title: Hepatocyte proliferation/growth arrest balance in the liver of mice during E. multilocularis infection: a coordinated 3-stage course.
abstract: BACKGROUND
  Alveolar echinococcosis (AE) is characterized by the tumor-like growth of Echinococcus (E.) multilocularis. Very little is known on the influence of helminth parasites which develop in the liver on the proliferation/growth arrest metabolic pathways in the hepatocytes of the infected liver over the various stages of infection.
  
  
  RESULTS
  Using Western blot analysis, qPCR and immunohistochemistry, we measured the levels of MAPKs activation, Cyclins, PCNA, Gadd45β, Gadd45γ, p53 and p21 expression in the murine AE model, from day 2 to 360 post-infection. Within the early (day 2-60) and middle (day60-180) stages, CyclinB1 and CyclinD1 gene expression increased up to day30 and then returned to control level after day60; Gadd45β, CyclinA and PCNA increased all over the period; ERK1/2 was permanently activated. Meanwhile, p53, p21 and Gadd45γ gene expression, and caspase 3 activation, gradually increased in a time-dependent manner. In the late stage (day180-360), p53, p21 and Gadd45γ gene expression were significantly higher in infected mice; JNK and caspase 3 were activated. TUNEL analysis showed apoptosis of hepatocytes. No significant change in CyclinE, p53 mRNA and p-p38 expression were observed at any time.
  
  
  CONCLUSIONS
  Our data support the concept of a sequential activation of metabolic pathways which 1) would first favor parasitic, liver and immune cell proliferation and survival, and thus promote metacestode fertility and tolerance by the host, and 2) would then favor liver damage/apoptosis, impairment in protein synthesis and xenobiotic metabolism, as well as promote immune deficiency, and thus contribute to the dissemination of the protoscoleces after metacestode fertility has been acquired. These findings give a rational explanation to the clinical observations of hepatomegaly and of unexpected survival of AE patients after major hepatic resections, and of chronic liver injury, necrosis and of hepatic failure at an advanced stage and in experimental animals.
authors.affiliation: State Key Laboratory Incubation Base of Major Diseases in Xinjiang and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
authors.forename: Chuanshan
authors.initials: C
authors.lastname: Zhang
authors.forename: Junhua
authors.initials: J
authors.lastname: Wang
authors.forename: Guodong
authors.initials: G
authors.lastname: Lü
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Lu
authors.forename: Georges
authors.initials: G
authors.lastname: Mantion
authors.forename: Dominique A
authors.initials: DA
authors.lastname: Vuitton
authors.forename: Hao
authors.initials: H
authors.lastname: Wen
authors.forename: Renyong
authors.initials: R
authors.lastname: Lin
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D018450:Disease Progression; D004443:Echinococcosis / Q000201:enzymology / Q000469:parasitology* / Q000473:pathology; D048210:Echinococcus multilocularis / Q000502:physiology*; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000201:enzymology / Q000469:parasitology* / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000201:enzymology / Q000469:parasitology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D002352:Carrier Proteins; D053148:Caspase 3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins; C121373:Gadd45g protein, mouse