Cleaved cytokeratin-18 is a mechanistically informative biomarker in idiopathic pulmonary fibrosisReport as inadecuate




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Respiratory Research

, 13:105

First Online: 20 November 2012Received: 04 September 2012Accepted: 16 November 2012

Abstract

BackgroundStress of the endoplasmic reticulum ER leading to activation of the unfolded protein response UPR and alveolar epithelial cell AEC apoptosis may play a role in the pathogenesis of idiopathic pulmonary fibrosis IPF. Our objectives were to determine whether circulating caspase-cleaved cytokeratin-18 cCK-18 is a marker of AEC apoptosis in IPF, define the relationship of cCK-18 with activation of the UPR, and assess its utility as a diagnostic biomarker.

MethodsIPF and normal lung tissues were stained with the antibody M30 that specifically binds cCK-18. The relationship between markers of the UPR and cCK-18 was determined in AECs exposed in vitro to thapsigargin to induce ER stress. cCK-18 was measured in serum from subjects with IPF, hypersensitivity pneumonitis HP, nonspecific interstitial pneumonia NSIP, and control subjects.

ResultscCK-18 immunoreactivity was present in AECs of IPF lung, but not in control subjects. Markers of the UPR phosphorylated IRE-1α and spliced XBP-1 were more highly expressed in IPF type II AECs than in normal type II AECs. Phosphorylated IRE-1α and cCK-18 increased following thapsigargin-induced ER stress. Serum cCK-18 level distinguished IPF from diseased and control subjects. Serum cCK-18 was not associated with disease severity or outcome.

ConclusionscCK-18 may be a marker of AEC apoptosis and UPR activation in patients with IPF. Circulating levels of cCK-18 are increased in patients with IPF and cCK-18 may be a useful diagnostic biomarker.

KeywordsIdiopathic interstitial pneumonia idiopathic pulmonary fibrosis lung fibrosis ER stress apoptosis AbbreviationsAECAlveolar epithelial cell

AUCArea under the receiver operating characteristic curve

BALBronchoalveolar lavage

BSABovine serum albumin

cCK-18Caspase-cleaved cytokeratin-18

CCL18CC-chemokine ligand 18

DABDiaminobenzidine

DLCODiffusing capacity for carbon monoxide

DNADeoxyribonucleic acid

ELISAEnzyme-linked immunosorbent assay

EREndoplasmic reticulum

FACSFluorescence-activated cell sorting

FVCForced vital capacity

HPHypersensitivity pneumonitis

HRPHorseradish peroxidase

ILDInterstitial lung disease

IPFIdiopathic pulmonary fibrosis

KL-6Krebs von den Lungen 6 antigen

M30Monoclonal antibody to cCK-18

MMP7Matrix metalloproteinase 7

NSIPNonspecific interstitial pneumonia

PBSPhosphate buffered saline

RNARibonucleic acid

RT-PCRReverse transcriptase polymerase chain reaction

SDS-PAGESodium dodecyl sulfate polyacrylamide gel electrophoresis

SP-ASurfactant protein A

SP-DSurfactant protein D

TBSTris-buffered saline

TGF-βTransforming growth factor-beta

TUNELTerminal deoxynucleotidyl transferase dUTP nick end labeling

UCSFUniversity of California San Francisco

UPRUnfolded protein response

XBP-1X-box binding protein 1.

Electronic supplementary materialThe online version of this article doi:10.1186-1465-9921-13-105 contains supplementary material, which is available to authorized users.

Seung-Ick Cha, Christopher J Ryerson contributed equally to this work.

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Author: Seung-Ick Cha - Christopher J Ryerson - Joyce S Lee - Jasleen Kukreja - Sophia S Barry - Kirk D Jones - Brett M Elicke

Source: https://link.springer.com/



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