Elsevier

Food and Chemical Toxicology

Volume 61, November 2013, Pages 240-247
Food and Chemical Toxicology

Biological importance of reactive oxygen species in relation to difficulties of treating pathologies involving oxidative stress by exogenous antioxidants

https://doi.org/10.1016/j.fct.2013.08.074Get rights and content

Highlights

  • Reactive oxygen species (ROS) are deleterious to essential biomacromolecules.

  • Yet, starting from life origin and evolution, ROS are involved in various physiological processes.

  • Many clinical trials failed to treat free-radical diseases by antioxidants likely due to affecting these critical processes.

  • A concept of positive signaling role of ROS, formed as a result of tissue injury, is discussed.

  • Undesired effects of ROS should be targeted exactly, at concrete sites of ROS production.

Abstract

Findings about involvement of reactive oxygen species (ROS) not only in defense processes, but also in a number of pathologies, stimulated discussion about their role in etiopathogenesis of various diseases. Yet questions regarding the role of ROS in tissue injury, whether ROS may serve as a common cause of different disorders or whether their uncontrolled production is just a manifestation of the processes involved, remain unexplained. Dogmatically, increased ROS formation is considered to be responsible for development of the so-called free-radical diseases. The present review discusses importance of ROS in various biological processes, including origin of life, evolution, genome plasticity, maintaining homeostasis and organism protection. This may be a reason why no significant benefit was found when exogenous antioxidants were used to treat free-radical diseases, even though their causality was primarily attributed to ROS. Here, we postulate that ROS unlikely play a causal role in tissue damage, but may readily be involved in signaling processes and as such in mediating tissue healing rather than injuring. This concept is thus in a contradiction to traditional understanding of ROS as deleterious agents. Nonetheless, under conditions of failing autoregulation, ROS may attack integral cellular components, cause cell death and deteriorate the evolving injury.

Introduction

Evidence from animal- and clinical-based studies about involvement of free oxygen radicals and reactive oxygen species (ROS) in a variety of pathologies prompted investigations on ROS in their etiology and pathogenesis. For several decades it was widely accepted that excessive ROS production is an underlying mechanism of particular tissue injuries (Fig. 1, black columns). Although mostly demonstrated under in vitro conditions, this concept was mainly substantiated by findings that ROS readily react with most biological macromolecules, causing their oxidative modification, which ultimately leads to the loss of their primary functions (Bartosz, 2009, Lenaz, 2012). Therefore, ROS started to be considered as one of the key players in tissue injury, which if occurring in a massive extent may result in organ dysfunction. Pathologies where ROS were identified as causal factors were then termed free-radical diseases. Disease states of this category comprise a heterogeneous group including adult respiratory distress syndrome, atherosclerosis, inflammation, rheumatoid arthritis and other autoimmune diseases, degenerative disorders associated with aging, diabetic complications, stress related injury, processes of mutagenesis and cancerogenesis, ischaemia-reperfusion injury, organ transplantation complications, etc. (Becker, 2004, Halliwell, 2007, Harman, 2003, Jaeschke, 2011, Reed, 2011, Venardos et al., 2007). Along these lines, in anticipation of beneficial effects, the use of exogenous antioxidants has been proposed as a treatment of choice for free radical diseases (Aboul-Enein et al., 2013, Apostolou et al., 2013, Jaeschke and Woolbright, 2012, Rodrigo et al., 2013, Stagos et al., 2012). However, antioxidants exerting protection of essential macromolecules in vitro often fail to do so in vivo.

Almost simultaneously questions started to be raised as to whether excess of ROS may indeed serve as a general mechanism underlying such a variety of diseases. More specifically, do oxidative modifications of essential macromolecules by ROS always lead to cell death and tissue injury? In fact, there were reports suggesting that ROS overproduction may be a consequence rather than a cause of tissue injury (Feinendegen, 2002, Halliwell, 1994, Halliwell, 2009). If the former holds, ROS could actually modulate processes in the affected tissue and/or serve as markers of its actual state. Indeed, an increasing number of reports highlight physiological functions of ROS, particularly their messenger and mediatory role in intracellular signaling and intercellular communication (Fig. 1, cross-hatched columns), i.e. mechanisms underlying homeostasis maintenance (Armogida et al., 2012, Halliwell et al., 2000, Nikitovic et al., 2013, Nair et al., 2007, Nisticò et al., 2008, Sarsour et al., 2009, Upham and Trosko, 2009, Zweier et al., 2011). To contribute to the understanding of the role of ROS in health and disease, the present review focuses on apparent paradoxes of ROS, and discusses controversial findings regarding effects of ROS. Special attention is paid to the difficulties encountered in treating oxidative stress-related disease by exogenous antioxidants.

Section snippets

Biological importance of ROS: role in emerging of life, evolution and biodiversity

Intriguing paradoxes regarding the involvement of free (oxygen) radicals, and ROS in processes of life emergence, evolution of higher forms of life and species diversity as well as in protecting vital functions of current aerobic organisms have been noted (Fig. 2).

ROS production, elimination and oxidative stress

Under physiological conditions, ROS are formed as by-products of basal cellular metabolism. It has been proposed that cellular respiration is regulated by ADP, O2 and NO preserving thus the notion that energy demands drive respiration but places the kinetic control of both respiration and energy supply in the availability of ADP to F1-ATPase and of O2 and NO to cytochrome oxidase. Indeed, for the regulation of the intramitochondrial steady state the concentration of NO itself and other reactive

ROS and cytosolic calcium in tissue injury

Involvement of ROS in tissue injuries developing during ischaemia–hypoxia events and subsequent reperfusion–reoxygenation has been widely established for many organs and systems (Jaeschke and Woolbright, 2012, Obrenovitch, 2008, Rodrigo et al., 2013). Mechanism of ROS generation by the xanthine oxidase-mediated process has been described in detail (Han et al., 2012). Briefly, mitochondrial respiration and oxidative phosphorylation and thus ATP synthesis are inhibited by a lack of oxygen.

Findings from experimental models

According to traditional free radical hypothesis, tissue injury evoked by ischaemia–reperfusion develops due to overproduction of ROS and their subsequent deleterious action towards essential cellular constituents (Cuzzocrea et al., 2001, Valko et al., 2007). Briefly, readily oxidizable fatty acids of phospholipid membranes are good targets for peroxidative attack of ROS, resulting in alterations of membrane permeability and fluidity. That in turn may cause dysfunction of membrane proteins,

Concluding remarks

Although the reaction of ROS with important cellular constituents may result in their degradation in vitro, mechanisms of ROS-mediated cytotoxicity in vivo are as yet not well understood. Free radical-mediated lipid peroxidation, protein oxidation and oxidative damage to nucleic acids are considered to be crucial events of the cytotoxic actions of ROS. Nonetheless, the most convincing evidence, i.e. unambiguous inhibition of free-radical diseases by pretreatment with antioxidants, is still

Conflict of Interest

The authors declare that there are no conflicts of interest.

Acknowledgement

The work was in part supported by the Slovak Scientific Grant Agency (VEGA Nos. 2/0011/11, 2/0048/11 & 2/0149/12).

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