Review article
Redox and oxidant-mediated regulation of apoptosis signaling pathways: immuno-pharmaco-redox conception of oxidative siege versus cell death commitment

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Abstract

The mechanisms controlling apoptosis remain largely obscure. Because apoptosis is an integral part of the developmental program and is frequently the end-result of a temporal course of cellular events, it is referred to as programmed cell death. While there is considerable variation in the signals and requisite cellular metabolic events necessary to induce apoptosis in diverse cell types, the morphological features associated with apoptosis are highly conserved. Free radicals, particularly reactive oxygen species (ROS), have been proposed as common mediators for apoptosis. Many agents that induce apoptosis are either oxidants or stimulators of cellular oxidative metabolism. Conversely, many inhibitors of apoptosis have antioxidant activities or enhance cellular antioxidant defenses. Mammalian cells, therefore, exist in a state of oxidative siege in which survival requires an optimum balance of oxidants and antioxidants. The respiratory tract is subjected to a variety of environmental stresses, including oxidizing agents, particulates and airborne microorganisms that, together, may injure structural and functional lung components and thereby jeopardize the primary lung function of gas exchange. To cope with this challenge, the lung has developed elaborate defense mechanisms that include inflammatory-immune pathways as well as efficient antioxidant defense systems. In the absence of adequate antioxidant defenses, the damage produced is detected by the cell leading to the activation of genes responsible for the regulation of apoptosis, conceivably through stress-responsive transcription factors. Oxidative stress, in addition, may cause a shift in cellular redox state, which thereby modifies the nature of the stimulatory signal and which results in cell death as opposed to proliferation. ROS/redox modifications, therefore, may disrupt signal transduction pathways, can be perceived as abnormal and, under some conditions, may trigger apoptosis.

Introduction

The regulation of programmed cell death, or apoptosis, can be considered as one mechanism, which is closely associated with cell development and another, which is involved in maintaining cell integrity and homeostasis. The asynchronous nature of cell death is attributed to variable duration and timing of events and the actual propagation of the apoptotic process. The multi-faceted complexity by which apoptosis is controlled requires the coordinated regulation of signaling cofactors, transcription factors and the presence of an extracellular motivation, which is represented by the effect of stimuli such as reactive oxygen and nitrogen species [1], [2], [3], [4], [5]. The airway epithelium has versatile roles that are key components of the mechanisms which help maintain and perpetuate the integrity and welfare of this delicate tissue of the lung. The integrity of the airway epithelium is particularly reinforced by a tightly regulated equilibrium existing between cell proliferation/differentiation and degeneration (apoptosis). This review summarizes our recent understanding of the mechanisms that regulate programmed cell death in physiologic and pathologic conditions, while focusing on elaborating pharmaco-redox concepts underlying pathways of redox/oxygen signaling mediating apoptosis.

Section snippets

Biochemical and biophysical properties that characterize the airway epithelium

Apoptosis, or programmed cell death (also referred to as an ‘orderly cell deletion’), is a genetically controlled mechanism involved in development, maturation and homeostasis [1], [2], [3], [4], [5]. The term ‘apoptosis’ is often used interchangeably with ‘programmed cell death’. In the strictest sense, programmed cell death may be applied to other forms of cell death that require gene expression without fulfilling some, or all, of the morphological criteria of apoptosis. Whatever the

Cell death regulation: the immunopharmacologic paradigm of necrosis versus apoptosis

In the last few decades, since the term ‘apoptosis’ was coined [33], [34], a vast quantity of work has been performed in search of the cause of the phenomenon it originally alluded to. It became clear, however, that some cells are genetically programmed, or destined, for death during the normal development of multi-cellular organisms [35]. The general apoptotic model today is one of intercellular signaling molecules operating in intracellular effector systems that balance each individual cell's

Redox dynamic equilibrium as determined by the glutathione/glutathione disulfide couple

‘Reduction-oxidation’ (redox) state is a term often widely adopted in the burgeoning field of free radical research and oxidative stress [29], [30], [43], [44]. The major determinant of redox status in mammalian cells is glutathione (GSH; l-γ-glutamyl-l-cysteinyl-glycine), a tripeptide thiol that couples with its disulfide form (GSSG) as a redox buffer system (2GSH/GSSG; GSSG+2H++2e→2GSH) (Fig. 2) [45], [46]. According to Walter H. Nernst's theory, redox potential can be determined by the

Conclusions and future prospects

Apoptosis research continues apace—a burgeoning field with fascinating and promising outcomes through immunopharmacologic gene therapy and tissue modulation. Apoptosis is a complex and multi-faceted pre-programmed process that involves a plethora of signaling cofactors which span the cell membrane all the way down to the nucleus. Despite this diversity and complexity, apoptotic pathways ultimately converge to cause a process that may well be part of proliferation and differentiation—as in

Acknowledgements

This manuscript was written at UCSF, when the author was a postdoctoral fellow. The author appreciatively thanks Jennifer Schuyler (UCSF) for her excellent editing and reviewing of this manuscript. The author's own publications are financially supported by the Anonymous Trust (Scotland), the National Institute for Biological Standards and Control (England), the Tenovus Trust (Scotland), the UK Medical Research Council (MRC, London) and the Wellcome Trust (London). Dr. John J. Haddad held the

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