title: Increased susceptibility to liver fibrosis with age is correlated with an altered inflammatory response.
abstract: It has been suggested that increasing age is correlated with an acceleration of the progression of liver fibrosis induced by various agents, such as hepatitis C virus or chronic alcohol consumption. However, the cellular and molecular changes underlying this predisposition are not entirely understood. In the context of an aging population, it becomes challenging to decipher the mechanisms responsible for this higher susceptibility of older individuals to this acquired liver disorder. To address this issue, we induced liver fibrosis by carbon tetrachloride (CCl(4)) chronic administration to 8-week- and 15-month-old mice. We confirmed that susceptibility to fibrosis development increased with age and showed that aging did not affect fibrosis resolution capacity. We then focused on the impairment of hepatocyte proliferation, oxidative stress, and inflammation as potential mechanisms accelerating the development of fibrosis in the elderly. We detected no inhibition of hepatocyte proliferation after CCl(4) injury in 15-month-old mice, whereas it was inhibited after a partial hepatectomy. Finally, we observed that, in a context in which liver oxidative stress was not differentially increased in both experimental groups, there was a higher recruitment of inflammatory cells, including mostly macrophages and lymphocytes, oriented toward a T helper 2 (T(H)2) response in older mice. Our data show that in conditions of equivalent levels of oxidative stress and maintained hepatocyte proliferative capacity, an increased inflammatory reaction mainly composed of CD4(+) lymphocytes and macrophages expressing T(H)2 cytokines is the main factor involved in the higher susceptibility to fibrosis with increasing age.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U.1016, Institut Cochin, 24 rue du Faubourg Saint-Jacques, Paris, France.
authors.forename: Meriem
authors.initials: M
authors.lastname: Mahrouf-Yorgov
authors.forename: Alexandra
authors.initials: A
authors.lastname: Collin de l'Hortet
authors.forename: Claudine
authors.initials: C
authors.lastname: Cosson
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Slama
authors.forename: Elsa
authors.initials: E
authors.lastname: Abdoun
authors.forename: Jacques-Emmanuel
authors.initials: JE
authors.lastname: Guidotti
authors.forename: Bernard
authors.initials: B
authors.lastname: Fromenty
authors.forename: Claudia
authors.initials: C
authors.lastname: Mitchell
authors.forename: Hélène
authors.initials: H
authors.lastname: Gilgenkrantz
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D002251:Carbon Tetrachloride; D049109:Cell Proliferation; D002908:Chronic Disease; D004198:Disease Susceptibility; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000473:pathology*; D008103:Liver Cirrhosis / Q000150:complications* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D018384:Oxidative Stress
chemical_list: D002251:Carbon Tetrachloride