group 3 (N = 4). The longest survival was 65 hours. Serum ammonia increased to over 2,000 micrograms/dl after 12 hours in Groups 1 and 2, but remained under 400 micrograms/dl in Group 3. This new type of hybrid system may be a pilot design for the complete artificial liver.

Animals↗
PubMed1995

A method for obtaining monodispersed cells from isolated porcine islets of Langerhans.

Micro or macroencapsulation of islets of Langerhans have been proposed as a bioartificial pancreas. Encapsulation of dispersed single cells instead of porcine islets should improve the oxygenation of encapsulated tissue. The aim of this work was, therefore, to develop techniques for dissociating porcine islets and test cell viability and function. After islet isolation and purification, islets were dispersed into single cells with collagenase and DNAse in either an extracellular type ionic solution or a UW solution. After culture, islets or cells were perfused with Krebs buffer. Two consecutive stimulations from 2.8 mM to 20 mM glucose were performed. Viability of cells (trypan blue) was higher than 85% after dispersion in ES or UW solutions. Islets or dispersed cells responded similarly to both stimulations with a return to basal rate between stimulations. No difference was found between cell function cultured during 18 hours or 6 days. However, islet function was improved by a long period of culture. In conclusion, this study demonstrates that dissociated cells performed as well as native islets up to six days culture.

Analysis of Variance↗
PubMed1993

Use of a novel bioartificial liver in a patient with acute liver insufficiency.

We have developed a bioartificial liver support system (BAL) using porcine hepatocytes attached to microcarriers and placed on the outer surface of hollow fibers. The BAL system was attached to a plasmapheresis device that was then used to treat the plasma of a patient with acute liver failure. Our aim was to test the efficacy and safety of this system after a single short treatment period. A patient with alcohol-induced, severe, acute liver failure manifested by coagulopathy, rising plasma ammonia level, and deteriorating mental status was studied. The procedure was well tolerated by the patient, who remained hemodynamically stable throughout the treatment period. A marked increase in coagulation factor V, VII, VIII, and IX activities, a decrease in serum ammonia level (120 to 32 mumol/L), a twofold increase in all serum amino acids except for aminobutyric acid, and an improvement in mental status were noted after a 6-hour treatment period. This preliminary report of the first use of this novel BAL system in conjunction with plasmapheresis appears promising. A clinical study is now in progress to prove its efficacy.

Adult↗
PubMed2000

Functional tissue engineering: the role of biomechanics.

"Tissue engineering" uses implanted cells, scaffolds, DNA, protein, and/or protein fragments to replace or repair injured or diseased tissues and organs. Despite its early success, tissue engineers have faced challenges in repairing or replacing tissues that serve a predominantly biomechanical function. An evolving discipline called "functional tissue engineering" (FTE) seeks to address these challenges. In this paper, the authors present principles of functional tissue engineering that should be addressed when engineering repairs and replacements for load-bearing structures. First, in vivo stress/strain histories need to be measured for a variety of activities. These in vivo data provide mechanical thresholds that tissue repairs/replacements will likely encounter after surgery. Second, the mechanical properties of the native tissues must be established for subfailure and failure conditions. These "baseline data" provide parameters within the expected thresholds for different in vivo activities and beyond these levels if safety factors are to be incorporated. Third, a subset of these mechanical properties must be selected and prioritized. This subset is important, given that the mechanical properties of the designs are not expected to completely duplicate the properties of the native tissues. Fourth, standards must be set when evaluating the repairs/replacements after surgery so as to determine, "how good is good enough?" Some aspects of the repair outcome may be inferior, but other mechanical characteristics of the repairs and replacements might be suitable. New and improved methods must also be developed for assessing the function of engineered tissues. Fifth, the effects of physical factors on cellular activity must be determined in engineered tissues. Knowing these signals may shorten the iterations required to replace a tissue successfully and direct cellular activity and phenotype toward a desired end goal. Finally, to effect a better repair outcome, cell-matrix implants may benefit from being mechanically stimulated using in vitro "bioreactors" prior to implantation. Increasing evidence suggests that mechanical stress, as well as other physical factors, may significantly increase the biosynthetic activity of cells in bioartificial matrices. Incorporating each of these principles of functional tissue engineering should result in safer and more efficacious repairs and replacements for the surgeon and patient.

