Mechanisms of Cell Death in Oxidative Stress

TLDR

Reactive oxygen and nitrogen species trigger cell death through necrotic and apoptotic pathways, involving receptor signaling, caspase activation, Bcl‑2 family regulation, mitochondrial dysfunction, and modulation by protein kinases and lipid mediators, while cells counteract these insults with survival mechanisms such as the heme‑oxygenase‑1/carbon‑monoxide system. Researchers investigate oxidative‑stress‑induced cell death using diverse models—including H₂O₂, nitric oxide derivatives, endotoxin, photodynamic therapy, UVA, ionizing radiation, and cigarette smoke—to dissect underlying mechanisms.

Abstract

Reactive oxygen or nitrogen species (ROS/RNS) generated endogenously or in response to environmental stress have long been implicated in tissue injury in the context of a variety of disease states. ROS/RNS can cause cell death by nonphysiological (necrotic) or regulated pathways (apoptotic). The mechanisms by which ROS/RNS cause or regulate apoptosis typically include receptor activation, caspase activation, Bcl-2 family proteins, and mitochondrial dysfunction. Various protein kinase activities, including mitogen-activated protein kinases, protein kinases-B/C, inhibitor-of-I-κB kinases, and their corresponding phosphatases modulate the apoptotic program depending on cellular context. Recently, lipid-derived mediators have emerged as potential intermediates in the apoptosis pathway triggered by oxidants. Cell death mechanisms have been studied across a broad spectrum of models of oxidative stress, including H2O2, nitric oxide and derivatives, endotoxin-induced inflammation, photodynamic therapy, ultraviolet-A and ionizing radiations, and cigarette smoke. Additionally ROS generated in the lung and other organs as the result of high oxygen therapy or ischemia/reperfusion can stimulate cell death pathways associated with tissue damage. Cells have evolved numerous survival pathways to counter proapoptotic stimuli, which include activation of stress-related protein responses. Among these, the heme oxygenase-1/carbon monoxide system has emerged as a major intracellular antiapoptotic mechanism.