Free radicals and related reactive species as mediators of tissue injury and disease: implications for Health

Abstract

A radical is any molecule that contains one or more unpaired electrons. Radicals are normal products of many metabolic pathways. Some exist in a controlled (caged) form as they perform essential functions. Others exist in a free form and interact with various tissue components. Such interactions can cause both acute and chronic dysfunction, but can also provide essential control of redox regulated signaling pathways. The potential roles of endogenous or xenobiotic-derived free radicals in several human pathologies have stimulated extensive research linking the toxicity of numerous xenobiotics and disease processes to a free radical mechanism. In recent years, improvements in analytical methodologies, as well as the realization that subtle effects induced by free radicals and oxidants are important in modulating cellular signaling, have greatly improved our understanding of the roles of these reactive species in toxic mechanisms and disease processes. However, because free radical-mediated changes are pervasive, and a consequence as well as a cause of injury, whether such species are a major cause of tissue injury and human disease remains unclear. This concern is supported by the fact that the bulk of antioxidant defenses are enzymatic and the findings of numerous studies showing that exogenously administered small molecule antioxidants are unable to affect the course of most toxicities and diseases purported to have a free radical mechanism. This review discusses cellular sources of various radical species and their reactions with vital cellular constituents, and provides examples of selected disease processes that may have a free radical component.

Keywords:

• Antioxidants
• autoxidation
• cell signaling
• free radicals
• mitochondria
• oxidative stress
• reactive oxygen species
• redox cycling

Acknowledgements

The authors thank Helmut Sies for helpful comments. We also extend our thanks to the three reviewers who provided exceptionally helpful comments that were used to improve the manuscript.

Declaration of interest

The affiliation of the authors is as shown on the cover page. Both authors are employed by academic institutions and have been throughout their careers. The manuscript was prepared during the normal course of their employment without outside financial support for this particular work. Over 95% of the authors’ research on free radicals has been supported by public funds. They have not received any personal compensation from any private entities with a commercial interest in free radicals. Over the past 10 years, neither author has been engaged in any legal or regulatory proceedings concerning free radicals other than as an independent expert for federal agencies. This work product was conceptualized by the authors and represents an independent professional evaluation of the literature. The conclusions drawn are exclusively those of the authors.