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

TitleCleaved cytokeratin-18 is a mechanistically informative biomarker in idiopathic pulmonary fibrosis
Publication TypeJournal Article
Year of Publication2012
AuthorsCha S-I, Ryerson CJ, Lee JS, Kukreja J, Barry SS, Jones KD, Elicker BM, Kim DSoon, Papa FR, Collard HR, Wolters PJ
JournalRespir Res
Volume13
Pagination105
Date Published2012
ISSN1465-993X
KeywordsAged, Apoptosis, Biomarkers, Case-Control Studies, Endoplasmic Reticulum Stress, Epithelial Cells, Female, Humans, Idiopathic Pulmonary Fibrosis, Keratin-18, Male, Middle Aged, Pulmonary Alveoli
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.

DOI10.1186/1465-9921-13-105
Alternate JournalRespir. Res.
PubMed ID23167970
PubMed Central IDPMC3547729
Grant ListHL086516 / HL / NHLBI NIH HHS / United States
HL104422 / HL / NHLBI NIH HHS / United States
HL108794 / HL / NHLBI NIH HHS / United States
P01 HL108794 / HL / NHLBI NIH HHS / United States
R21 HL104422 / HL / NHLBI NIH HHS / United States