title: Systematic phenotyping and correlation of biomarkers with lung function and histology in lung fibrosis.
abstract: To date, phenotyping and disease course prediction in idiopathic pulmonary fibrosis (IPF) primarily relies on lung function measures. Blood biomarkers were recently proposed for diagnostic and outcome prediction in IPF, yet their correlation with lung function and histology remains unclear. Here, we comprehensively assessed biomarkers in liquid biopsies and correlated their abundance with lung function and histology during the onset, progression, and resolution of lung fibrosis, with the aim to more precisely evaluate disease progression in the preclinical model of bleomycin-induced pulmonary fibrosis in vivo. Importantly, the strongest correlation of lung function with histological extent of fibrosis was observed at day 14, whereas lung function was unchanged at days 28 and 56, even when histological assessment showed marked fibrotic lesions. Although matrix metalloproteinase-7 (MMP-7), MMP-9, and PAI-1 were significantly elevated in broncheoalveolar lavage of fibrotic mice, only soluble ICAM-1 (sICAM-1) was elevated in the peripheral blood of fibrotic mice and was strongly correlated with the extent of fibrosis. Importantly, tissue-bound ICAM-1 was also elevated in lung homogenates, with prominent staining in hyperplastic type II alveolar epithelial and endothelial cells. In summary, we show that lung function decline is not a prerequisite for histologically evident fibrosis, particularly during the onset or resolution thereof. Plasma levels of sICAM-1 strongly correlate with the extent of lung fibrosis, and may thus be considered for the assessment of intraindividual therapeutic studies in preclinical studies of pulmonary fibrosis.
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig Maximilians University and Helmholtz Zentrum München, Munich, Germany.
authors.forename: Isis E
authors.initials: IE
authors.lastname: Fernandez
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig Maximilians University and Helmholtz Zentrum München, Munich, Germany.
authors.forename: Oana V
authors.initials: OV
authors.lastname: Amarie
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig Maximilians University and Helmholtz Zentrum München, Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mutze
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig Maximilians University and Helmholtz Zentrum München, Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig Maximilians University and Helmholtz Zentrum München, Munich, Germany.
authors.forename: Ali Önder
authors.initials: AÖ
authors.lastname: Yildirim
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig Maximilians University and Helmholtz Zentrum München, Munich, Germany oliver.eickelberg@helmholtz-muenchen.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000097:blood* / Q000473:pathology
chemical_list: D015415:Biomarkers; D018799:Intercellular Adhesion Molecule-1
keywords: interstitial lung diseases; lung injury and repair; monitoring; outcome; pulmonary fibrosis; surveillance