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1.
J Pathol ; 263(4-5): 482-495, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38872438

RESUMO

Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated ΔEGFR mice when compared with CCl4-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Tetracloreto de Carbono , Receptores ErbB , Hepatócitos , Transdução de Sinais , Animais , Receptores ErbB/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Fígado/patologia , Fígado/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Camundongos , Camundongos Endogâmicos C57BL , Masculino , Comunicação Celular , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Transgênicos
2.
Aging (Albany NY) ; 13(6): 7800-7827, 2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33780353

RESUMO

The liver exhibits a variety of functions that are well-preserved during aging. However, the cellular hallmarks of aging increase the risk of hepatic alterations and development of chronic liver diseases. Acetaminophen (APAP) is a first choice for relieving mild-to-moderate pain. Most of the knowledge about APAP-mediated hepatotoxicity arises from acute overdose studies due to massive oxidative stress and inflammation, but little is known about its effect in age-related liver inflammation after chronic exposure. Our results show that chronic treatment of wild-type mice on the B6D2JRcc/Hsd genetic background with APAP at an infratherapeutic dose reduces liver alterations during aging without affecting body weight. This intervention attenuates age-induced mild oxidative stress by increasing HO-1, MnSOD and NQO1 protein levels and reducing ERK1/2 and p38 MAPK phosphorylation. More importantly, APAP treatment counteracts the increase in Cd8+ and the reduction in Cd4+ T lymphocytes observed in the liver with age. This response was also found in peripheral blood mononuclear cells. In conclusion, chronic infratherapeutic APAP treatment protects mice from age-related liver alterations by attenuating oxidative stress and inflammation.


Assuntos
Acetaminofen/farmacologia , Envelhecimento/efeitos dos fármacos , Inflamação/tratamento farmacológico , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Acetaminofen/uso terapêutico , Envelhecimento/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Inflamação/metabolismo , L-Lactato Desidrogenase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Substâncias Protetoras/uso terapêutico
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