Pentamidine blocks hepatotoxic injury in mice

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 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.

Spermine Alleviates Acute Liver Injury by Inhibiting Liver-Resident Macrophage Pro-Inflammatory Response Through ATG5-Dependent Autophagy

“…Liver sterile inflammation caused by the innate immune response of liver-resident macrophages (Kupffer cells, KCs) plays a major role in the pathogenesis of toxin-induced liver injury ( 4 ). KCs are resident and non-migratory phagocytes serving as sentinels for liver homeostasis ( 5 ).…”

Complement-5 Inhibition Deters Progression of Fulminant Hepatitis to Acute Liver Failure in Murine Models

“…Because C5-KO and anti-C5-Ab suppressed apoptosis by 80% and 70%, respectively, we comprehensively assessed the upstream signaling pathways leading to apoptosis, including c-jun N-terminal kinase (JNK) signaling and caspases. 24 , 37 , 38 , 39 , 40 , 41 As shown in Figure 5 , only JNK activation was downregulated upon C5-KO and anti-C5-Ab treatment at 2 hours. Furthermore, downstream cascades, caspase-8/-9 activation, cytochrome c (Cyt C) release, and the subsequent cleavage of caspase-3/-7 was assessed at 2 and 4 hours using Western blotting.…”

“… 44 Hence, MACs may be intricately involved in the upregulation of inflammatory mediators and cause microcirculatory dysfunction, both being crucial to ALF pathogenesis. 13 , 14 , 39 …”

“…The severity of liver damage (steatosis, apoptosis/necrosis, or inflammation) was graded by 2 independent pathologists in a blinded manner as follows: 0, absent; 0.5, minimal; 1, mild; 1.5, mild to moderate; 2, moderate; 2.5, moderate to marked; 3, marked. 25 , 39 …”

Human amniotic mesenchymal stromal cells alleviate acute liver injury by inhibiting the pro-inflammatory response of liver resident macrophage through autophagy

“…The most essential function of the Liver is to metabolize the drugs or other toxic compounds, which make itself viable target organ for toxicity. Macrophages in the liver [Kupffer cells, (KCs)] had been identified to play a core role during the pathogenesis of toxin-induced liver injury (5). Ju reported that KCs settled down in the liver and maintained the homeostasis of liver in different liver disease (6).…”