Systematic phenotyping and correlation of biomarkers with lung function and histology in lung fibrosis.

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 pre-clinical 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, while lung function was unchanged at day 28 and 56, even when histology showed marked fibrotic lesions. While MMP7, MMP9, and PAI1 were significantly elevated in BAL of fibrotic mice, only sICAM1 was elevated in the peripheral blood of fibrotic mice and strongly correlated with the extent of fibrosis. Importantly, tissue-bound ICAM1 was also elevated in lung homogenates, with prominent staining in hyperplastic type II alveolar epithelial and endothelial cells. In sum, we show that lung function decline is not a prerequisite for histologically evident fibrosis, particularly during the onset or resolution thereof. Plasma levels of sICAM1 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.