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

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. Copyright 2004 Elsevier B.V.