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Cleaved cytokeratin-18 is a mechanistically informative biomarker in idiopathic pulmonary fibrosis

Seung-Ick Cha12, Christopher J Ryerson1, Joyce S Lee1, Jasleen Kukreja3, Sophia S Barry1, Kirk D Jones4, Brett M Elicker5, Dong Soon Kim6, Feroz R Papa1, Harold R Collard1 and Paul J Wolters1*

Author Affiliations

1 Department of Medicine, University of California, San Francisco School of Medicine, Box 0111, San Francisco, 94143-0111, CA, USA

2 Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea

3 Department of Surgery, University of California, San Francisco, CA, USA

4 Department of Pathology, University of California, San Francisco, CA, USA

5 Department of Radiology, University of California, San Francisco, CA, USA

6 Department of Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

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Respiratory Research 2012, 13:105  doi:10.1186/1465-9921-13-105

Published: 20 November 2012

Abstract

Background

Stress 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.

Methods

IPF 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.

Results

cCK-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.

Conclusions

cCK-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.

Keywords:
Idiopathic interstitial pneumonia; idiopathic pulmonary fibrosis; lung fibrosis; ER stress; apoptosis