title: Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling.
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 CCl4injections (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 higherMmp13induction 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.
  
  
  
  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.
authors.affiliation: Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Delire
authors.affiliation: Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lebrun
authors.affiliation: Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Selvais
authors.affiliation: Cell Biology Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Henriet
authors.affiliation: Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bertrand
authors.affiliation: Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium.|Department of Hepato-Gastroenterology, Cliniques Universitaires Saint-Luc and Institute of Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Horsmans
authors.affiliation: Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Isabelle A
authors.initials: IA
authors.lastname: Leclercq
mesh_terms: D000199:Actins / Q000378:metabolism; D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D016212:Transforming Growth Factor beta
keywords: collagen crosslinking; fibrosis resolution; inflammation; macrophages; matrix metalloproteinase