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A5775 - Circulating Fibrocytes Predict Biomarkers of Immune Dysregulation and Fibrogenesis in a Genetic Interstitial Lung Disease
Author Block: S. M. Fortier1, M. D. Burdick2, T. C. Markello3, K. J. O'Brien4, W. A. Gahl3, B. R. Gochuico5, B. Mehrad6; 1University of Michigan Health System, Ann Arbor, MI, United States, 2Univ of Virginia, Charlottesville, VA, United States, 3National Human Genome Research Institute (NHGRI), Washington, DC, United States, 4National Human Genome Research Institute (NHGRI), Bethesda, MD, United States, 5Natl Inst of Hlth, Bethesda, MD, United States, 6Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, FL, United States.
Rationale: The development of pulmonary fibrosis characteristic of diffuse parenchymal lung diseases (DPLD) is thought to follow the paradigm of epithelial lung injury, followed by immune dysregulation that leads to fibrogenesis. Fibrocytes are a population of bone marrow-derived circulating progenitor cells that have been shown to home to the lungs and contribute to fibrosis in animal models. Prior studies have also shown that episodic elevations in circulating fibrocytes are strongly predictive of death in diffuse parenchymal lung diseases, suggesting a causal role for these cells in human disease. It is not known where fibrocytes fit into the paradigm of epithelial injury, immune dysregulation, and fibrogenesis. Hermansky-Pudlak syndrome type-1 (HPS-1) is a monogenic disease that uniformly leads to DPLD in early adulthood, and represents a unique opportunity to longitudinally study a group of individuals with an identical cause of DPLD who are at different stages of disease severity. Objectives: To test the hypothesis that concentrations of plasma biomarkers of lung epithelial injury, immune dysregulation and fibrogenesis correlate with levels of circulating fibrocytes longitudinally in subjects with HPS. Methods: A cohort of 32 subjects with HPS were followed longitudinally over a median 614 days. We assessed the longitudinal correlation of circulating fibrocytes with 20 plasma protein biomarkers. Fibrocyte levels were determined by flow cytometry and plasma proteins concentration was quantified by ELISA and multiplex assays. Correlations were assessed using Spearman and Pearson tests. Measurements and Main Results: Plasma concentration of 12 proteins showed a significant positive correlation with circulating fibrocyte counts (r value range 0.37-0.60). These included 9 markers of immune dysregulation (CCL2, CCL7, CCL8, CCL13, CCL18, CXCL8, CXCL12, CXCL13, GM-CSF) and 3 of fibrogenesis (VEGF, OPN, MMP1). In contrast, markers of epithelial injury (KL6 and SPD) did not correlate with circulating fibrocytes. These correlations were also observed among the subset of fibrocytes expressing the chemokine receptor CXCR4 and activated fibrocytes expressing the myofibroblast marker alpha-smooth muscle actin. The correlation was strongest among the 7 subjects who died during the follow-up period (r value range 0.78-0.99). Conclusions: Circulating levels of fibrocytes correlate with biomarkers of immune dysregulation and fibrogenesis, but not with markers of epithelial lung injury.