LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis

Jul 15, 2018Clinical science (London, England : 1979)

LTBP2 released by lung repair cells may be a marker for unexplained lung scarring

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Abstract

Serum LTBP2 concentrations in patients were significantly higher than in healthy volunteers, with a mean of 21.4 ng/ml compared to 12.4 ng/ml.

LTBP2 is associated with the differentiation of lung fibroblasts into , which is important in idiopathic pulmonary fibrosis (IPF).
The expression of LTBP2 was up-regulated in myofibroblasts from bleomycin-treated mouse lungs and human lung myofibroblasts induced by TGF-β1.
In IPF patients, LTBP2 staining was observed in the fibrotic interstitium and some αSMA-positive myofibroblasts.
Higher serum LTBP2 levels correlated negatively with lung function as measured by % predicted forced vital capacity.
LTBP2 could serve as a prognostic biomarker for predicting respiratory event-related mortality in IPF patients.

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Although differentiation of lung fibroblasts into α-smooth muscle actin (αSMA)-positive is important in the progression of (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, the gene encoding latent transforming growth factor-β (TGF-β) binding protein-2 (LTBP2), because of the signal similarity to, 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. Ltbp2Acta2

Key numbers

21.4 ng/ml

Serum LTBP2 Concentration Increase

Mean serum LTBP2 in patients compared to 12.4 ng/ml in healthy controls

-0.369

Negative Correlation with Lung Function

Correlation coefficient between serum LTBP2 and % predicted FVC in patients

1.040

Hazard Ratio for Death

Hazard ratio for death by respiratory events per 1 ng/ml increase in serum LTBP2

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LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis

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