176 - Mitochondrial UCP2 in Age-Related Lung Fibrosis

Abstract

Background Rationale: Idiopathic pulmonary fibrosis (IPF) is an age-related disease with inexorable progression and limited therapeutic options. Mitochondrial dysfunction, a hallmark of aging, is known to result in altered bioenergetics and excessive production of reactive oxygen species (ROS). Mitochondrial uncoupling protein-2 (UCP2) is purported to play a role in redox and bioenergetic homeostasis. In this study, we examined the potential role of UCP2 in modulating lung fibrosis. Methods We performed our studies on tissues and fibroblasts obtained from lung explants of patients with IPF undergoing transplant. We utilized in vivo murine model of lung fibrosis and resolution following bleomycin-induced lung injury. We used siRNA for silencing UCP2 in all in vitro and in vivo studies. Analytic techniques included RT-PCR, SDS-PAGE western blotting, immunofluorescence, flow cytometry and extracellular flux analysis. Results UCP2 expression was increased in lung fibroblasts of IPF patients with rapidly progressive clinical course compared to those with slower course. UCP2 expression was also increased in human lung fibroblasts with replicative senescence. UCP2 silencing in IPF fibroblasts in vitro led to a decrease in mitochondrial ROS, and decreased expression of senescence markers and of pro-fibrotic markers such as collagen 1a1, α-SMA and fibronectin. In bleomycin-treated aged mice, airway administration of UCP2 siRNA after peak fibrogenesis decreased tissue collagen, with resultant improved lung architecture. Conclusion Our results indicate that high levels of mitochondrial UCP2 are seen in senescence and in rapidly progressive IPF. Further studies are warranted to elucidate the relationship between high levels of UCP2, mitochondrial dysfunction, senescence and aging, and the therapeutic potential of targeting UCP2 in age-related fibrotic disorders such as IPF. Funding NIH grants, P01 HL114470, R01 AG046210