Pentamidine blocks hepatotoxic injury in mice

Enpeng Zhao, Ghulam Ilyas, Francesca Cingolani, Jae Ho Choi, François Ravenelle, Kathryn E. Tanaka, Mark J. Czaja

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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 compared with vehicle-injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (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 hours 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. (Hepatology 2017;66:922–935).

Original languageEnglish (US)
Pages (from-to)922-935
Number of pages14
JournalHepatology
Volume66
Issue number3
DOIs
StatePublished - Sep 1 2017

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Pentamidine
Galactosamine
Wounds and Injuries
Liver
Lipopolysaccharides
Alanine Transaminase
Liver Diseases
Tumor Necrosis Factor-alpha
Initiator Caspases
Effector Caspases
Caspase 7
Caspase 8
JNK Mitogen-Activated Protein Kinases
Gastroenterology
Therapeutics
Aspartate Aminotransferases
Anti-Infective Agents
Serum
Innate Immunity
Caspase 3

ASJC Scopus subject areas

  • Hepatology

Cite this

Zhao, E., Ilyas, G., Cingolani, F., Choi, J. H., Ravenelle, F., Tanaka, K. E., & Czaja, M. J. (2017). Pentamidine blocks hepatotoxic injury in mice. Hepatology, 66(3), 922-935. https://doi.org/10.1002/hep.29244

Pentamidine blocks hepatotoxic injury in mice. / Zhao, Enpeng; Ilyas, Ghulam; Cingolani, Francesca; Choi, Jae Ho; Ravenelle, François; Tanaka, Kathryn E.; Czaja, Mark J.

In: Hepatology, Vol. 66, No. 3, 01.09.2017, p. 922-935.

Research output: Contribution to journalArticle

Zhao, E, Ilyas, G, Cingolani, F, Choi, JH, Ravenelle, F, Tanaka, KE & Czaja, MJ 2017, 'Pentamidine blocks hepatotoxic injury in mice', Hepatology, vol. 66, no. 3, pp. 922-935. https://doi.org/10.1002/hep.29244
Zhao E, Ilyas G, Cingolani F, Choi JH, Ravenelle F, Tanaka KE et al. Pentamidine blocks hepatotoxic injury in mice. Hepatology. 2017 Sep 1;66(3):922-935. https://doi.org/10.1002/hep.29244
Zhao, Enpeng ; Ilyas, Ghulam ; Cingolani, Francesca ; Choi, Jae Ho ; Ravenelle, François ; Tanaka, Kathryn E. ; Czaja, Mark J. / Pentamidine blocks hepatotoxic injury in mice. In: Hepatology. 2017 ; Vol. 66, No. 3. pp. 922-935.
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