Liver repair and regeneration after ischemia-reperfusion injury is associated with prolonged fibrosis.
Am J Physiol Gastrointest Liver Physiol
; 316(3): G323-G331, 2019 03 01.
Article
em En
| MEDLINE
| ID: mdl-30543462
ABSTRACT
Liver recovery after hepatic ischemia-reperfusion (I/R) injury is characterized by clearance of dead tissue and its replacement with functional liver parenchyma. Previous reports have observed fibrosis after liver I/R. To determine whether liver fibrosis after I/R was a pathologic consequence of the injury response, we assessed the development of liver fibrosis after I/R and its impact on subsequent insult. A murine model of partial I/R was used to induce liver injury and study the reparative response. During liver remodeling after I/R, expression of the profibrotic genes increased in the ischemic liver. Histologically, α-smooth muscle actin (α-SMA)-positive hepatic stellate cells (HSCs)/myofibroblasts increased, and collagen deposition was enhanced along the injured site. Selective staining experiments showed that HSCs, not portal fibroblasts, were the major source of myofibroblasts. During liver repair after I/R, liver fibrosis was readily observed at the interface between necrotic tissue and regenerating liver in association with HSCs/myofibroblasts. The number of HSCs/myofibroblasts decreasing shortly after the full resolution of necrotic injury and restoration are normal liver architecture. However, liver fibrosis persisted for several more weeks before gradually resolving. Resolution of liver fibrosis was accompanied by upregulated expression of matrix metalloproteinase-13. After resolution of fibrosis, the administration of CCl4 did not result in exacerbated liver injury, suggesting that I/R injury does not predispose the liver to future fibrotic insults. The data suggest that liver fibrosis is a component of tissue repair after I/R, is caused by myofibroblasts derived from HSC, and does not increase susceptibility of the liver to subsequent hepatic injury. NEW & NOTEWORTHY This study is the first to assess pathology of liver fibrosis during the reparative process after ischemia-reperfusion (I/R) injury. Here we show that profibrotic gene expression increased in the liver after I/R, and collagen accumulation produced by hepatic stellate cells (HSCs)/myofibroblasts enhanced at the interface between necrotic tissue and regenerating liver. Liver fibrosis gradually resolved concomitant with decreasing activation of HSC and upregulating matrix metalloproteinase-13. After resolution of fibrosis, the liver was not more susceptible to subsequent hepatic injury.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Traumatismo por Reperfusão
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Células Estreladas do Fígado
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Fibroblastos
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Fígado
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Regeneração Hepática
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article