Hepatic cell division and tissue repair: a key to survival after liver injury

doi:10.1016/1357-4310(96)88743-0

Molecular Medicine Today

Volume 2, Issue 2, February 1996, Pages 82-89

Molecular Medicine T...

https://doi.org/10.1016/1357-4310(96)88743-0 Get rights and content

Abstract

The survival of patients suffering from severe liver damage depends heavily on the ability of the remaining hepatocytes to regenerate and replace the dead or dying cells; death usually occurs when the regenerating ability of the liver is compromised owing to heavy damage to the liver. The current approach to therapy aims only to block additional liver injury from hepatotoxicants or hepatic disease. It hepatocellular regeneration and tissue repair could be stimulated after hepatic damage by a therapeutically compatible mechanism, then it might be possible to prevent death arising from serious liver injury.

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Cited by (39)

Cell Proliferation
2014, Encyclopedia of Toxicology: Third Edition
Cell proliferation – the increase in cell numbers resulting from cell division – is a complex, tightly controlled, well-defined process. The mechanisms of normal cell proliferation, as well as the pathologic consequences occurring when the system malfunctions, are critical to many areas of medicine, from embryogenesis, to tissue repair, to oncogenesis. This article describes the normal process of cell division, including the cells involved, the normal series of steps that take places, and the growth factors and cytokines that mediate the process. Particular emphasis is placed on the crucial role cell proliferation plays in tissue repair following toxic injury.
Role of tissue repair and death proteins in liver injury
2013, Drug-Induced Liver Disease
The extraordinary ability of the liver to regenerate after tissue loss from resection of liver tissue or due to injury has been known for a long time. Investigations during the last third of a century have revealed a similar dynamic regeneration response to toxic drugs and chemicals. Upon initiation of drug-induced injury, a cascade of signaling mechanisms is activated by cytokines and growth factors stimulate the surrounding cells to divide and replace the lost tissue, thereby restoring the structure and function of the liver. Drugs such as acetaminophen and toxicants such as carbon tetrachloride and thioacetamide stimulate cell division and tissue repair. The newly divided liver cells also impart resiliency to additional injury. At low-to-moderate doses, tissue repair restores the lost tissue. At higher doses, such as lethal doses, drug-induced liver injury continues to progress and expand, leading to liver failure and animal death. The mechanisms of injury expansion remained undefined until recently. Recent findings indicate that the liver cells affected by initiation of injury lose osmoregulation, and swelling cells develop blebs on the plasma membrane and rupture, spilling their cytoplasm in the calcium-rich extracellular space. The hydrolytic enzymes contained in the leakage are highly activated, and activated death proteins hydrolyze their respective substrates contained within the plasma membranes of surrounding cells, thereby establishing a self-perpetuating cycle of tissue destruction. When liver cells divide, they overexpress endogenous inhibitors of the death proteins, thus stopping the expansion of liver injury. Unabated expansion of liver injury can also be arrested by synthetic inhibitors of death proteins, thus enabling the survival of lethally drug overdosed or poisoned animals. These new findings raise the possibility of saving life by stopping the progressive expansion of liver injury, liver failure, and death.
Liver Regeneration and Tissue Repair
2010, Comprehensive Toxicology, Second Edition
The ability to overcome injury caused by physical or chemical agents encountered in the environment is a remarkable attribute of all living organisms. In an attempt to enhance survival from any noxious injury, organisms have developed several lines of defense mechanisms. By and large, such mechanisms may be categorized into two classes, each representing a tier. One is the biochemical mechanisms, which enable the organism to prevent injury after a noxious insult (e.g., antioxidant defense systems in the cell), and the second is a biological response intended to overcome injury (compensatory regeneration). While much attention has been focused on the endogenous biochemical defense mechanisms that participate in preventing the infliction of cellular and tissue injury, the biology of endogenous mechanisms, which might be recruited to overcome tissue injury after it occurs, has received little attention. This chapter is intended to highlight the latter mechanism.
Prior administration of a low dose of thioacetamide protects type 1 diabetic rats from subsequent administration of lethal dose of thioacetamide
2006, Toxicology
Previously, we reported that an ordinarily non-lethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic rats due to inhibited liver tissue repair, whereas 30 mg TA/kg allows 100% survival due to stimulated although delayed tissue repair. Objective of this investigation was to test whether prior administration of a low dose of TA (30 mg/kg) would lead to sustainable stimulation of liver tissue repair in type 1 diabetic rats sufficient to protect from a subsequently administered lethal dose of TA. Therefore, in the present study, the hypothesis that preplacement of tissue repair by a low dose of TA (30 mg TA/kg, ip) can reverse the hepatotoxicant sensitivity (autoprotection) in type 1 diabetic rats was tested.
