Overview of the Mechanisms of Oxidative Stress: Impact in Inflammation of the Airway Diseases

Abstract

Inflammation of the human lung is mediated in response to different stimuli (e.g., physical, radioactive, infective, pro-allergenic or toxic) such as cigarette smoke and environmental pollutants. They often promote an increase in inflammatory activities in the airways that manifest themselves as chronic diseases (e.g., allergic airway diseases, asthma, chronic bronchitis/chronic obstructive pulmonary disease (COPD) or even lung cancer). Increased levels of oxidative stress (OS) reduce the antioxidant defenses, affect the autophagy/mitophagy processes, and the regulatory mechanisms of cell survival, promoting inflammation in the lung. In fact, OS potentiate the inflammatory activities in the lung, favoring the progression of chronic airway diseases. OS increases the production of reactive oxygen species (ROS), including superoxide anions (O₂^-), hydroxyl radicals (OH) and hydrogen peroxide (H₂O₂), by the transformation of oxygen through enzymatic and non-enzymatic reactions. In this manner, OS reduces endogenous antioxidant defenses in both nucleated and non-nucleated cells. The production of ROS in the lung can derive from both exogenous insults (cigarette smoke or environmental pollution) and endogenous sources such as cell injury and/or activated inflammatory and structural cells. In this review, we describe the most relevant knowledge concerning the functional interrelation between the mechanisms of OS and inflammation in airway diseases.

Keywords: COPD; asthma; lung; natural and synthetic antioxidants; oxidative stress.

Figure 1

ROS led to activation of several signaling events including mitogen- activated protein kinase (MAPK) pathways, NF-E2-related factor (Nrf2)-mediated activation of nuclear factor-kB (NF-kB). In addition, ROS through Nrf2 influences proteins involved in autophagy/mitophagy (like, ATG5, ATG7, Beclin, and PTEN). Thus, ROS signaling events play a central role in regulation of proinflammatory events, proliferation, epithelial-mesenchymal transition and autophagy/mitophagy mechanisms. (A) Endogenous factors leading to reactive oxygen species (ROS) generation through: (I) highly reactive free radicals, including the superoxide anion (O₂^_), the hydroxyl radical (●OH) and (II) non-radical species such as hydrogen peroxide (H₂O₂), singlet oxygen (O₂) [4,5], ozone (O₃), hypochlorite anion (OCl⁻) and nitric oxide (NO). (B) Schematic depiction of multiple signaling pathways that generate ROS and the intracellular events activated by ROS accumulation.

Figure 2

Effects of environmental pollution on OS damaging the activity of immune and structural cells in the airways of patients with chronic inflammatory diseases.

Figure 3

Antioxidants. (A) Classification of enzymatic and non-enzymatic antioxidants and (B) Examples of antioxidants for COPD and asthma treatment.