Scleroderma lung disease and β-thymosins:bronchoalveolar lavage fluid biomarkers

Objective. The role of β-thymosins (Tβ4, Tβ4 sulfoxide [sTβ4], Tβ10) in cytoscheleton rearrangement, angiogenesis, fibrosis and reparative process suggests a possible involvement of these peptides in the pathogenesis of systemic sclerosis (SSc). The aims of the study were to demonstrate the presence of Tβ4, sTβ4 and Tβ10 in bronchoalveolar lavage fluid (BALF) of SSc patients with interstitial lung disease (ILD) and to correlate their levels with the biologic, functional and radiological parameters of the lung involvement and to the progression of ILD. Considering the role of β-thymosins in the angiogenetic process and in modulation of vascular endothelial growth factor (VEGF) production, also the VEGF BAL levels were investigated. Patients and Methods. Tβ4, sTβ4, Tβ10 were determined by HPLC-ESI-MS in BALF samples of 46 SSc patients with ILD and of 15 control subjects. VEGF levels were evaluated by ELISA. Results. Tβ4 levels were significantly higher in SSc patients than in controls (SSc: 0.310 +/- 0.372 µmol/L vs controls: 0.112 +/- 0.084 µmol/L, p=0.008). Nevertheless, lower BALF Tβ4 levels were found in the SSc patients with significantly worsening in the alveolar score on HRCT after one-year follow-up. In SSc cohort, patients with alveolitis presented higher BAL levels of sTβ4 (0.025 +/- 0.052 µmol/L) than SSc patient without alveolitis (0.006 +/- 0.022 µmol/L), p=0.05. Higher sTβ4 BALF levels correlated with the smoking habits, the presence of alveolitis, the BALF neutrophil percentage count, an inverted BALF CD4/CD8 ratio, and a lower forced vital capacity. Tβ10 levels directly correlated with the BALF lymphocyte percentage count and inversely with the carbon monoxide diffusing capacity. Furthermore SSc patients presented lower BAL VEGF levels compared to controls, principally the SSc patients with alveolitis. Conclusion. In this study for the first time the presence of Tβ4, its sulfoxide form and Tβ10 in human BALF has been described and the results suggested the possible involvement of these paracrine factors in the pathogenesis of scleroderma lung disease. As described in other studies, Tβ4 seems to have a protective role against tissue damage even in SSc lung disease and its oxidation product sTβ4 seems to mirror the presence of an inflammatory condition. The correlation between Tβ10 and DLCO suggests an inhibitory role of Tβ10 in the alveolar capillary permeability, while the inverse correlation between VEGF levels and sTβ4 levels implies a opposite role of these two molecules.