Therapeutic Potential of Small Molecules Targeting Oxidative Stress in the Treatment of Chronic Obstructive Pulmonary Disease (COPD): A Comprehensive Review

Abstract

Chronic obstructive pulmonary disease (COPD) is an increasing and major global health problem. COPD is also the third leading cause of death worldwide. Oxidative stress (OS) takes place when various reactive species and free radicals swamp the availability of antioxidants. Reactive nitrogen species, reactive oxygen species (ROS), and their counterpart antioxidants are important for host defense and physiological signaling pathways, and the development and progression of inflammation. During the disturbance of their normal steady states, imbalances between antioxidants and oxidants might induce pathological mechanisms that can further result in many non-respiratory and respiratory diseases including COPD. ROS might be either endogenously produced in response to various infectious pathogens including fungi, viruses, or bacteria, or exogenously generated from several inhaled particulate or gaseous agents including some occupational dust, cigarette smoke (CS), and air pollutants. Therefore, targeting systemic and local OS with therapeutic agents such as small molecules that can increase endogenous antioxidants or regulate the redox/antioxidants system can be an effective approach in treating COPD. Various thiol-based antioxidants including fudosteine, erdosteine, carbocysteine, and N-acetyl-L-cysteine have the capacity to increase thiol content in the lungs. Many synthetic molecules including inhibitors/blockers of protein carbonylation and lipid peroxidation, catalytic antioxidants including superoxide dismutase mimetics, and spin trapping agents can effectively modulate CS-induced OS and its resulting cellular alterations. Several clinical and pre-clinical studies have demonstrated that these antioxidants have the capacity to decrease OS and affect the expressions of several pro-inflammatory genes and genes that are involved with redox and glutathione biosynthesis. In this article, we have summarized the role of OS in COPD pathogenesis. Furthermore, we have particularly focused on the therapeutic potential of numerous chemicals, particularly antioxidants in the treatment of COPD.

Keywords: antioxidants; chronic obstructive pulmonary disease (COPD); cigarette smoke; oxidative stress; reactive nitrogen species; reactive oxygen species; small molecules.

Figure 1

A schematic presentation of the role of oxidative stress in the development of COPD.

Figure 2

The effects of cigarette smoking on oxidative stress and inflammation in alveolar epithelial cells. Abbreviations: ERK—extracellular signal-regulated kinase; IL-1—interleukin 1; IL-1β—interleukin-1β; IL-6—interleukin 6; IL-8—interleukin 8; JNK—jun-N-terminal kinase; NF-κB,—nuclear factor-κB; TNF-α—tumor necrosis factor α.

Figure 3

The chemical structures of various antioxidants that can be used to target oxidative stress in the treatment of COPD.