Similarities And Differences Between Lung Ligands For Mouse Siglec-f And Human Siglec-8

S A T U R D A Y 185 Pro-fibrotic Effect Of Dexamethasone In Human Airway Fibroblasts W. Manuyakorn, D. Davies, P. Howarth; Faculty of Medicine, University of Southampton, Southampton, UNITED KINGDOM, Faculty of Medicine, Ramathobodi Hospital, Mahidol University, Bangkok, THAILAND. RATIONALE: Airway remodelling in asthma is characterized by deposition of extracellular matrix proteins (ECMs). Collagen is the most abundant ECMprotein in the airways and its cross-linking by lysyl oxidase (LOX) influences its strength and stability. Inhaled corticosteroids are the standard treatment for chronic asthma. We hypothesized that corticosteroids may have a role in regulating the production of LOX by fibroblasts from asthmatic airways. METHODS: Bronchial fibroblasts fromnormal or asthmatic subjectswere treated with dexamethasone in the presence and absence of TGFb2. LOX and collagen I mRNA expression was measured using RT-qPCR. The level of LOX in culture supernatants was measured using western blot analysis. RESULTS: TGFb2 significantly up-regulated collagen I mRNA expression. In contrast, dexamethasone had no effect on collagen I mRNA expression. TGFb2 also up-regulated LOX mRNA expression in fibroblasts from both healthy and asthmatic subjects (p50.002). In fibroblasts from asthmatic donors only, dexamethasone up-regulated LOX mRNA expression and had an additive effect with TGFb2 (p50.02). Both TGFb2 and dexamethasone enhanced the production of pro-LOX and active LOX in fibroblasts from normal or asthmatic donors (p50.03). CONCLUSIONS: TGFb2 and dexamethasone up-regulated LOX expression by bronchial fibroblasts with the potential for increased cross-linking of collagen in the airways. These findings suggest that apart from their immediate anti-inflammatory effects, corticosteroids may have a long term detrimental effect on collagencross-linking, affecting airwaywallmechanics. Should suchanactionbeevident invivo this couldhave adetrimental effect on decline in lung function and disease persistence in asthma.