scholarly journals Paradoxical Role of Matrix Metalloproteinases in Liver Injury and Regeneration after Sterile Acute Hepatic Failure

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 247 ◽  
Author(s):  
Débora Alvarenga ◽  
Matheus Mattos ◽  
Mateus Lopes ◽  
Sarah Marchesi ◽  
Alan Araújo ◽  
...  
Keyword(s):  
Liver Injury ◽  
Matrix Metalloproteinases ◽  
Hepatic Failure ◽  
Acute Hepatic Failure ◽  
Neutrophil Infiltration ◽  
Hepatic Necrosis ◽  
Pharmacological Intervention ◽  
Neutrophil Accumulation ◽  
Drug Induced

Acetaminophen (APAP) poisoning is one of the leading causes of acute hepatic failure and liver transplantation is often the only lifesaving alternative. During the course of hepatocyte necrosis, an intense accumulation of neutrophils is often observed within the liver microenvironment. Despite the classic idea that neutrophil accumulation in tissues causes collateral tissue damage, there is a growing body of evidence showing that neutrophils can also orchestrate the resolution of inflammation. In this work, drug-induced liver injury was induced by oral administration of APAP and pharmacological intervention was made 12 h after this challenge. Liver injury and repair kinetics were evaluated by a novel combination of enzyme quantifications, ELISA, specific antagonists of neutrophil enzymes and confocal intravital microscopy. We have demonstrated that neutrophil infiltration is not only involved in injury amplification, but also in liver tissue repair after APAP-induced liver injury. In fact, while neutrophil depletion led to reduced hepatic necrosis during APAP poisoning, injury recovery was also delayed in neutropenic mice. The mechanisms underlying the neutrophil reparative role involved rapid degranulation and matrix metalloproteinases (MMPs) activity. Our data highlights the crucial role of neutrophils, in particular for MMPs, in the resolution phase of APAP-induced inflammatory response.

Acute Fulminant Hepatic Failure in a Woman Treated With Phenytoin and Trimethoprim-Sulfamethoxazole

2000 ◽  
Vol 124 (12) ◽  
pp. 1800-1803 ◽  
Author(s):  
Marius J-M. Ilario ◽  
Jose E. Ruiz ◽  
Constantine A. Axiotis
Keyword(s):  
Liver Injury ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Fulminant Hepatic Failure ◽  
Hepatic Failure ◽  
Acute Hepatic Failure ◽  
Hepatic Necrosis ◽  
Rare Occurrence ◽  
Autopsy Findings ◽  
Massive Hepatic Necrosis

Abstract Massive hepatic necrosis following exposure to phenytoin and trimethoprim-sulfamethoxazole is a rare occurrence and to the best of our knowledge has not been reported previously. Acute hepatic failure following administration of trimethoprim-sulfamethoxazole has rarely been seen, and only 4 cases have been well documented pathologically. We report a case of acute liver failure in a 60-year-old woman following ingestion of phenytoin and trimethoprim-sulfamethoxazole concomitantly over a 9-day period. Autopsy findings revealed acute fulminant hepatic failure. This case demonstrates the effects of chemical-chemical interactions in the potentiation of hepatotoxicity of single agents and specifically illustrates the need for discontinuing trimethoprim-sulfamethoxazole in the presence of early liver injury.

scholarly journals Partial deletion of argininosuccinate synthase protects from pyrazole plus lipopolysaccharide-induced liver injury by decreasing nitrosative stress

2012 ◽  
Vol 302 (3) ◽  
pp. G287-G295 ◽  
Author(s):  
Yongke Lu ◽  
Tung Ming Leung ◽  
Stephen C. Ward ◽  
Natalia Nieto
Keyword(s):  
Nitric Oxide ◽  
Liver Injury ◽  
Nitrosative Stress ◽  
Neutrophil Infiltration ◽  
Positive Staining ◽  
Neutrophil Accumulation ◽  
Argininosuccinate Synthase ◽  
Relevant Role ◽  
Oxide Synthase

Argininosuccinate synthase (ASS) is the rate-limiting enzyme in the urea cycle. Along with nitric oxide synthase (NOS)-2, ASS endows cells with the l-citrulline/nitric oxide (NO·) salvage pathway to continually supply l-arginine from l-citrulline for sustained NO· generation. Because of the relevant role of NOS in liver injury, we hypothesized that downregulation of ASS could decrease the availability of intracellular substrate for NO· synthesis by NOS-2 and, hence, decrease liver damage. Previous work demonstrated that pyrazole plus LPS caused significant liver injury involving NO· generation and formation of 3-nitrotyrosine protein adducts; thus, wild-type (WT) and Ass+/−mice ( Ass−/−mice are lethal) were treated with pyrazole plus LPS, and markers of nitrosative stress, as well as liver injury, were analyzed. Partial ablation of Ass protected from pyrazole plus LPS-induced liver injury by decreasing nitrosative stress and hepatic and circulating TNFα. Moreover, apoptosis was prevented, since pyrazole plus LPS-treated Ass+/−mice showed decreased phosphorylation of JNK; increased MAPK phosphatase-1, which is known to deactivate JNK signaling; and lower cleaved caspase-3 than treated WT mice, and this was accompanied by less TdT-mediated dUTP nick end labeling-positive staining. Lastly, hepatic neutrophil accumulation was almost absent in pyrazole plus LPS-treated Ass+/−compared with WT mice. Partial Ass ablation prevents pyrazole plus LPS-mediated liver injury by reducing nitrosative stress, TNFα, apoptosis, and neutrophil infiltration.

scholarly journals Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Lin Xu ◽  
Xinge Zhang ◽  
Yue Xin ◽  
Jie Ma ◽  
Chenyan Yang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Hepatic Steatosis ◽  
Liver Steatosis ◽  
Pharmacological Intervention ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Pathological Effect ◽  
Mtorc1 Pathway

AbstractAlcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.

Acute hepatic failure due to Plasmodium falciparum liver injury

2008 ◽  
Vol 6 (6) ◽  
pp. 357-360 ◽  
Author(s):  
Y. K. Joshi ◽  
B. N. Tandon ◽  
S. K. Acharya ◽  
S. Babu ◽  
M. Tandon
Keyword(s):  
Plasmodium Falciparum ◽  
Liver Injury ◽  
Hepatic Failure ◽  
Acute Hepatic Failure

Multicombination Approach SuppressesListeria monocytogenes-Induced Septicemia-Associated Acute Hepatic Failure: The Role of iRhom2 Signaling

2018 ◽  
Vol 7 (17) ◽  
pp. 1800427 ◽  
Author(s):  
Min-Xuan Xu ◽  
Chen-Xu Ge ◽  
Yu-Ting Qin ◽  
Ting-Ting Gu ◽  
De-Shuai Lou ◽  
...  
Keyword(s):  
Hepatic Failure ◽  
Acute Hepatic Failure
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