Background Sarcoidosis is a systemic disease of unknown aetiology characterised by granuloma formation and the presence of interferon g (IFNg)-producing T cells that cause inflammation and tissue damage in multiple organs, especially the lung. Exosomes are nano-sized immunomodulatory vesicles of endosomal origin released from a diverse range of cells and are also found in physiological fluids including bronchoalveolar lavage fluid (BALF) from healthy individuals. Objective To investigate whether exosomes are enriched in the lungs of patients with sarcoidosis compared with healthy individuals and whether they could contribute to pathogenesis. Design BALF exosomes from patients with sarcoidosis (n¼36) and healthy controls (n¼14) were compared by electron microscopy, flow cytometry, western blot analysis and mass spectrometry. BALF exosomes were incubated with autologous peripheral blood mononuclear cells (PBMCs) or the human bronchial epithelial cell line 16HBE14o-. Cytokines were measured by ELISPOT and ELISA.

Background: Activated T helper (Th)-1 pulmonary CD4 + cells and their mediators are essential for the inflammation and granulomatous process in sarcoidosis. Recently, T-cell immunoglobulin and mucin domain (TIM) molecules were suggested to be important regulators of immune function. In this study, we wanted to investigate whether TIM molecules could play a role in sarcoidosis.

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The aim of this study was to compare the expression of different surface markers on T lymphocytes in bronchoalveolar lavage (BAL) fluid and blood in healthy subjects. Twenty healthy non−smoking individuals (13 males), mean age 27 years (18−46), were included in the study. We analysed T cell markers CD3, CD4, and CD8, activation markers CD69, CD25 and HLA−DR, the T regulatory cell (Treg) marker FOXP3 and the costimulatory marker CD28, cytotoxic marker CD57 and intraepithelial marker CD103. Whole blood (after lysis of red blood cells) and paired BAL cells were analysed by flow cytometry using an 8 color FACSCanto II (BD Biosciences, USA). Approximately 2.5x10 5 cells were analysed in each sample.Results: The CD4/CD8 ratio was similar in both compartments (median 2.2 vs 2.0, n.s.). The percentage of CD4 + cells expressing FOXP3 was significantly higher in BAL compared to blood (median 8.0 % vs 2.4 %, p< 0.0001). The frequencies of CD4 + cells expressing the activation markers CD69 and HLA−DR, as well as CD57 and CD103 were also significantly higher in BAL fluid compared to blood, and similar results applied to CD8 + cells. In contrast, the expression of the costimulatory molecule CD28 was significantly reduced in BAL cells.

2Corresponding author's email: abraham.roos@ki.se RATIONALE: Smokers with COPD exhibit decreased activity of airway epithelial-C/EBPβ compared to healthy smokers (Didon et al. Chest 2005;127:1341). Here, we investigated the role of lung epithelial-C/EBPβ in LPS-induced inflammation and in the effects of a in vivo glucocorticoid, budesonide (BUD), and a long acting β -agonist, formoterol (FM), either alone or in combination. 2 METHODS: Wild-type mice and mice with a lung epithelial-specific deletion of C/EBPβ ( ), injected with BUD and/or FM, both 3 Cebpb ΔLE mg/kg, were challenged with aerosolized LPS after 1 h. Inflammatory cells in bronchoalveolar lavage fluid Pseudomonas aeruginosa (BALF), lung tissue mRNA of inflammatory genes (TNFα, IL-1β, IL-6, GM-CSF, GROα, MIP-2, and COX-2), an anti-inflammatory gene (IκB) and host-defense genes (SAA3, CC16 and SP-A) were analyzed 5 h after LPS-challenge.RESULTS: LPS-induced inflammation was significantly blunted in mice, resulting in 65% fewer neutrophils and 70%, 30% and Cebpb ΔLE 17% lower expression of GROα, IL-6 and COX-2, respectively. The 41% suppression of total BALF cells by BUD (p<0.05) and the 79% suppression of neutrophils by FM (p<0.01) in wild-type mice were lost in mice, whereas the 70% suppression of total BALF cells Cebpb ΔLE (p<0.05) and nearly complete suppression of neutrophils (p<0.01) by BUD+FM combination were retained. The significant suppression of LPS-induced inflammatory genes by FM (from 40% to 53%) in wild-type mice, were lost in mice, whereas the significant Cebpb ΔLE suppressive effects of BUD (from 60% to 93%) and similar effects of BUD+FM were mostly preserved. The LPS-induced mRNA expression of the NFκB inhibitor, IκB, was reduced 41% by BUD (p<0.05) in mice but spared by BUD+FM. Furthermore, expression of the Cebpb ΔLE host-defense gene SAA3 was increased approximately 2-fold by either FM (p<0.05) or BUD (p<0.1) in wild-type mice, while rather decreased in mice but preserved by BUD+FM treatment. The expression of anti-inflammatory host-defense gene CC16 was not Cebpb ΔLE affected by either drug alone in any type of mice but was increased 1.2-fold (p<0.01) by BUD+FM in wild-type mice. The LPS-induced SP-A expression was significantly reduced 23% by FM but spared by BUD±FM in both types of mice. CONCLUSIONS: These results demonstrate an essential role of lung epithelial-C/EBPβ expression in the inflammatory response to LPS in and in the anti-inflammatory effects of BUD and FM. Importantly, in the absence of C/EBPβ, when some anti-inflammatory effects of vivo either BUD or FM are lost, the anti-inflammatory efficacy of BUD+FM combination is largely preserved and host-defense remains intact or is stimulated. This abstract is funded by: Swedish Heart-lung foundation, Astra-Zeneca

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