Accumulation of intracellular damage by reactive oxygen species accelerates biological aging, leading to the development of age-related lung diseases such as idiopathic pulmonary fibrosis (IPF). Mitochondrial dysfunction and mitochondria-related oxidative stress has been implicated in the pathogenesis of many age-related diseases. Selective autophagic degradation of mitochondria (mitophagy) is critical to maintain a proper pool of the organelle and preserve cellular energy homeostasis. Oxidative stress resulting from age-dependent defects in the quality of proteins and degradation of mitochondria promotes alveolar epithelial cell damage potentiating lung injury. Our research found diminished autophagy corresponding with elevated levels of oxidized proteins and lipofuscin in response to lung injury in old and middle-aged mice compared to younger animals. More importantly, older mice exposed to lung injury are characterized by deficient mitophagic responses. The pro-fibrotic cytokine transforming growth factor beta 1 (TGFβ1) plays a pivotal role in driving fibroblast-to-myofibroblast differentiation (FMD), an important feature of pulmonary fibrosis. TGFβ1-mediated FMD is characterized by reduced autophagy flux, altered mitophagy and defects in mitochondrial function. In accordance, PINK1 expression is reduced in the aging murine lung and biopsies from IPF patients compared to controls. "nOur research also revealed a decline in mitochondrial protein deacetylase sirtuin 3 (SIRT3) expression in the lungs of aging mice. Low levels of SIRT3 transcripts were observed in two different animal models of pulmonary fibrosis. SIRT3 expression was reduced in fibrotic regions of lung tissues from patients with fibrotic diseases. We demonstrated that down-regulation of SIRT3 by TGFβ1 promotes acetylation of major oxidative stress response regulators, such as superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2), and that resveratrol induced SIRT3 expression and ameliorated acetylation changes induced by TGFβ1. Knockdown of SIRT3 expression by siRNA exacerbated TGFβ1-induced FMD. By contrast, promotion of SIRT3 expression attenuated the effect of TGFβ1 on myofibroblast differentiation. Finally, SIRT3-deficient mice were more susceptible to pulmonary fibrosis in response to bleomycin and had increased collagen deposition compared to control mice. Collectively, our research indicates that an age-related decline in autophagy, SIRT3 expression, and mitochondrial homeostasis may contribute to the promotion and/or perpetuation of pulmonary fibrosis. / Meredith L Sosulski
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_50343 |
| Date | January 2016 |
| Contributors | Sosulski, Meredith L. (author), Sanchez, Cecilia (Thesis advisor), School of Medicine Biomedical Sciences Graduate Program (Degree granting institution) |
| Source Sets | Tulane University |
| Detected Language | English |
| Type | Text |
| Format | electronic |
| Rights | Embargo |
Page generated in 0.0019 seconds