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A2202 - Overexpression of V-ATPase B2 Prevent Bleomycin Induced Lung Injury/Fibrosis by Attenuate Lysosomal Membrane Permeabilization(LMP) And Increasing Collagen Degradation
Author Block: S. Park, M. Kim, A. Baek, J. Lee, A. Jang, D. Kim, C. Park; Soonchunhyang University Bucheon Hospital, bucheon, Korea, Republic of.
RATIONALE : Excessive oxidative stress cause lysosomal membrane permeabilization (LMP) that lead to cell death. Vacuolar ATPase(V-ATPase) is the enzyme responsible for pumping H+ into cytosol, that maintain intracellular PH. We had reported that V-ATPase B2 subunit expression is upregulated in TiO2 nanoparticle exposed alveolar epithelial cells. We investigated the role of lysosomal V-ATPase B2 subunit in the H2O2 induced cell death in alveolar epithelial cells and following acute lung injury/fibrosis mouse model. METHODS: Transgenic human V-ATPase B2 mice(V-ATPase B2 TG) were treated to bleomycin. Histological examinations, collagen assay and cytokine measurements were performed. Apoptosis, lysosomal functions and collagen uptake/degradation activates were evaluated in the V-ATPase B2 overexpressing and knock down stable cells. RESULTS: V-Atpase B2 overexpression cells increased survival of H2O2 induced apoptosis and diminished LMP by oxidative stress. Overexpression of V-Atpase B2 increased lysosomal activities, increased cellular PH, and lysosomal degradation activity against H2O2. In contrast, silencing of V-ATPase B2 subunits dramatically increased H2O2 induced cell death by increasing LMP. V-atpase B2 overexpressing macrophagy significantly enhanced up take and degradation of collagen. V-atpase B2 overexprssing transgenic mice showed significantly inhibit bleomycin induced increased lung inflammation and fibrosis. CONCLUSIONS: V-ATPase B2 is critical for maintain lysosomal activities against excessive oxidative stress. Our finding revealed a previously unrealized role of V-ATPase subunit in lung injury/fibrosis model. Grant : 2016R1E1A1A01943481