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Initiating Oxidative Events Induced by Particulate Matter Component 1,2-Naphthoquinone in Human Airway Cells
Başlık:
Initiating Oxidative Events Induced by Particulate Matter Component 1,2-Naphthoquinone in Human Airway Cells
Yazar:
Lavrich, Katelyn Susan, author.
ISBN:
9780438033962
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (171 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: James M. Samet Committee members: Rebecca C. Fry; Avram Gold; Steven O. Simmons; Mirek Styblo; Zhenfa Zhang.
Özet:
Over three million premature deaths are caused by ambient Particulate Matter (PM) worldwide each year, rendering it one of the deadliest environmental public health problems. Oxidative stress has been frequently cited as an initiating mechanism of PM-induced health effects, but has not been well-characterized. There is a growing awareness that oxidative events, particularly those resulting in perturbation of mitochondrial function and hydrogen peroxide levels, play a vital role in cellular health and function. Here, we sought to investigate the effect of the ubiquitous PM component, 1,2-naphthoquinone (1,2-NQ), on specific oxidative events in human airway cells. First, I show that 1,2-NQ increases hydrogen peroxide production through both non-mitochondrial redox cycling and inhibition of mitochondrial processes in human bronchial epithelial cells. This was the first time PM-associated quinones have been shown to disrupt mitochondrial substrate oxidation processes. I next expanded our model to characterize bioenergetics in primary human lung macrophages. 1,2-NQ caused similar mitochondrial dysfunction in human lung macrophages. This is the first report utilizing extracellular flux analysis in primary human lung macrophages, allowing us to identify distinct subpopulations of macrophages based on anatomical location in the lung. We also observed novel mechanisms of inflammatory activation that did not require metabolic reprogramming. Lastly, I showed that 1,2-NQ induced glycolytic inhibition through peroxide-mediated mechanisms, the first time that an environmentally relevant exposure has been shown to modify protein function through sulfenylation. I adapted novel technology developed originally in the redox biology field, bridging the gap to make these technologies accessible to toxicologists. Ultimately, the work here highlights the central role of bioenergetic function both as an initiator and target of oxidative stress mechanisms and provides a basis to utilize bioenergetic measurements in a translational setting as a biomarker of PM-induced adverse cellular responses. In summary, this work identifies novel molecular mechanisms of PM-induced health effects to better our understanding and ideally improve public health through effective policy.
Notlar:
School code: 0153
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
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XX(678925.1) | 678925-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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