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Pathophysiological Roles of Reactive Oxygen and Nitrogen Species

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Systems Biology of Free Radicals and Antioxidants

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive molecules that are implicated in both normal and abnormal cellular processes. ROS and RNS are produced during normal cellular metabolism via diverse enzymatic pathways, but excessive production can occur in response to such stressors as toxicant exposure, radiation damage, and disease, resulting in local oxidative stress. These high levels of ROS/RNS induce a complex series of downstream adaptive and reparative events often associated with inflammation and fluid accumulation. Examples of ROS include peroxides and free oxygen ions generated during the normal metabolism of oxygen. Similarly, RNS such as nitric oxide (NO), peroxynitrite, and nitrogen dioxide are generated via the activity of enzymes such as inducible nitric oxide synthase 2 (NOS2) and NADPH oxidase (NOX).

One of the main sources of ROS is the mitochondria where ROS superoxides are produced as a by-product of normal oxidative phophorylation; excess superoxide leaking into the cytoplasm can be converted into further ROS, whereas reactivity with NO generates peroxynitrite and further downstream nitrogen species. Here we review the main intracellular pathways and extracellular pathways involved in ROS and RNS signaling and the consequential damage to DNA, proteins, and lipids. Key mechanisms such as antioxidant defense and redox sensors are considered along with the key regulating kinases and transcription factors such as PI3K and NFkB. The roles of ROS and RNS in aging and associated diseases such as COPD, asthma, and neurodegeneration are discussed in detail along with an analysis of probable mechanisms. Finally, we consider future challenges such as how do ROS and RNS interact at multiple places within signaling networks and how do we understand and predict likely outcome? Also, how do ROS/RNS activate key molecules such as JNK and p38 MAPK and cell cycle genes? More detailed knowledge of these interactions may provide opportunities for future lifestyle advice and therapeutic intervention.

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Acknowledgments

The authors wish to thank Richard Jackson for his bioinformatics expertise used to generate Fig. 8.4.

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  1. Global Safety Assessment, AstraZeneca R and D, Alderley Park, Macclesfield, UK

    Joanne Kilgour & Ruth Roberts

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  1. Joanne Kilgour
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  1. Department of Pharmacology and Therapeutics, University of British Colombia, Vancouver, British Columbia, Canada

    Ismail Laher

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Kilgour, J., Roberts, R. (2014). Pathophysiological Roles of Reactive Oxygen and Nitrogen Species. In: Laher, I. (eds) Systems Biology of Free Radicals and Antioxidants. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30018-9_10

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