Prognostic and Pathophysiologic Significance of IL-8 (CXCL8) in Biliary Atresia.

Nimish Godbole,Mikko P Pakarinen,Päivi Heikkilä,Markku Heikinheimo,Marjut Pihlajoki,Joseph R Davidson,Athanasios Tyraskis,Mark Davenport,Noora Andersson,Katja Eloranta,Maria Hukkinen,Iiris Nyholm,Jouko Lohi,Antti Kyrönlahti

doi:10.3390/jcm10122705

Abstract

Interleukin (IL)-8 (CXCL8), a chemokine involved in neutrophil recruitment, has been implicated in ductular reaction and liver fibrogenesis. We studied liver and serum IL-8 expression in a large biliary atresia (BA) cohort and explored its prognostic and pathophysiological potential. IL-8 expression was assessed in liver utilizing quantitative polymerase chain reaction (qPCR), immunohistochemistry and in situ hybridization and in serum using an enzyme-linked immunosorbent assay, among 115 BA patients, 10 disease controls and 68 normal controls. Results were correlated to portoenterostomy (PE) outcomes, biochemical and histological liver injury, transcriptional markers of fibrosis and cholangiocytes, and expression of other related cytokines. IL-8 was markedly overexpressed in liver and serum of BA patients at PE (n = 88) and in serum samples obtained during postoperative follow-up (n = 40). IL-8 expression in the liver was predominantly in cholangiocytes within areas of ductular reaction. Liver IL-8 mRNA expression correlated positively with its serum concentration, bile ductular proliferation, Metavir fibrosis stage, and transcriptional markers of activated myofibroblasts (ACTA2) and cholangiocytes (KRT19). Taken together, IL-8 may mediate liver injury in BA by promoting ductular reaction and associated liver fibrogenesis. Prognostic value of serum IL-8 to predict native liver survival was limited and confined to the postoperative period after PE.

Highlights

IntroductionBiliary atresia (BA), presenting in the neonatal period, is characterized by fibroinflammatory obliteration of the extra- and intrahepatic bile ducts
To address effects of different expression levels on native liver survival, Kaplan–Meier analysis with log-rank test was used to predict native liver survival between tertiles for serum IL-8 concentration and relative liver mRNA expression. p < 0.05 was considered as statistically significant and all analyses were done on RStudio version 1.2.5033 (RStudio, Boston, MA, USA)
In this study we have comprehensively addressed the prognostic value of liver and serum expression of IL-8 for PE outcomes in a large number of biliary atresia (BA) patients in relation to histological liver fibrosis, markers of liver fibrogenesis and cholangiocytes as well as biochemical markers of liver injury

Summary

Introduction

Biliary atresia (BA), presenting in the neonatal period, is characterized by fibroinflammatory obliteration of the extra- and intrahepatic bile ducts. The resulting bile duct disruption and cholestasis rapidly progresses to fatal biliary cirrhosis and end-stage liver disease within 2 years from birth [2,3]. The current management of BA involves an early attempt at restoration of bile flow with excision of the obliterated extrahepatic bile ducts and biliary reconstruction using a Roux jejunal loop (portoenterostomy (PE)) [2]. Consequent normalization of serum bilirubin levels is regarded as a successful outcome. PE is successful in over half of the patients, progressive fibrosis continues in their native livers necessitating liver transplantation (LT) in the majority of patients before the age of 20 years [3]. BA is the leading cause of LT in children [4]

Objectives

Methods

Findings

Conclusion