Biocompatible Materials↗
PubMed1995

Plasma separation for artificial liver support.

A bioartificial liver (BAL) support system, using plasma separation, has been developed to support acute liver failure patients. This study examined 14 consecutive BAL treatments in nine patients with severe acute liver failure. We report methods to achieve and manage plasma separation for an extended period of time. The mean duration of a BAL treatment was 435 minutes, with 26-59 liters of blood processed. Ionized hypocalcemia resulting in muscle twitching was a side effect of the therapy. Ionized calcium levels decreased significantly (P < .02) after BAL treatment; however, total calcium levels increased (P < .05). No significant changes were noted in heart rate, electrocardiogram [Q-T (Q-Tc) interval], blood pressure, prothrombin time, partial thromboplastin time, hematocrit, platelet count and serum phosphorous, magnesium, glucose, and pH. Plasma fibrinogen levels decreased significantly (P < .002). Ionized hypocalcemia due to the chelating effect of sodium citrate was controlled by calcium chloride administration, adjustment of blood separation rates, and reduction of the blood-to-citrate ratio. This report demonstrates that intensive, large-volume plasma separation for long periods of time can be achieved safely in critically ill patients without serious adverse effects.

Adolescent↗
PubMed2004

Expansion of chondrocytes in a three-dimensional matrix for tracheal tissue engineering.

BACKGROUND: The generation of autologous tracheal implants by tissue-engineering techniques is a promising concept for otherwise untreatable patients. A functional cartilaginous backbone represents a prerequisite for any bioartificial tracheal graft. The aim of this study was to define suitable cell types and culture conditions for the generation of tracheal cartilage. METHODS: We obtained tracheal, costal, and auricular cartilage from porcine donor animals (n = 10). The chondrocytes were cultured two-dimensionally in cell flasks or mixed with a liquid collagen solution forming a three-dimensional culture system. Labeling with carboxy fluorescein diacetate succinimidyl ester (CFDA SE) and biochemical reduction of formazan served to determine cell viability and proliferation. The extracellular matrix produced by the chondrocytes was characterized by Western blot. RESULTS: The CFDA SE labeling proved viability and the MTT assays documented a proliferation of the chondrocytes over time in vitro. While the chondrocytes in the three-dimensional cell culture system produced hyaline cartilage composed of collagen II, the two-dimensional culture conditions resulted in nonspecific collagen synthesis. CONCLUSIONS: Chondrocytes grown in a three-dimensional matrix can effectively proliferate and produce cartilage and are viable for more than 2 weeks. Costal chondrocytes are suitable for tracheal cartilage tissue engineering.

Animals↗
PubMed2006

[Observation on hybrid bioartificial liver support systems in treating chronic severe hepatitis: a study of 60 cases].

OBJECTIVE: To study the clinical efficacy of three kinds of hybrid bioartificial liver support systems (HBLSS) in treating chronic severe hepatitis. METHODS: A bioartificial liver support system (BAL), comprising porcine hepatocytes and fiber tube style bioreactor, was constructed. Then three kinds of HBLSS were constructed: Molecular absorbent recirculating system (MARS) plus BAL; slow plasma exchange (SPE) plus continuous hemodiafiltration (CHDF) and BAL; and SPE plus hemoperfusion (HP) and BAL. One hundred-twenty patients in middle or late stages of chronic severe hepatitis were enrolled in this study. They were randomly divided into 6 groups: H1 group was treated with BAL+MARS, H2 with BAL+SPE+CHDF and H3 with BAL+SPE+HP (as treatment groups); C1 group was treated with MARS, C2 with SPE+CHDF and C3 with SPE+HP (as control groups). The changes in the clinical symptoms, in the hepatic encephalopathy stages, and in the serum total bilirubin (TBIL), the serum albumin (ALB), the prothrombin activities (PTA), endotoxin, ammonia, creatinine and a-fetal protein (AFP) were all observed before the treatment, right after it and 72 hours later. The improving and curing rates and the rates of side effect occurrences in each group were observed. RESULTS: In all 6 groups, the patients' clinical symptoms ameliorated; their TBIL, endotoxin and ammonia levels decreased (P<0.05), and their PTA and AFP levels lowered significantly (P<0.05). But in the H1, H2 and H3 groups they were more distinctive than in the control groups. In H1 and H2 groups creatinine and ammonia levels were decreased more significantly than in the H3 group (P<0.05). The improving and curing rates of each group were 65 % (13/20), 60% (12/20), 45% (9/20), 45% (9/20), 40% (8/20) and 20% (4/20) respectively. No serious side effects were observed during the treatment. CONCLUSION: In treating middle and late stage chronic severe hepatitis, the measures used in H1, H2 and H3 are better than those in C1, C2 and C3. Furthermore, H1 and H2 treatments can ameliorate hepatic and renal functions, prevent the development of multiple organ dysfunction syndrome, and are better than those used in H3.

