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?-Thymosins and interstitial lung disease: study of a scleroderma cohort with a one-year follow-up.

ABSTRACT: BACKGROUND: ?-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins ?4, ?4 sulfoxide, and ?10 in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters. METHODS: ?-thymosins concentrations were determined by reverse phase-high performance liquid chromatography-electrospray-mass spectrometry in the bronchoalveolar lavage fluid of 46 scleroderma patients with lung involvement and of 15 controls. RESULTS: Thymosin ?4, ?4 sulfoxide, and ?10 were detectable in bronchoalveolar lavage fluid of patients and controls. Thymosin ?4 levels were significantly higher in scleroderma patients than in controls. In addition, analyzing the progression of scleroderma lung disease at one-year follow-up, we have found that higher thymosin ?4 levels seem to have a protective role against lung tissue damage. Thymosin ?4 sulfoxide levels were higher in the smokers and in the scleroderma patients with alveolitis. CONCLUSIONS: We describe for the first time ?-thymosins in bronchoalveolar lavage fluid and their possible involvement in the pathogenesis of scleroderma lung disease. Thymosin ?4 seems to have a protective role against lung tissue damage, while its oxidation product mirrors an alveolar inflammatory status.

SUBMITTER: De Santis M

PROVIDER: S-EPMC3045324 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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β-Thymosins and interstitial lung disease: study of a scleroderma cohort with a one-year follow-up.

De Santis Maria M Inzitari Rosanna R Bosello Silvia L SL Peluso Giusy G Fanali Chiara C Iavarone Federica F Zizzo Gaetano G Bocci Mario M Cabras Tiziana T Messana Irene I Fuso Leo L Varone Francesco F Pagliari Gabriella G Castagnola Massimo M Ferraccioli Gianfranco G

Respiratory research 20110211

<h4>Background</h4>β-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins β4, β4 sulfoxide, and β10 in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters.<h4>Methods</h4>β-thymosins con ...[more]

PMID: 21314931

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Project description:Patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) are thought to have the greatest decline in lung function (forced vital capacity [FVC]% predicted) in the early years after disease onset. The aim of this study was to assess the natural history of the decline in FVC% predicted in patients receiving placebo in the Scleroderma Lung Study and to evaluate possible factors for cohort enrichment in future therapeutic trials.Patients randomized to receive placebo (n=79) were divided into 3 groups based on the duration of SSc (0-2 years, 2-4 years, and >4 years). Descriptive statistics and a mixed-effects model were used to analyze the rate of decline in the FVC% predicted over a 1-year period. Additional analyses stratified according to the severity of fibrosis on high-resolution computed tomography (HRCT) were performed, and interactions between disease severity and disease duration were explored.The mean±SD decline in the unadjusted FVC% predicted during the 1-year period was 4.2±12.8%. At baseline, 28.5%, 43.0%, and 28.5% of patients were in the groups with disease durations of 0-2 years, 2-4 years, and >4 years, respectively. The rate of decline in the FVC% predicted was not significantly different across the 3 disease groups (P=0.85). When stratified by baseline fibrosis on HRCT, the rate of decline in the FVC% predicted was statistically significantly greater in the group with severe fibrosis (mean annualized decline in the FVC% predicted 7.2% versus 2.7% in the groups with no or moderate fibrosis; P=0.008). The decline observed in the group with severe fibrosis was most pronounced in those with a relatively short disease duration (0-2 years; annualized decline 7.0%).Among patients with SSc-ILD in the Scleroderma Lung Study, the rates of progression of lung disease were similar irrespective of disease duration. The baseline HRCT fibrosis score is a predictor of a future decline in the FVC% predicted in the absence of effective treatment.

Project description:Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n?=?503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), pcorr?=?0.015) and rs10488631 (OR 1.48 (1.14-1.92), pcorr?=?0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), pcorr?=?0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), pcorr?=?0.0098), and rs2004640 (OR 1.39 (1.11-1.75), pcorr?=?0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), pcorr?=?6.6?×?10-6). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), pcorr?=?0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.

Dataset Information

?-Thymosins and interstitial lung disease: study of a scleroderma cohort with a one-year follow-up.

Publications

β-Thymosins and interstitial lung disease: study of a scleroderma cohort with a one-year follow-up.

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