Circulating Endothelial Compartment and Progenitor Cell Dynamics in Idiopathic Pulmonary Fibrosis: Findings from the COFI Trial.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease in which the contribution of vascular alterations remains poorly understood. While most previous studies focused on epithelial and fibroblast dysfunction, recent evidence suggests that endothelial cell injury and vascular remodeling are integral to disease pathogenesis. This study aimed to longitudinally characterize the circulating endothelial compartment in IPF and explore its association with clinical outcomes. In this multicenter substudy of the COFI (COhorte FIbrose) prospective cohort, 95 patients with IPF underwent 243 serial assessments of circulating endothelial biomarkers. These included the quantification of circulating endothelial cells (CECs) using immunomagnetic isolation, and CD34⁺CD45DIM cells, total CD34⁺ cells, and the proportions of CD34⁺KDR⁺ and CD34⁺CD133⁺ subsets within the CD34⁺ population, assessed by flow cytometry. In addition, hematopoietic endothelial progenitor cells (hEPCs) and endothelial colony-forming cells (ECFCs) were measured using standardized culture-based assays. Longitudinal analysis revealed a significant increase in CD34⁺KDR⁺ progenitor cells (p = 0.04) and CECs (p = 0.03) over time. ECFCs showed no significant variation. Higher BMI was associated with lower levels of CD34⁺KDR⁺ cells (p = 0.04), CD34⁺CD133⁺ cells (p = 0.05), whereas ECFCs were undetectable in obese patients (median 0 [0-0], p = 0.063). Multivariate analysis indicated no significant associations between baseline levels of any endothelial biomarkers and progression-free survival, exacerbation, or mortality. To the best of our knowledge, this study provides the first multicenter longitudinal profiling of the circulating endothelial compartment in IPF. Our findings suggest that endothelial dysfunction reflects a chronic, possibly secondary process in IPF rather than a primary driver of fibrosis. Circulating endothelial biomarkers may offer insight into disease activity and therapeutic response.