Adult↗
PubMed1995

Effects of hepatocyte growth factor on viability and biotransformation functions of hepatocytes in gel entrapped and monolayer culture.

OBJECTIVES: An extracorporeal bioartificial liver device must maintain viability and differentiated function of hepatocytes cultivated at high cell density. Growth factors, such as hepatocyte growth factor, found in high concentrations in the plasma of patients with fulminant hepatic failure, have the potential to promote hepatocyte dedifferentiation and thus, decrease function. We tested the hypothesis that hepatocyte growth factor would improve viable cell density and decrease biotransformation functions of liver cells in monolayer culture and in hepatocytes entrapped in collagen cylindrical gel "noodles" as found in the extracorporeal bioartificial liver. DESIGN: In vitro, controlled study. SETTING: University research laboratory. SUBJECTS: Adult Sprague Dawley Rats. INTERVENTIONS: Hepatocytes were harvested by a two-step collagenase technique. Harvested hepatocytes were plated onto type 1 collagen coated plates or entrapped in type 1 collagen cylindrical gels and cultured in different concentrations of hepatocyte growth factor. Interval measurements of 3H-thymidine incorporation, albumin synthesis, biotransformation functions, and viability were made. MEASUREMENTS AND MAIN RESULTS: In monolayer culture, the addition of hepatocyte growth factor caused a dramatic increase in 3H-thymidine incorporation. This increase was accompanied by a decrease in the appearance of the lidocaine metabolite, monoethyglycinexylidide. Albumin production was unchanged. In cylindrical gel entrapment cultures, hepatocyte growth factor caused a significant increase in 2-day viability but had no effect on the metabolite appearance of lidocaine or 4-methyl umbelliferone or albumin production. CONCLUSIONS: Hepatocyte growth factor induces dedifferentiation of hepatocytes in monolayer culture. Collagen matrix entrapment appears to abrogate this effect and improve liver cell viability. There may be reciprocal regulation of hepatocyte reproductive and differentiated functions, such as biotransformation, which can be influenced by the entrapment of hepatocytes in an extracellular type 1 collagen matrix.

Animals↗
PubMedDate not supplied

Immunoprotection of xenocytes in a hollow fiber bioartificial liver.

A new, hollow fiber bioartificial liver (BAL) was tested in an anhepatic rabbit model to assess the hollow fiber membrane as an immunologic barrier. The extracorporeal BAL contained rat hepatocytes (xenocytes) entrapped in collagen gel inside the lumen of hollow fibers with 100 kd nominal molecular weight cut-off. Blood from the anhepatic rabbit flowed in the extracapillary compartment. After 4 h of BAL hemoperfusion, the hepatocyte gels were tested for evidence of rabbit immunoglobulin and complement. Samples of the gels were stained with fluorescein isothiocyanate (FITC)-labeled antibodies directed against rabbit IgM, rabbit IgG (Fc and F[ab]2), and rabbit complement (C3) and studied by immunofluorescence microscopy. Enzyme-linked immunosorbent assay and Western blotting were used, respectively, to quantify and identify proteins inside the BAL and in the rabbit blood. These studies suggest that very little rabbit IgG (primarily fragments of IgG) and no IgM or C3 crossed the hollow fibers during hemoperfusion. Rat albumin steadily accumulated in the rabbit blood during hemoperfusion, which indicated membrane permeability to molecules of that size and stable hepatocyte function by the BAL. The authors conclude that hollow fibers with 100 kd nominal molecular weight cut-off provide immunoprotection for xenocytes in an extracorporeal BAL.

