Immune Mechanisms in Drug-Induced Liver Injury

Jaeschke, Hartmut; Naisbitt, Dean J.

doi:10.1007/978-1-4939-7677-5_25

Cited by 6 publications

(10 citation statements)

References 113 publications

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“…While their specific roles have not been investigated as fully as in other disease, all of these inflammatory populations have been implicated in DILI [2,6,7,31]. Many of these cells also have critical roles in immunity, and thus their overall contributions are not well understood.…”

Section: Mechanisms Of Liver Inflammationmentioning

confidence: 99%

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Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity

Woolbright

Jaeschke

2018

Curr Pharmacol Rep

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Purpose of Review This article provides a brief overview of mechanisms of inflammatory liver injury and how this applies to drug hepatotoxicity with a particular emphasis on the role of inflammation in acetaminophen-induced liver injury. Recent Findings Significant progress has been made in the last decade in our understanding of the initiation of sterile inflammation after necrotic cell death by the release of damage-associated molecular patterns and their recognition by toll-like receptors and others on macrophages. These events trigger the formation of cytokines and chemokines directly or with assistance of inflammasome activation thereby activating and recruiting leukocytes including neutrophils and monocyte-derived macrophages into the necrotic areas. Although this sterile inflammatory response is mainly geared towards the removal of necrotic cell debris and preparation of regeneration, there are conditions where these innate immune cells can aggravate the initial injury. The mechanisms and controversial findings of the innate immunity are being discussed in detail. In contrast, drug metabolism and formation of a reactive metabolite that binds to proteins in the absence of extensive cell death, can induce an adaptive immune response, which eventually also results in severe liver injury. However, the initiating event appears to be the formation of protein adducts, which act as haptens to activate an adaptive immune response. Overall, these mechanisms are less well understood. Summary The past decade has revolutionized our understanding of the mechanisms that control the interplay between cell death and innate or adaptive immune responses. This report provides an update on these mechanisms.

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Section: Mechanisms Of Liver Inflammationmentioning

confidence: 99%

“…Idiosyncratic DILI, which generally is not dose-dependent, delayed in onset and affects only very few individuals exposed to therapeutic doses. Although the innate immune system can be involved in the initiation of the response, it is generally established that the injury is caused by the adaptive immune system [6,7]. …”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity

Woolbright

Jaeschke

2018

Curr Pharmacol Rep

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“…Liver is a key organ and site where the metabolism of carbohydrates, lipids and proteins take place [17]. Activities of ROS also affect the liver and therefore the need to assess liver function.…”

Section: Introductionmentioning

confidence: 99%

“…Unconjugated bilirubin is estimated by substracting conjugated bilirubin from total bilirubin [18]. The aminotransferases are enzymes that catalyze reversible transfer of the amino group from an amino acid to a ketoacid in which Pyridoxal-5'-phosphate (PLP) serves as a cofactor [17,18]. Estimation of ALT and AST are sensitive and relatively specific test for hepatocyte damage.…”

Section: Introductionmentioning

confidence: 99%

“…Estimation of ALT and AST are sensitive and relatively specific test for hepatocyte damage. Their activities in serum rises even in a small damage of the liver cell, caused by increased permeability of the cell membrane [17,18]. Alkaline phosphatase (ALP) is a family of zinc metaloenzymes, with a serine at the active center; they release inorganic phosphate from various organic orthophosphates.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Antioxidants Supplementation on Renal, Hepatic and Cardiac Function Markers in Alloxan Induced Diabetes Mellitus Wister Rats

Ben-Chioma

Sheudeen

Dornu

et al. 2020

JOCAMR

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Aim: To evaluate antioxidants supplementation (selenium and vitamin E) on renal, hepatic and cardiac function markers in alloxan induced diabetes mellitus in Wister rats. Study Design: Rats were randomly assigned into 5 groups with each group consisting of 5 rats. The treatment pattern involved the induction of hyperglycaemia in the rats followed by oral administration of selenium and vitamin E supplements singularly and in combination. The groups are as follow: Group A: Alloxan induced diabetic Rats treated with selenium (0.02 mg/kg) for 35 days. Group B: Alloxan induced diabetic Rats treated with Vitamin E (70.0 mg/kg) for 35 days. Group C: Alloxan induced diabetic Ratstreated with both Selenium and Vitamin E (0.02 mg/kg + 70.0 mg/kg) for a period of 35 days. Group D: Alloxan induced diabetic Rats without any treatment (Positive control) for 35 days. Group E: Rats in this group were fed normally for 35 days without induction and treatment (Negative control). Place and Duration of the Study Area: The study was carried out in the Department of Medical Laboratory Science, Rivers State University, Port Harcourt, Nigeria over a period of 9 months (January, 2019 – September, 2019). Methodology: After the inducement of hyperglycaemia in the rats (Group A – D) with a single dose intraperitoneal (IP) injection of 140mg/kg body weight of alloxan hydrate, treatment with the antioxidants (selenium and Vitamin E) was performed for 35 days. At the end of 35 days, the animals were allowed to fast for 18 hours and sacrificed. Plasma specimen collected was used for the assay of Na+, K+, HCO3, urea, creatinine, cardiac troponin I, LDH, AST, ALT, ALP, bilirubin, protein, albumin globulin and MDA while renal, hepatic and cardiac tissues collected were used for histological investigations. Results: Significantly lower values were seen in Na+, K+, HCO3 and conjugated bilirubin in the diabetic rats without antioxidants supplementation (group D) when compared to diabetic rats with antioxidants supplementation of selenium and vitamin E (group A, B & C) and non-diabetic control group (group E). There were no significant differences seen when Group A, B, C and E were compared among one another. Also, significantly higher values were seen in AST, ALT, ALP, Unconjugated bilirubin, urea, creatinine, cardiac troponin I and MDA in the diabetic rats without antioxidants supplementation (group D) when compared with diabetic rats treated with antioxidants supplements of selenium and vitamin E (group A, B & C) and non-diabetic control group (group E). However, no significant differences were seen in LDH, total protein, albumin, globulin and total bilirubin at P=.05. Histological findings in the kidneys, liver and cardiac tissues of the rats treated with antioxidants supplement showed recovery tendencies compared to diabetic rats without antioxidant supplementation. Conclusion: Results obtained suggest that the use of selenium or vitamin E singularly or in combination has ameliorative effect on cardiac, renal and hepatic function markers in alloxan-induced diabetic rats. However, the combination of selenium and vitamin E had no synergistic advantage over the use of selenium or vitamin E alone.

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