Abundant Expression of Lysyl Oxidase-like 2 Protein in Intrahepatic Bile Ducts of Infants with Biliary Atresia

Stefany Honigbaum, Qingfeng Zhu, Andrew Layman, Robert A Anders, Kathleen Schwarz

Research output: Contribution to journalArticle

Abstract

Introduction:Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract, which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase-like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti-LOXL2 drugs have been shown to be antifibrotic in animals.Objective:The aim of the study was to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues.Methods:Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared with non-BA livers (n = 20). Liver fibrosis was scored using the Ishak scale, and immunohistochemistry was performed using a commercially available polyclonal anti-LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed.Results:Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 [P ≤ 0.001]) for non-BA and distribution of bile duct-staining score of 3.0 versus 2.8 (P = 0.001) for non-BA. Fibrosis score of all BA samples was 4.2 versus 3.1 for non-BA. Nonhepatic pediatric tissue displayed minimal to no LOXL2 staining.Conclusions:There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extrahepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti-LOXL2 therapeutics in BA.

Original languageEnglish (US)
Pages (from-to)344-350
Number of pages7
JournalJournal of pediatric gastroenterology and nutrition
Volume69
Issue number3
DOIs
StatePublished - Sep 1 2019

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Protein-Lysine 6-Oxidase
Intrahepatic Bile Ducts
Biliary Atresia
Liver
Proteins
Staining and Labeling
Fibrosis
Bile Ducts
Fibrillar Collagens
Pediatrics
Elastin
Biliary Tract
Liver Cirrhosis
Extracellular Matrix
Anti-Idiotypic Antibodies
Immunohistochemistry
Inflammation
Biopsy
Bone and Bones
Muscles

Keywords

  • antifibrotic therapy
  • hepatic fibrosis
  • neonatal cholestasis

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Gastroenterology

Cite this

@article{24240a692f354104bbd8a772c59123fd,
title = "Abundant Expression of Lysyl Oxidase-like 2 Protein in Intrahepatic Bile Ducts of Infants with Biliary Atresia",
abstract = "Introduction:Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract, which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase-like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti-LOXL2 drugs have been shown to be antifibrotic in animals.Objective:The aim of the study was to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues.Methods:Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared with non-BA livers (n = 20). Liver fibrosis was scored using the Ishak scale, and immunohistochemistry was performed using a commercially available polyclonal anti-LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed.Results:Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 [P ≤ 0.001]) for non-BA and distribution of bile duct-staining score of 3.0 versus 2.8 (P = 0.001) for non-BA. Fibrosis score of all BA samples was 4.2 versus 3.1 for non-BA. Nonhepatic pediatric tissue displayed minimal to no LOXL2 staining.Conclusions:There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extrahepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti-LOXL2 therapeutics in BA.",
keywords = "antifibrotic therapy, hepatic fibrosis, neonatal cholestasis",
author = "Stefany Honigbaum and Qingfeng Zhu and Andrew Layman and Anders, {Robert A} and Kathleen Schwarz",
year = "2019",
month = "9",
day = "1",
doi = "10.1097/MPG.0000000000002414",
language = "English (US)",
volume = "69",
pages = "344--350",
journal = "Journal of Pediatric Gastroenterology and Nutrition",
issn = "0277-2116",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - Abundant Expression of Lysyl Oxidase-like 2 Protein in Intrahepatic Bile Ducts of Infants with Biliary Atresia

AU - Honigbaum, Stefany

AU - Zhu, Qingfeng

AU - Layman, Andrew

AU - Anders, Robert A

AU - Schwarz, Kathleen

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Introduction:Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract, which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase-like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti-LOXL2 drugs have been shown to be antifibrotic in animals.Objective:The aim of the study was to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues.Methods:Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared with non-BA livers (n = 20). Liver fibrosis was scored using the Ishak scale, and immunohistochemistry was performed using a commercially available polyclonal anti-LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed.Results:Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 [P ≤ 0.001]) for non-BA and distribution of bile duct-staining score of 3.0 versus 2.8 (P = 0.001) for non-BA. Fibrosis score of all BA samples was 4.2 versus 3.1 for non-BA. Nonhepatic pediatric tissue displayed minimal to no LOXL2 staining.Conclusions:There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extrahepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti-LOXL2 therapeutics in BA.

AB - Introduction:Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract, which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase-like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti-LOXL2 drugs have been shown to be antifibrotic in animals.Objective:The aim of the study was to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues.Methods:Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared with non-BA livers (n = 20). Liver fibrosis was scored using the Ishak scale, and immunohistochemistry was performed using a commercially available polyclonal anti-LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed.Results:Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 [P ≤ 0.001]) for non-BA and distribution of bile duct-staining score of 3.0 versus 2.8 (P = 0.001) for non-BA. Fibrosis score of all BA samples was 4.2 versus 3.1 for non-BA. Nonhepatic pediatric tissue displayed minimal to no LOXL2 staining.Conclusions:There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extrahepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti-LOXL2 therapeutics in BA.

KW - antifibrotic therapy

KW - hepatic fibrosis

KW - neonatal cholestasis

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U2 - 10.1097/MPG.0000000000002414

DO - 10.1097/MPG.0000000000002414

M3 - Article

VL - 69

SP - 344

EP - 350

JO - Journal of Pediatric Gastroenterology and Nutrition

JF - Journal of Pediatric Gastroenterology and Nutrition

SN - 0277-2116

IS - 3

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