Animals↗
PubMed1994

Comparative studies of in vitro and in vivo function of three different shaped bioartificial pancreases made of agarose hydrogel.

Various kinds of bioartificial pancreas (BAP) have been developed in the past. There have been many disputes about the advantages and disadvantages of each BAP. However, little attention has been paid to the shape of the devices. In this study, three different shaped BAPs were made of the same material, agarose hydrogel. These are microbead-, rod- and disc-shaped BAPs, which are comparable to microcapsules, hollow fibre diffusion chambers and disc-shaped diffusion chambers, respectively, in shape. Their performances were studied by in vitro culture, mathematical simulations and in vivo implantation into diabetic animals. The islets in the BAPs could survive and release insulin for more than 100 d regardless of the BAP shape during in vitro culture. Numerical analyses showed that insulin release kinetics depended greatly on the thickness of the gel membrane but not on the shape of the agarose hydrogel. The microbead BAP normalized blood glucose levels of all five recipients for more than 100 d. Three of eight recipients of the rod BAP and only one of six recipients of the disc BAP demonstrated long normoglycaemia. These results suggest that the shape of the BAPs determines the in vivo functioning period of the BAPs and that the microbead is the most suitable shape for the BAP.

Animals↗
PubMed1993

Development of a hybrid bioartificial liver.

OBJECTIVE: The authors developed an extracorporeal liver support system and tested its efficacy in experimental animals with liver failure. The first clinical use of this system to treat a patient with liver failure is reported. SUMMARY BACKGROUND DATA: Multiple attempts have been made, ranging from plasma exchange to use of charcoal columns, to develop liver support systems for treating patients with acute severe liver failure. None of these systems has achieved wide clinical use. There is a need for providing liver support as a "bridge" to transplantation and for treating patients with potentially reversible liver dysfunction. METHODS: A hybrid liver support system has been developed consisting of plasma perfusion through a charcoal column and a porous hollow fiber module inoculated with 5 x 10(9) matrix-attached hepatocytes. The system was tested in dogs with ischemic liver failure (n = 7) who underwent plasmapheresis; a control group (n = 6) underwent charcoal perfusion alone. A patient with liver failure was treated with this hybrid system. RESULTS: After 6 hours of hybrid liver support treatment, animals had significantly decreased serum ammonia and lactate levels, increased glucose level, normal prothrombin time, and increased systolic blood pressure compared with controls treated with charcoal perfusion alone. Use of the system to treat a patient was well tolerated with evidence of clinical improvement. CONCLUSIONS: Plasma perfusion through a system consisting of a charcoal column and matrix-attached porcine hepatocytes had significant beneficial effects in animals with liver failure and was well tolerated by a patient with liver failure.

Animals↗
PubMed1995

Gel-entrapment bioartificial liver therapy in galactosamine hepatitis.

A need exists for an effective, safe bioartificial liver to support patients in fulminant hepatic failure (FHF). The purpose of this study was to determine the treatment efficacy of the novel gel-entrapment porcine hepatocyte bioartificial liver (BAL) in a fatal model of canine hepatic failure. FHF was produced in 27- to 30-kg halothane-anesthetized dogs by bolus infusion of the hepatotoxin D-galactosamine (D-Gal). Three groups were studied during the 48-hr experiment: Group D-Gal (n = 5) received galactosamine, 1.0 g/kg, iv at Time O, Group HepBAL (n = 5) received D-Gal followed by continuous hemoperfusion with the BAL device loaded with approximately 6 billion viable pig hepatocytes starting at Time 24 hr, and three dogs served as healthy controls (Group Control) and received no galactosamine. The primary endpoints were survival and coma development. Group D-Gal demonstrated 100% mortality from liver failure by 42 hr, characterized by a progressive rise in liver enzymes, total bilirubin, ammonia, and lactate and associated with coagulopathy, hypoglycemia, coma, and brain death. BAL therapy significantly delayed the onset of coma and improved survival (median 47 hr vs D-Gal median 36 hr). A significant delay in the rise of lactate and ammonia was also noted. BAL therapy prolonged survival and improved both laboratory and clinical markers of fatal liver failure. These data indicate that this BAL may have clinical utility in supporting human liver failure.

