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Introduction

Molecular oxygen is a prerequisite to life of all aerobic organisms. The human lung with its large surface area and extensive blood supply is engineered for its primary function in gas exchange. While oxygen is essential for its many roles in human physiology, high concentrations of oxygen or its metabolites, commonly referred to as reactive oxygen species (ROS), have the potential to cause cellular injury and contribute to disease pathogenesis. The most damaging forms of ROS are free radicals. A free radical, by definition, refers to any chemical species containing one or more unpaired electrons in their atomic or molecular orbitals. These unpaired electron(s) give considerable reactivity to free radical species, which can trigger chemical reactions that damage cellular constituents of living organisms. Molecular oxygen (dioxygen) is itself, a radical based on the presence of unpaired electrons in its outermost orbital; however, their parallel spin retrains its reactivity. O2 can form the superoxide anion radical (O2•−) upon addition of an electron; thus, overcoming this restraint and making O2•− a highly reactive species.1,2 The photodynamic activation of oxygen can result in the formation of singlet oxygen, and its reductive activation results in the formation of hydrogen peroxide (H2O2) or the highly reactive hydroxyl radical (OH).3,4 When two free radicals share their unpaired electrons, nonradical species of lower reactivity are generated. Thus, ROS constitute both free radicals and nonradicals.

Nitric oxide (NO) is another small gaseous molecule that serves as an important signaling molecule in diverse physiological processes, including vasorelaxation and immune regulation during chronic inflammation in the lung.5,6 The regulated production of NO by lung cells is critical for homeostasis of the lung. However, in some contexts, the reaction of NO with O2•− to form reactive nitrogen species (RNS), such as peroxynitrite (ONOO), may contribute to the pathophysiology of chronic lung diseases.79

ROS and RNS together play important roles in regulation of cell proliferation, differentiation, and survival.1012 ROS/RNS can inactivate enzymes including antiproteases, induce apoptosis, regulate cell proliferation, and modulate the immune-inflammatory system in the lungs and other tissues.1316 ROS/RNS have been implicated in initiating inflammatory responses in the lungs through the activation of transcription factors, protein kinase pathways, chromatin remodeling, and gene expression of proinflammatory mediators.1316 Under normal physiological conditions, the balance between generation and elimination of ROS/RNS maintains the functional integrity of redox-sensitive signaling cascades regulating cellular phenotypes. In this context, it is important to differentiate the roles of ROS/RNS in “oxidative stress” from “redox signaling.” Paradoxically, it appears that nature has co-opted the chemical reactivities of ROS/RNS to function as signaling molecules in homeostasis and normal cellular physiology.

Redox homeostasis of cells/tissues is maintained by the regulated balance of oxidant ...

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