CCTα and GVI iPLA2-induced aberrant phosphatidylcholine metabolism contributes to pulmonary inflammation and fibrosis.

To date, no comprehensive profiling of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) with pulmonary inflammation and fibrosis has been published. Our study aimed to analyze PC and LPC metabolism with the development and persistence of pulmonary inflammation and the progression to fibrosis; and their relationship. Mice and cell models exposed to bleomycin and/or transforming growth factor-β1 (TGF-β1) were developed; and porcine surrogates for pulmonary fibrosis were included. Histopathological, immunofluorescence and immunohistochemical staining, transmission electron microscopy, colorimetric, activity and immune complex (IC) assay, lipidomics analysis; and pharmacological intervention assay were used to analyze PC and LPC profile, pulmonary fibrosis and their relationship. Current evidence suggests that 16:0 20:5 PC is a conserved biomarker; and 16:0 18:1 PC, 16:0 18:2 PC; and 16:0 LPC are the potential targets for this disease. Specifically, 16:0 18:1 PC accumulation and exogenous treatment affected lung cell recruitment, migration, transformation, cross-talk, survival/death; and enhanced profibrotic factor release, IC and extracellular matrix (ECM) deposition, where CTP:phosphocholine cytidylyltransferase α (CCTα) and group VI Ca-independent phospholipase A2 (GVI iPLA2) play an important role, particularly in lung and spleen neutrophils, macrophages, and T lymphocytes. Overall, these results provide new insights into how the dysregulated PC metabolism, particularly for 16:0 18:1 PC, affects the development and persistence of lung inflammation and the progression to fibrosis, and thus may facilitate the discovery of biomarkers and targets for this disease.