Animals↗
PubMed1999

Subzero osmotic characteristics of intact and disaggregated hepatocyte spheroids.

This study has been conducted to examine basic transport characteristics of pig hepatocytes cultured as spheroids for use in a bioartificial liver. Static osmotic experiments were conducted by subjecting hepatocyte spheroids in solutions of increasing sucrose concentrations. A Boyle-van't Hoff plot was used to extrapolate an osmotically inactive volume, V(b), of 0.60, which is unusually high and might not represent the inactive volume of the individual cells. The spheroids were disaggregated and low-temperature cryomicroscopy experiments performed to examine the transport and intracellular ice formation (IIF) characteristics. A hydraulic permeability, L(pg), of 7.6 x 10(15) m(3)/Ns and an activation energy, E(lp), of 82 kJ/mol was determined for the individual cells. The kinetic (Omega(o)) and thermodynamic (kappa(o)) coefficients for IIF were determined to be 5.9 x 10(8) m(-2) s(-1) and 3.0 x 10(9) K(5), respectively. These results infer a decrease in the temperature range over which IIF is observed compared to freshly isolated pig hepatocytes. The technique of freeze substitution was used to examine the structure inside the spheroid during freezing. At a low cooling rate of 1 degrees C/min, increasing amounts of intercellular ice formed between the cells. At a higher cooling rate of 100 degrees C/min small intracellular ice crystals formed. This study shows the location of ice in a freezing hepatocyte spheroid and confirms that the cells cultured as spheroids do not transport water in the same manner as isolated cells.

Animals↗
PubMedDate not supplied

Analysis of multivariables during porcine liver digestion to improve hepatocyte yield and viability for use in bioartificial liver support systems.

In order to achieve optimal BALSS function, preparation of porcine hepatocytes with high yield, viability, and P450 activity is known to be important. To date hepatocyte yields have varied from 0.58 x 10(10) to 3.45 x 10(10) and viabilities from 75% to 95% within and between laboratories, even when using the same digestion methods and procedures, indicating that hepatocyte isolation during porcine liver digestion is not fully optimized. The aim of this work was to identify the critical parameters affecting cell recovery during porcine liver harvesting by investigating 21 variables involved in the process, including pig body and liver weight, different digestion times of perfusates, pH, a range of concentrations of sodium and chloride in EDTA, and collagenase perfusates. Univariate and multivariate analysis of a retrospective study (n = 23) revealed that low perfusate pH during the process of digestion had a positive effect on hepatocyte yield (p < 0.05), while high (relative) concentrations of sodium and chloride in the perfusates had significant negative effects on hepatocyte viability (both p < 0.05). Sodium and chloride had narrow optimal ranges for achieving a >90% viability. These findings were then tested in a prospective study (n = 10) and further verified. High hepatocyte viabilities (91.8+/-1.6% p = 0.036) and yields (2.56+/-0.48 x 10(10)) were achieved consistently, and P450IA1 activity was increased after sodium and chloride concentrations and pH in the perfusates were controlled. The physiological mechanism by which sodium and chloride affects hepatocyte viability during porcine liver digestion is discussed.

Animals↗
PubMed2002

UW solution: a promising tool for cryopreservation of primarily isolated rat hepatocytes.

