4.6 Article

HEPATIC FIBROSIS IN A LONG-TERM MURINE MODEL OF SEPSIS

Journal

SHOCK
Volume 37, Issue 4, Pages 399-407

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SHK.0b013e31824a670b

Keywords

Polymicrobial peritonitis; inflammation; sepsis model; hepatic stellate cells; transdifferentiation

Funding

  1. German Federal Ministry of Education and Research (BMBF) [FKZ 01EO1002]

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Chronic sequelae of sepsis represent a major, yet underappreciated clinical problem, contributing to long-term mortality and quality-of-life impairment. In chronic liver disease, inflammation perpetuates fibrogenesis, but development of fibrosis in the post-acute phase of systemic inflammation has not been studied. Therefore, a mouse model of post-acute sequelae of sepsis was established based on polymicrobial peritonitis under antibiotic protection. Survival decreased to approximately 40% within 7 days and remained constant until day 28 (post-acute phase). In survivors, clinical recovery was observed within 1 week, whereas white blood cell and platelet count, as well as markers of liver injury, remained elevated until day 28. Macroscopically, inflammation and abscess formation were detected in the peritoneal space and on/in the liver. Microscopically, acute-chronic inflammation with ductular proliferation, focal granuloma formation in the parenchyma, and substantial hepatic fibrosis were observed. Increased numbers of potentially pathogenetic macrophages and alpha-smooth muscle actin-positive cells, presumably activated hepatic stellate cells, were detected in the vicinity of fibrotic areas. Fibrosis was associated with the presence of elastin and an augmented production/deposition of collagen types I and III. Microarray analyses revealed early activation of canonical and noncanonical pathways of hepatic stellate cell transdifferentiation. Thus, chronic sequelae of experimental sepsis were characterized by abscess formation, persistent inflammation, and substantial liver injury and fibrosis, the latter associated with increased numbers of macrophages/alpha-smooth muscle actin-positive cells and deposition of collagen types I and III. This suggests persistent activation of stellate cells, with consecutive fibrosis-a hallmark of chronic liver disease-as a result of acute life-threatening infection.

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