Fibroblast proliferative capacity predicts prognosis in idiopathic pulmonary fibrosis and identifies PITX1 as a growth-associated gene.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Lung fibroblasts isolated from patients with IPF exhibit enhanced proliferative capacity; however, the molecular determinants linking fibroblast proliferation to clinical outcomes remain incompletely understood. METHODS: Fibroblast growth slopes were measured in primary lung fibroblast derived from patients with IPF and control subjects. Transcriptome microarray data were integrated with fibroblast growth kinetics to identify growth slope-associated genes. Differential expression analysis was performed between IPF and control fibroblasts, and candidate genes were further evaluated at the mRNA and protein levels in lung fibroblasts and bronchoalveolar lavage (BAL) fluids. Associations with clinical outcomes were assessed. RESULTS: Fibroblasts derived from patients with IPF showed significantly higher growth slope than control fibroblasts, and increased fibroblast growth slope were associated with reduced survival in IPF. Integration of fibroblast growth kinetics with transcriptomic analysis identified a fibroblast growth slope-associated gene signature, from which PITX1 emerged as a disease-relevant candidate gene. PITX1 mRNA and protein levels were elevated in IPF fibroblasts compared with controls. In BAL fluids, PITX1 protein levels were significantly higher in patients with IPF and were associated with clinical outcomes, although they did not correlate with pulmonary function parameters. CONCLUSIONS: Enhanced fibroblast proliferative capacity is associated with poor prognosis in IPF, and PITX1 represents a fibroblast growth slope-associated gene reflecting fibroblast heterogeneity and prognostic relevance. These findings suggest that assessment of fibroblast growth behavior and PITX1 expression may provide insight into disease progression in IPF, although further validation studies are required.