Oxidative stress in chronic lung disease: From mitochondrial dysfunction to dysregulated redox signaling

Abstract

The lung is a delicate organ with a large surface area that is continuously exposed to the external environment, and is therefore highly vulnerable to exogenous sources of oxidative stress. In addition, each of its approximately 40 cell types can also generate reactive oxygen species (ROS), as byproducts of cellular metabolism and in a more regulated manner by NOX enzymes with functions in host defense, immune regulation, and cell proliferation or differentiation. To effectively regulate the biological actions of exogenous and endogenous ROS, various enzymatic and non-enzymatic antioxidant defense systems are present in all lung cell types to provide adequate protection against their injurious effects and to allow for appropriate ROS-mediated biological signaling. Acute and chronic lung diseases are commonly thought to be associated with increased oxidative stress, evidenced by altered cellular or extracellular redox status, increased irreversible oxidative modifications in proteins or DNA, mitochondrial dysfunction, and altered expression or activity of NOX enzymes and antioxidant enzyme systems. However, supplementation strategies with generic antioxidants have been minimally successful in prevention or treatment of lung disease, most likely due to their inability to distinguish between harmful and beneficial actions of ROS. Recent studies have attempted to identify specific redox-based mechanisms that may mediate chronic lung disease, such as allergic asthma or pulmonary fibrosis, which provide opportunities for selective redox-based therapeutic strategies that may be useful in treatment of these diseases.

Keywords: Asthma; ER stress; Epithelium; Fibrosis; NOX; S-glutathionylation; Sulfenylation.

Figure 1:. Distribution of various ROS sources and antioxidant systems throughout the cell.

All cells (as well as all lung cells) contain actively respiring mitochondria that generate ROS at their electron transfer chain (ETC), as well as various NOX/DUOX isoform distributed across different organelles. Other cytoplasmic or organelle-specific ROS sources include nitric oxide synthase (NOS), cyclooxygenase (COX), lipoxygenase (LOX), monoamine oxidase (MAO, D-amino acid oxidase (DAO), MICAL, ERO1, and others. Moreover, all cells contain various isoforms of (organelle-specific) antioxidant enzymes that metabolize ROS. Please refer to manuscript text for further clarifications.

Figure 2:. Schematic illustration of reversible oxidation of protein cysteine or methionine residues in redox-based signaling.

(A) Oxidation of protein cysteines (P-SH) by e.g. H₂O₂ results in initial formation of sulfenic acid (P-SOH), which can subsequently react with other protein cysteines to form inter- or intra-molecular disulfides, or with GSH (potentially catalyzed by GSTP1) to form S-glutationylated proteins (P-SSG). These disulfides can then be reduced by thioredoxins (TRX), protein disulfide isomerases (PDI) or glutaredoxins (GRX). (B) Oxidation of methionine by H₂O₂ (potentially catalyzed by MICAL) results in formation of methionine sulfoxide, which can be reduced by methionine sulfoxide reductases (MRSA and MRSB).

Figure 3:. Schematic illustration of NOX-dependent activation of protein tyrosine kinases in epithelial responses to injury or allergens.

Injurious stimuli typically trigger Ca²⁺ mobilization or influx, which activates DUOX1 to produce H₂O₂. This contributes to oxidative activation of Src, and release of ligands for the epidermal growth factor receptor (EGFR). EGFR can also be oxidatively activated, which appears to depend on activation of NOX2. These collective events contribute to induction of mucus genes and IL-8, and release of alarmins such as IL-33.