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Humphrey Hodgson

Publications and source records attributed to Humphrey Hodgson.

13 recordsLinked to original sources
PubMed2006

During thioacetamide-induced acute liver failure, the proliferative response of hepatocytes to thyroid hormone is maintained, indicating a potential therapeutic approach to toxin-induced liver disease.

In toxic liver injury, proliferation of preexisting hepatocytes helps restore liver mass and function. While loss of liver mass per se stimulates hepatocyte proliferation, exogenous mitogens have a potential role in enhancing liver regeneration. The aim of this study was to characterize the effects of the mitogen, tri-iodothyonine, on the regenerative capacity of hepatocytes during thioacetamide-induced liver failure. Rats received (two) thioacetamide injections and, 12 hr later, either tri-iodothyonine or vehicle-only control. Liver cell proliferation was assessed and comparison made with other control groups receiving tri-iodothyonine or vehicle only. In rats with thioacetamide-induced hepatitis the proportion of hepatocytes in S-phase was greater in the tri-iodothyonine group (27+/-3.5%) compared to the vehicle-only group (20+/-2.5%; P < 0.05), with, notably, a greater number of midzonal (BrdU) positive hepatocytes in the tri-iodothyonine group. We conclude that the ability of hepatocytes in the midzonal areas of rat liver to proliferate in response to tri-iodothyonine is maintained during severe acute toxic injury.

Animals↗
PubMed2005

Benign recurrent intrahepatic cholestasis with secondary renal impairment treated with extracorporeal albumin dialysis.

Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive condition characterized by intermittent episodes of pruritus and jaundice that may last days to months. Treatment is often ineffective and symptoms, particularly pruritus, can be severe. Extracorporeal albumin dialysis (molecular adsorbent recycling system, MARS) is a novel treatment which removes albumin bound toxins including bilirubin and bile salts. We describe a case of a 34-year-old man with BRIC and secondary renal impairment who, having failed standard medical therapy, was treated with MARS. The treatment immediately improved his symptoms, renal and liver function tests and appeared to terminate the episode of cholestasis. We conclude that MARS is a safe and effective treatment for BRIC with associated renal impairment.

Acute Kidney Injury↗
PubMed2005

Co-transplantation of encapsulated HepG2 and rat Sertoli cells improves outcome in a thioacetamide induced rat model of acute hepatic failure.

Hepatocyte transplantation offers therapeutic opportunities in liver disease. Xenogeneic hepatocytes are a potential resource, but rejection presents a major problem. We combined cell encapsulation with modulation by local generation of an immunosuppressant by co-encapsulating Sertoli cells with HepG2 cells. We assessed in vitro rat leukocyte proliferative responses and HepG2 cell survival after intraperitoneal injection in rats. Empty beads, and beads containing HepG2 cells or HepG2/Sertoli cells were injected intra-peritoneally into rats and survival of implanted cells followed over 4 weeks; in some animals acute hepatic failure (AHF) using thioacetamide (TAA) was also induced. The marked proliferative response of rat leukocytes to HepG2 cells and HepG2-containing beads was reduced by Sertoli cell-conditioned medium and HepG2/Sertoli encapsulates. After intra-peritoneal transplantation, Sertoli cells co-encapsulation protected the HepG2 cells in normal and AHF animals. Combined encapsulation and locally generated immuno-suppression may be a valuable strategy in hepatocyte transplantation.

Animals↗
PubMed2005

Increased expression of uncoupling protein 2 in HepG2 cells attenuates oxidative damage and apoptosis.

INTRODUCTION: Oxidative damage plays a major part in the pathogenesis of liver disease. Uncoupling proteins (UCPs) may be able to limit the generation of reactive oxygen species (ROS) and be cytoprotective. METHODS: We investigated the effect of up-regulation of UCP2 in a hepatoblastoma cell line exposed to menadione or hypoxia/re-oxygenation. RESULTS: Lipid and protein oxidation was increased in HepG2 cells exposed to ROS but this increase was significantly lower in cells over-expressing UCP2 under identical conditions. LDH release increased 2.5-fold in response to hypoxia/re-oxygenation in control HepG2 cells with no significant increase in UCP2 transfected cells. Hypoxia/re-oxygenation resulted in a reduction in liver-specific protein secretion that was attenuated in transfected cells and UCP2 over-expression also resulted in a 66% reduction in apoptosis compared with non-transfected controls. CONCLUSIONS: These data suggest that UCP2 can limit oxidative damage in HepG2 cells in response to oxidative stress resulting in improved cell function and resistance to apoptosis.

Antifibrinolytic Agents↗
PubMed2005

Exogenous thyroid hormone induces liver enlargement, whilst maintaining regenerative potential--a study relevant to donor preconditioning.

