Background:Systemic sclerosis-related interstitial lung disease (SSc-ILD) involves a combination of inflammation, fibrosis and vascular pathology that is typically assessed on CT imaging as a mixture of ground-glass opacification (GGO) and fibrotic changes. We hypothesized that proteins recovered from bronchoalveolar lavage (BAL) could be used to probe the underlying pathobiology associated with GGO and fibrotic changes.Objectives:(1) To assess the relationship between 68 unique BAL proteins measured in participants of Scleroderma Lung Study (SLS) I1and radiographic and physiologic measures of ILD; (2) To identify inter-correlations among specific proteins to enlighten our understanding of how specific biological pathways contribute to SSc-ILD.Methods:Bronchoscopy was performed on 144 of the 158 participants in SLS I with 103 BAL samples available for analysis. BAL was lyophilized, concentrated 10X and used in a multiplex protein analysis for 68 different cytokines, chemokines and other factors. Kendall tau correlations were performed to assess the relationship between individual proteins and baseline measures of pulmonary function and quantitative CT scores for fibrosis, GGO and total ILD. Those proteins found to correlate significantly with at least 2 clinical measures of ILD were entered into a cluster analysis with inter-correlations expressed as a heatmap.Results:Significant correlations were observed between fibrosis scores and several biologic pathways including pro-fibrotic factors (transforming growth factor beta [TGF-β], platelet-derived growth factor [PDGF]), proteins involved in tissue remodeling (Matrix metallopeptidase [MMP]-1,7,8,9; Hepatocyte growth factor [HGF]), and those involved in monocyte/macrophage migration and activation (Monocyte chemoattractant protein [MCP]-1,3; macrophage colony-stimulating factor [MCSF]). These same pathways correlated with the diffusing capacity for carbon monoxide (DLCO). In contrast, GGO scores correlated primarily with immune and inflammatory mediators (interleukin [IL]-5,8,13,15, IL-1 receptor antagonist and interferon gamma) with only limited overlap to proteins that related to fibrosis. Vascular endothelial growth factor (VEGF) levels were lower in patients with more extensive GGO, fibrosis and diffusion impairment, suggesting that vascular changes are a central feature of SSc-ILD. Specific proteins were highly correlated with one another in a pattern suggesting biologically-related networks (Figure) that might provide additional insight regarding disease pathogenesis.Conclusion:Combining a diverse analysis of BAL proteins with the rich dataset available from SSc-ILD patients participating in SLS I, the study findings suggest the involvement of distinct biologic pathways, inter-related networks, and specific biologic signatures associated with unique radiographic features of ILD. The relationship of these factors to other SSc disease features, patient outcomes and as predictors of treatment responses will be studied in future analyses.References:[1]Tashkin DP, et al. NEJM 2006.Figure.Correlation heatmap of BAL proteins associated with at least 2 clinical measures of ILD in SSc patients. Absolute correlations are depicted, and darker colors signify stronger correlations.Disclosure of Interests:Elizabeth Volkmann Grant/research support from: Forbius, Corbus Pharmaceuticals, Consultant of: Boehringer Ingelheim, Forbius, Speakers bureau: Boehringer Ingelheim, Donald Tashkin: None declared, Ning Li: None declared, Grace Kim: None declared, Jonathan Goldin: None declared, Airi Harui: None declared, Michael Roth Grant/research support from: Genentech/Roche
The relationship between ras protein and odontogenic lesions
