title: Cleaved cytokeratin-18 is a mechanistically informative biomarker in idiopathic pulmonary fibrosis.
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.
authors.affiliation: Department of Medicine, University of California, San Francisco School of Medicine, San Francisco, CA 94143-0111, USA.
authors.forename: Seung-Ick
authors.initials: SI
authors.lastname: Cha
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ryerson
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Lee
authors.forename: Jasleen
authors.initials: J
authors.lastname: Kukreja
authors.forename: Sophia S
authors.initials: SS
authors.lastname: Barry
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Jones
authors.forename: Brett M
authors.initials: BM
authors.lastname: Elicker
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Kim
authors.forename: Feroz R
authors.initials: FR
authors.lastname: Papa
authors.forename: Harold R
authors.initials: HR
authors.lastname: Collard
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
mesh_terms: D000368:Aged; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D053538:Keratin-18 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D053538:Keratin-18