We have investigated thyroid hormone- (T3) induced liver cell hyperplasia in rats to explore the potential utility of primary mitogens within the clinical context of donor conditioning prior to living-related transplantation. A single injection of T3 induced a semi-synchronized proliferative response in hepatocytes, resulting at 10 days in a peak increase in liver mass, liver/body mass ratio, total DNA and total protein. Importantly, the hyperplastic liver induced by T3 exhibits a commensurate increase in metabolic capacity, as assessed by enhanced galactose elimination capacity. Furthermore, when the liver mass had been increased by an injection of T3 given 10 days previously and 70% partial hepatectomy performed, there was a larger remnant liver mass, liver/body mass ratio, total DNA and total protein content 24 h after surgery, compared with animals given a control injection. Interestingly, the regenerative response to surgery was the same in both groups, indicating that prior T3 conditioning did not impair the regenerative response of the liver. Using more stringent conditions to test hepatic functional reserve, following 90% hepatectomy, there was a greater (57%) survival in animals pre-treated with T3 compared to 14% in controls.

Animals↗
PubMed2004

Cellular therapies for liver replacement.

Insufficient donor organs for orthotopic liver transplantation worldwide have urgently increased the requirement for new therapies for acute and chronic liver disease. Whilst none are yet clinically proven there are at least two different approaches for which there is extensive experimental data, some human anecdotal evidence and some data emerging from Phase 1 clinical trials. Both approaches involve bio-engineering. In vivo tissue engineering involves isolated liver cell transplantation into the liver and/or other ectopic sites and in vitro tissue engineering, using an extracorporeal hepatic support system or bioartificial liver. Some questions are common to both these approaches, such as the best cell source and the therapeutic mass required, and are discussed. Others are specific to each approach. For cell transplantation in vivo the initial engraftment and repopulation will make a critical difference to the outcome, and development of markers for transplanted cells has enabled significant advances in understanding, and therefore manipulating, the process. Moreover, the role of immunosuppression is also important and novel approaches to natural immunosuppression are discussed. For use in a bioartificial liver, the ability for hepatocytes to perform ex vivo at in vivo levels is critical. Three dimensional culture improves cell performance over monolayer cultures. Alginate encapsulated cells offer a suitable 3-D environment for a bioartificial liver since they are both easily manipulatable and cryopreservable. The use of cells derived from stem cells or foetal rather than adult liver cells is also emerging as a potential human cell source which may overcome problems associated with xenogeneic cells.

Animals↗
PubMed2003

Triiodothyronine enhances the regenerative capacity of the liver following partial hepatectomy.

This study investigates the effects of administering a primary mitogen, triiodothyronine (T(3)), at the time of 70% partial hepatectomy (PH) in the rat, thus combining the 2 distinct pathways of liver growth: direct hyperplasia and compensatory regeneration. T(3) enhances the proliferative response of hepatocytes within the liver following PH. Flash bromodeoxyuridine (BrdU) labeling showed a cell proliferation index 24 hours after PH alone of 26.5% +/- 2.8%; when T(3) was administered at PH, it increased to 39.5% +/- 5.0% (P <.01 compared with PH alone). Continuous BrdU labeling performed every 6 hours between 15 and 72 hours following surgery showed an index of 84.0% +/- 4.0% when T(3) was administered at PH compared with 71.0% +/- 4.0% with PH alone (P <.01 compared with PH alone). This increase in cell proliferation resulted in a larger liver mass at 4 days in rats receiving T(3) at PH compared with PH alone (P <.05 compared with PH alone). The difference in liver mass was matched with corresponding increases in total DNA and total protein levels as well as cell division, as confirmed by the frequent demonstration of twin daughter cells on histology. In conclusion, this study shows that a single dose of T(3) enhances the regenerative capacity of the liver following PH. The ability to enhance cell proliferation during compensatory hyperplasia following PH could be therapeutically valuable if applicable to humans.

Alanine Transaminase↗
PubMed2002

The role of non-parenchymal cells in liver growth.

The main non-parenchymal cells of the liver, Kupffer cells, sinusoidal endothelial cells and stellate cells, participate in liver growth with respect to both their own proliferation, and effects on hepatocyte proliferation. In the well-characterised paradigm of 70% partial hepatectomy, they undergo DNA synthesis and cell division 20-24h later than the hepatocyte population. They exert both positive and negative influences on hepatocyte proliferation, including provision of an extracellular matrix-bound reservoir of hepatocyte growth factor that is activated after damage; priming of hepatocytes for DNA synthesis through rapid generation of TNF-alpha and IL-6; and generation of factors at later time points that curb hepatocyte DNA synthesis (IL-1, TGF-beta) and initiate reconstruction and reformation of matrix proteins.

Animals↗
PubMedDate not supplied

Liver cells: biology to therapeutics.

The liver has a remarkable capacity to regenerate after injury. Recent work has demonstrated that repair may call upon either the division of pre-existing mature cells, or the expansion of intrahepatic progenitor cells. Furthermore, progenitors may migrate into the liver from the bone marrow. Understanding and exploiting the cell biology of the liver provides the basis for innovational treatment, including the use of growth factors, transplantation of isolated cells, genetic manipulation of hepatocytes and liver cell progenitors, and the development of artificial liver support systems.

Cell Transplantation↗