Research Paper Volume 9, Issue 1 pp 98—113

Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling

Bénédicte Delire 1, , Valérie Lebrun 1, , Charlotte Selvais 1, , Patrick Henriet 2, , Amélie Bertrand 1, , Yves Horsmans 1, 3, , Isabelle A. Leclercq 1, ,

  • 1 Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium
  • 2 Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium
  • 3 Department of Hepato-Gastroenterology, Cliniques Universitaires Saint-Luc and Institute of Clinical Research, Université catholique de Louvain, Brussels, Belgium

received: July 1, 2016 ; accepted: November 24, 2016 ; published: December 9, 2016 ;

https://doi.org/10.18632/aging.101124
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Abstract

Clinical data identify age as a factor for severe liver fibrosis. We evaluate whether and how aging modulates the fibrotic response in a mouse model. Liver fibrosis was induced by CCl4 injections (thrice weekly for 2 weeks) in 7 weeks- and 15 months-old mice (young and old, respectively). Livers were analyzed for fibrosis, inflammation and remodeling 48 and 96 hours after the last injection. Old mice developed more severe fibrosis compared to young ones as evaluated by sirius red morphometry. Expression of pro-fibrogenic genes was equally induced in the two age-groups but enhanced fibrolysis in young mice was demonstrated by a significantly higher Mmp13 induction and collagenase activity. While fibrosis resolution occurred in young mice within 96 hours, no significant fibrosis attenuation was observed in old mice. Although recruitment of monocytes-derived macrophages was similar in young and old livers, young macrophages had globally a remodeling phenotype while old ones, a pro-fibrogenic phenotype. Moreover, we observed a higher proportion of thick fibers and enhanced expression of enzymes involved in collagen maturation in old mice. Conclusion: Impaired fibrolysis of a matrix less prone to remodeling associated with a pro-inflammatory phenotype of infiltrated macrophages contribute to a more severe fibrosis in old mice.

Abbreviations

ECM: extracellular matrix; (a)HSC: (activated) hepatic stellate cell; HCV: hepatitis C virus; MMP: matrix metalloproteinase; NAFLD: non-alcoholic fatty liver disease; CCl4: carbon tetrachloride; FRIDA: FRamework for Image Dataset Analysis; SEM: standard error of the mean; TGFbeta: transforming growth factor beta; alphaSMA: alpha smooth muscle actin; TIMP: tissue inhibitor of metaloproteinase CXCL9: chemokine (C-X-C motif) ligand 9; CCL2: chemokine (C-C motif) ligand 2, VEGF: vascular endothelial growth factor; MIF: macrophage migration inhibitor factor; LOX: lysyl oxidase; LOXL2: LOX like 2,TG2: tissue transglutaminase 2; ADAMTS2: a disintegrin and metalloproteinase with thrombospondin type I motif.