title: Chronic bile duct hyperplasia is a chronic graft dysfunction following liver transplantation.
abstract: OBJECTIVE
  To investigate pathological types and influential factors of chronic graft dysfunction (CGD) following liver transplantation (LT) in rats.
  
  
  METHODS
  The whole experiment was divided into three groups: (1) normal group (n = 12): normal BN rats without any drug or operation; (2) syngeneic transplant group (SGT of BN-BN, n = 12): both donors and recipients were BN rats; and (3) allogeneic transplant group (AGT of LEW-BN, n = 12): Donors were Lewis and recipients were BN rats. In the AGT group, all recipients were subcutaneously injected by Cyclosporin A after LT. Survival time was observed for 1 year. All the dying rats were sampled, biliary tract tissues were performed bacterial culture and liver tissues for histological study. Twenty-one day after LT, 8 rats were selected randomly in each group for sampling. Blood samples from caudal veins were collected for measurements of plasma endotoxin, cytokines and metabonomic analysis, and faeces were analyzed for intestinal microflora.
  
  
  RESULTS
  During the surgery of LT, no complications of blood vessels or bile duct happened, and all rats in each group were still alive in the next 2 wk. The long term observation revealed that a total of 8 rats in the SGT and AGT groups died of hepatic graft diseases, 5 rats in which died of chronic bile duct hyperplasia. Compared to the SGT and normal groups, survival ratio of rats significantly decreased in the AGT group (P < 0.01). Moreover, liver necrosis, liver infection, and severe chronic bile duct hyperplasia were observed in the AGT group by H and E stain. On 21 d after LT, compared with the normal group (25.38 ± 7.09 ng/L) and SGT group (33.12 ± 10.26 ng/L), plasma endotoxin in the AGT group was remarkably increased (142.86 ± 30.85 ng/L) (both P < 0.01). Plasma tumor necrosis factor-α and interleukin-6 were also significantly elevated in the AGT group (593.6 ± 171.67 pg/mL, 323.8 ± 68.30 pg/mL) vs the normal (225.5 ± 72.07 pg/mL, 114.6 ± 36.67 pg/mL) and SGT groups (321.3 ± 88.47 pg/mL, 205.2 ± 53.06 pg/mL) (P < 0.01). Furthermore, Bacterial cultures of bile duct tissues revealed that the rats close to death from the SGT and AGT groups were strongly positive, while those from the normal group were negative. The analysis of intestinal microflora was performed. Compared to the normal group (7.98 ± 0.92, 8.90 ± 1.44) and SGT group (8.51 ± 0.46, 9.43 ± 0.69), the numbers of Enterococcus and Enterobacteria in the AGT group (8.76 ± 1.93, 10.18 ± 1.64) were significantly increased (both P < 0.01). Meanwhile, compared to the normal group (9.62 ± 1.60, 9.93 ± 1.10) and SGT group (8.95 ± 0.04, 9.02 ± 1.14), the numbers of Bifidobacterium and Lactobacillus in the AGT group (7.83 ± 0.72, 8.87 ± 0.13) were remarkably reduced (both P < 0.01). In addition, metabonomics analysis showed that metabolic profiles of plasma in rats in the AGT group were severe deviated from the normal and SGT groups.
  
  
  CONCLUSIONS
  Chronic bile duct hyperplasia is a pathological type of CGD following LT in rats. The mechanism of this kind of CGD is associated with the alterations of inflammation, intestinal barrier function and microflora as well as plasma metabolic profiles.
authors.affiliation: The Key Lab of Combined Multi-organ Transplantation, Ministry of Public Health, The Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.
authors.forename: Jian-Wen
authors.initials: JW
authors.lastname: Jiang
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Ren
authors.forename: Guang-Ying
authors.initials: GY
authors.lastname: Cui
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hai-Yang
authors.initials: HY
authors.lastname: Xie
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001649:Bile Duct Diseases / Q000209:etiology* / Q000473:pathology*; D001652:Bile Ducts / Q000473:pathology*; D002908:Chronic Disease; D006965:Hyperplasia / Q000473:pathology*; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew