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Background: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare idiopathic interstitial pneumonia characterized by an upper lobe-dominant interstitial increase in predominantly elastic fibers. The accumulation of cases has resulted in a refinement of the disease concept, but there are no blood biomarkers to aid in the diagnosis or prediction of a progressive phenotype among PPFE patients. Several organizers, including latent transforming growth factor-β binding protein 4 (LTBP-4), are known to be involved in elastogenesis. However, the potential of LTBP-4 as a blood biomarker for PPFE has not been investigated., Methods: We selected cases of clinically or histologically diagnosed IPPFE (n = 20) along with idiopathic pulmonary fibrosis (IPF) patients (n = 39) and healthy controls (n = 10). We quantified the protein levels of LTBP-4 in lung tissues and serum samples., Results: The LTBP-4 levels in lung tissue of PPFE patients were 2.16 times higher than those of IPF patients (p = 0.032). The serum concentration of LTBP-4 (pg/ml) in IPPFE was higher than that in healthy controls (1429 [154-3620] vs. 187 [56.4-490], p = 0.013). The serum concentration of LTBP-4 in IPPFE was markedly higher than that in IPF without a significant difference (1429 [154-3620] vs. 915 [491-1967], p = 0.671). In addition, a higher concentration of LTBP-4 was associated with a poor prognosis in IPPFE patients., Conclusions: The serum concentration of LTBP-4 may aid in the diagnosis of IPPFE or the prediction of an aggressive phenotype., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Although differentiation of lung fibroblasts into α-smooth muscle actin (αSMA)-positive myofibroblasts is important in the progression of idiopathic pulmonary fibrosis (IPF), few biomarkers reflecting the fibrotic process have been discovered. We performed microarray analyses between FACS-sorted steady-state fibroblasts (lineage (CD45, TER-119, CD324, CD31, LYVE-1, and CD146)-negative and PDGFRα-positive cells) from untreated mouse lungs and myofibroblasts (lineage-negative, Sca-1-negative, and CD49e-positive cells) from bleomycin-treated mouse lungs. Amongst several genes up-regulated in the FACS-sorted myofibroblasts, we focussed on Ltbp2 , the gene encoding latent transforming growth factor-β (TGF-β) binding protein-2 (LTBP2), because of the signal similarity to Acta2 , which encodes αSMA, in the clustering analysis. The up-regulation was reproduced at the mRNA and protein levels in human lung myofibroblasts induced by TGF-β1. LTBP2 staining in IPF lungs was broadly positive in the fibrotic interstitium, mainly as an extracellular matrix (ECM) protein; however, some of the αSMA-positive myofibroblasts were also stained. Serum LTBP2 concentrations, evaluated using ELISA, in IPF patients were significantly higher than those in healthy volunteers (mean: 21.4 compared with 12.4 ng/ml) and showed a negative correlation with % predicted forced vital capacity (r = -0.369). The Cox hazard model demonstrated that serum LTBP2 could predict the prognosis of IPF patients (hazard ratio for death by respiratory events: 1.040, 95% confidence interval: 1.026-1.054), which was validated using the bootstrap method with 1000-fold replication. LTBP2 is a potential prognostic blood biomarker that may reflect the level of differentiation of lung fibroblasts into myofibroblasts in IPF., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)