Cryopreserved hepatocytes are a ready source of metabolic and synthetic functions for hepatocyte transplantation and bioartificial livers. In this study, we evaluated a cytoprotective effect of University of Wisconsin (UW) solution during cryopreservation of rat hepatocytes. We also investigated the feasibility of lentivirus-based gene transfer into thawed hepatocytes after cryopreservation. Primary rat hepatocytes were isolated using a two-step collagenase perfusion technique, and the resulting hepatocytes with more than 85% viability assessed by a trypan blue exclusion test were subjected to the present study. These cells were subjected to the present study. Cells were cryopreserved with UW solution containing 10% fetal bovine serum (FBS) with 12% dimethylsulfoxide (DMSO) (group 1, G1), Cellbanker solution (group 2, G2), and 10% FBS-containing Dulbecco modified Eagle medium (DMEM) with 12% DMSO (group 3, G3). After thawing the cryopreserved hepatocytes, cell viability, plating efficiency, morphological appearance, and ammonia clearance activity were determined for each group. The efficacy of lentivirus-mediated Escherichia coli LacZ gene delivery was evaluated. Hepatocyte viabilities after 3- and 7-day cryopreservation were 73.2% and 62.5% for G1, 57.5% and 46.5% for G2, and 57.3% and 41.5% for G3, respectively. Plating efficiency and ammonia clearance activity were improved in G1 hepatocytes compared to G2 and G3 cells. Lentiviral transfer of a LacZ gene was confirmed in the thawed hepatocytes after cryopreservation by an X-gal stain assay.

Adenosine↗
PubMed1996

Function of culturing monolayer hepatocytes by collagen gel coating and coculture with nonparenchymal cells.

Since 1987, we have been developing a bioartificial liver (BAL) using multiplated cultured hepatocyte monolayers. With the goal of promoting hepatic functions of cultured hepatocyte monolayers, we combined the use of a collagen gel layer over the monolayers of hepatocytes and/or cocultured hepatocytes with nonparenchymal cells (NPCs). The study was divided into four groups according to culture configurations: Group 1: hepatocyte monolayer culture (control); Group 2; coculture of hepatocytes and NPCs; Group 3: hepatocyte monolayer with a overlaid collagen gel layer; and Group 4: coculture with a overlaid collagen gel layer. The culture continued for 14 days. Morphological changes and hepatic functions were evaluated by urea and albumin syntheses. The morphological status of the hepatocytes remained for 2 weeks in Groups 3 and 4. Deterioration and detachment of hepatocytes and/or NPCs started in Group 1 and 2 on the third day in culture. Significantly high urea synthesis was noted in Group 4 (p < 0.001 compared with Group 1 and 2: p = 0.0014 compared with Group 3). Although there was no significant difference in albumin synthesis among the four groups, those hepatocytes covered by the collagen gel (Groups 3 and 4) tended to secrete albumin throughout the observation period. These results indicted that the environment, although artificial (but close to the in vivo state), supplied with collagen gel and the coculture, enhanced the activities of the cultured hepatocyte monolayers. We suggest that use of cocultured hepatocytes under a collagen gel is a promising candidate for a bioreactor of multiplated BAL.

Albumins↗
PubMed2004

Influence of serum from rats with fulminant hepatic failure on hepatocytes in a bioartificial liver system.

Fulminant hepatic failure (FHF) is a life-threatening condition marked by many excessively increased unmetabolized toxins and growth factors. Recently developed bioartificial liver (BAL) systems containing hepatocytes can be used to treat patients with FHF However, the behavior of these hepatocytes on exposure to FHF serum in vitro remains unclear. In the present study, we used FHF rat models and the sera from these rats (i.e., FHF serum) contained elevated inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), HGF, and TGF-beta1. In addition, 1x10(8) hepatocytes were harvested from the livers of inbred rats and incubated with microcarrier beads. Four hours later, the hepatocyte-coated beads were inoculated into a hollow-fiber module (=BAL system). FHF serum or normal control serum circulated for 6 hours through the BAL system. Expressions of mRNA for albumin, GST A1, CYP 1A2, OTC and c-fos were investigated by RT-PCR, and PCNA staining was performed before and after perfusion. The expressions of albumin, GST A1, and CYP 1A2 mRNAs were markedly decreased, whereas those of OTC and c-fos were modestly decreased. PCNA positive cells were low and showed no difference between FHF and normal serum-exposed hepatocytes. In conclusion, the exposure of hepatocytes to hypercytokinemia, including inflammatory cytokines and positive and negative growth factors, caused a loss in liver specific functions. This environment also failed to facilitate hepatocyte regeneration.

Animals↗