Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice

Autor: Sara Crespo Yanguas, Joost Willebrords, Isabel Veloso Alves Pereira, Tereza Cristina da Silva, Elke Decrock, Anwar Farhood, Bruno Cogliati, James L. Weemhoff, Luc Leybaert, Michaël Maes, Margitta Lebofsky, Hartmut Jaeschke, Mathieu Vinken
Přispěvatelé: Faculty of Medicine and Pharmacy, Pharmaceutical and Pharmacological Sciences, Experimental in vitro toxicology and dermato-cosmetology, Connexin Signalling Research Group, Liver Connexin and Pannexin Research Group
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
connexin
Time Factors
Chemical and Drug Induced Liver Injury/etiology
Adenosine Triphosphate/metabolism
Anti-Inflammatory Agents
Connexin
Pharmacology
Toxicology
medicine.disease_cause
Connexins
Rats
Sprague-Dawley
Adenosine Triphosphate
0302 clinical medicine
Liver/drug effects
Signal Transduction/drug effects
Anti-Inflammatory Agents/pharmacology
Cells
Cultured
Peptides/pharmacology
Liver injury
biology
HEPATOPATIAS
Gap junction
Alanine Transaminase
General Medicine
3. Good health
Connexin 43/antagonists & inhibitors
Liver
Inflammation Mediators/blood
Cytokines
Chemical and Drug Induced Liver Injury
Inflammation Mediators
Signal Transduction
medicine.drug
hepatotoxicity
hemichannel
Oxidative Stress/drug effects
Cytokines/blood
Article
Connexon
Proinflammatory cytokine
gap junction
03 medical and health sciences
medicine
Animals
Alanine Transaminase/blood
Acetaminophen
Connexins/antagonists & inhibitors
business.industry
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
Oxidative Stress
030104 developmental biology
Alanine transaminase
inflammation
Cytoprotection
Connexin 43
Immunology
biology.protein
Peptides
business
030217 neurology & neurosurgery
Oxidative stress
Zdroj: Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual)
Universidade de São Paulo (USP)
instacron:USP
ISSN: 0378-4274
DOI: 10.1016/j.toxlet.2017.07.007
Popis: Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficiency of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5 hour. Sampling was performed 3, 6, 24 and 48 hours following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure.
Databáze: OpenAIRE
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