Preliminary studies revealed that a single intraperitoneal (ip) administration of TA causes 90% mortality in diabetic rats with as low as 75 mg/kg. To establish an autoprotection model in diabetic condition, diabetic rats were treated with 30 mg TA/kg (priming dose). Administration of priming dose stimulated tissue repair that peaked at 72 h, at which time these rats were treated with a single ip dose of 75 mg TA/kg. Our results show that tissue repair stimulated by the priming dose enabled diabetic rats to overexpress, calpastatin, endogenous inhibitor of calpain, to inhibit calpain-mediated progression of liver injury induced by the subsequent administration of lethal dose, resulting in 100% survival. Further investigation revealed that protection observed in these rats is not due to decreased bioactivation. These studies underscore the importance of stimulation of tissue repair in the final outcome of liver injury (survival/death) after hepatotoxicant challenge. Furthermore, these results also suggest that it is possible to stimulate tissue repair in diabetics to overcome the enhanced sensitivity of hepatotoxicants.
Augmented hepatic injury followed by impaired regeneration in metallothionein-I/II knockout mice after treatment with thioacetamide
2006, Toxicology and Applied Pharmacology
A previous study (Oliver, J.R., Mara, T.W., Cherian, M.G. 2005. Impaired hepatic regeneration in metallothionein-I/II knockout mice after partial hepatectomy. Exp. Biol. Med. 230, 61–67) has shown an impairment of liver regeneration following partial hepatectomy (PH) in metallothionein (MT)-I and MT-II gene knockout (MT-null) mice, thus suggesting a requirement for MT in cellular growth. The present study was undertaken to investigate whether MT may play a similar role in hepatic injury and regeneration after acute treatment with thioacetamide (TAA). Hepatotoxicity of TAA is caused by the generation of oxidative stress. TAA was injected ip to both wild-type (WT) and MT-null mice. Mice were killed at 6, 12, 24, 48, 60, and 72 h after injection of TAA (125 mg/kg) or 48 h after injection of saline (vehicle control), and different parameters of hepatic injury were measured. The levels of hepatic lipid peroxidation were increased at 12 h in both types of mice; however, lipid peroxidation was significantly less in WT mice than MT-null mice at 48 h after injection of TAA. Analysis of hepatic glutathione (GSH) levels after TAA injection showed depletion of GSH at 12 h in WT mice and at 6 h in MT-null mice; however, significantly more GSH was depleted early (6–24 h) in MT-null mice than WT mice. An increase in hepatic iron (Fe) levels was observed in both types of mice after injection of TAA, but Fe levels were significantly higher in MT-null mice than WT mice at 6–60 h. The levels of hepatic copper (Cu) and zinc (Zn) were significantly higher in WT mice than MT-null mice at 6–60 h for Cu, and at 24 h and 60 h for Zn, respectively. Histopathological examination showed hemorrhagic necrosis in the liver of both types of mice at 12–72 h, with hepatic injury being more prominent in MT-null mice than WT mice. The hepatic MT levels were increased in WT mice after injection of TAA, and were highest at 24–72 h. Immunohistochemical staining for MT in WT mice indicated the presence of MT in both nucleus and cytoplasm of hepatocytes at 24–72 h after TAA injection. Cell proliferation, as assessed by immunohistochemical staining for proliferating cell nuclear antigen, was detected mainly in the livers of WT mice at 48–72 h after TAA treatment. Hepatic proliferation index in MT-null mice was very low as compared to WT mice during liver regeneration after injection of TAA. These results show that the liver cells of MT-null mice with no functional MT are unable to regenerate after TAA-induced hepatic injury, demonstrating an important role for MT in cellular regeneration.
Cell proliferation
2005, Encyclopedia of Toxicology

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ReviewHepatic cell division and tissue repair: a key to survival after liver injury

Abstract

Toxicol. Appl. Pharmacol

Hepatology

Toxicology

Toxicol. Appl. Pharmacol

Toxicology

J. Hepatol

Biochem. Biophys. Res. Commun

Gastroenterology

Postnatal mice have low susceptibility to paracetamol toxicity

Pediatr. Res

Acetaminoophen overdose in young children

Am. J. Dis. Child

Liver regeneration: an overview

J. Gastroenterol Hepatol

Biochemical mechanisms of biphasic dose-response relationships: role of hormesis

Cell proliferation and promotion of rat liver carcinogenesis: different effect of hepatic regeneration and mitogen induced hyperplasia on the development of enzyme-altered foci

Carcinogenesis

Amplified interactive toxicity of chemicals at nontoxic levels: mechanistic considerations and implications to public healt

Environ. Health Perspect

Hepatocellular regeneration- key to thioacetamide autoprotection

Pharmacol Toxicol

Tissue regeneration as a function of dose in thioacetamide hepatotoxicity

Environ. Health Perspect

Effect of aging on rat liver regeneration after hepatectomy

Biochem. Mol. Biol. Intern

Review
Hepatic cell division and tissue repair: a key to survival after liver injury