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Fibrogenesis and Tissue Repair

, 1:6

Gastrointestinal and Liver Disease


Obstructive cholestasis causes hepatic cirrhosis and portal hypertension. The pathophysiological mechanisms involved in the development of liver disease are multiple and linked. We propose grouping these mechanisms according to the three phenotypes mainly expressed in the interstitial space in order to integrate them.

Experimental extrahepatic cholestasis is the model most frequently used to study obstructive cholestasis. The early liver interstitial alterations described in these experimental models would produce an ischemia-reperfusion phenotype with oxidative and nitrosative stress. Then, the hyperexpression of a leukocytic phenotype, in which Kupffer cells and neutrophils participate, would induce enzymatic stress. And finally, an angiogenic phenotype, responsible for peribiliary plexus development with sinusoidal arterialization, occurs. In addition, an intense cholangiocyte proliferation, which acquires neuroendocrine abilities, stands out. This histopathological finding is also associated with fibrosis.

It is proposed that the sequence of these inflammatory phenotypes, perhaps with a trophic meaning, ultimately produces a benign tumoral biliary process – although it poses severe hepatocytic insufficiency. Moreover, the persistence of this benign tumor disease would induce a higher degree of dedifferentiation and autonomy and, therefore, its malign degeneration.

List of abbreviationsBDLbile duct ligation

ECMextracellular matrix

ERKextracellular signal-regulated kinase


HGFhepatocyte growth factor

HSChepatic stellate cell

HDLhigh-density lipoprotein

HIFhypoxia-inducible factor

IGFinsulin-like growth factor


iNOSinducible nitric oxide synthase

IFNγinterferon gamma

JNKc-Jun N-terminal kinase

LBPlipopolysaccharide binding protein


MMPmatrix metalloproteinase

NADPHreduced nicotinamide dinucleotide phosphate

NOnitric oxide

PAFplatelet activation factor

PDGFplatelet-derived growth factor

ROSreactive oxygen species

RNSreactive nitrogen species

TLRToll-like receptors

TGFtransforming growth factor

TNFαtumor necrosis factor α

VEGFvascular endothelial growth factor.

Electronic supplementary materialThe online version of this article doi:10.1186-1755-1536-1-6 contains supplementary material, which is available to authorized users.

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Autor: María-Angeles Aller - Jorge-Luis Arias - Jose García-Domínguez - Jose-Ignacio Arias - Manuel Durán - Jaime Arias

Fuente: https://link.springer.com/

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