Pentamidine blocks hepatotoxic injury in mice
| Autor: | Ghulam Ilyas, François Ravenelle, Jae Ho Choi, Kathryn E. Tanaka, Francesca Cingolani, Mark J. Czaja, Enpeng Zhao |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Lipopolysaccharides
Male 0301 basic medicine Alcoholic liver disease Pentamidine Isethionate Blotting Western Galactosamine Inflammation Pharmacology Real-Time Polymerase Chain Reaction Article Proinflammatory cytokine Mice Random Allocation 03 medical and health sciences 0302 clinical medicine Liver Function Tests In Situ Nick-End Labeling medicine Animals Pentamidine Liver injury Hepatology medicine.diagnostic_test business.industry Biopsy Needle Liver Failure Acute medicine.disease Immunohistochemistry Mice Inbred C57BL Survival Rate Disease Models Animal 030104 developmental biology Immunology Cytokines 030211 gastroenterology & hepatology Tumor necrosis factor alpha medicine.symptom Liver function tests business medicine.drug |
| Zdroj: | Hepatology. 66:922-935 |
| ISSN: | 1527-3350 0270-9139 |
| DOI: | 10.1002/hep.29244 |
| Popis: | Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the D-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality as compared to vehicle-injected controls. VLX103 decreased GalN/LPS induction of TNF but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7 which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 h after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells. Conclusion: VLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text