Oxidative stress in ARDS: mechanisms and therapeutic potential

Abstract

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by acute lung inflammation, increased vascular permeability, and hypoxemic respiratory failure. Oxidative stress, driven by excessive reactive oxygen species (ROS), is a key contributor to ARDS pathogenesis, causing cellular damage, inflammation, and alveolar-capillary barrier disruption. This review elucidates the mechanisms of oxidative stress in ARDS, focusing on ROS production via NADPH oxidase (NOX) and mitochondria, which activate pathways like NF-κB and MAPK, promoting pro-inflammatory cytokine release. ROS-induced lipid and protein peroxidation, endothelial dysfunction, and programmed cell death (PCD), including apoptosis, pyroptosis, and ferroptosis, exacerbate lung injury. In COVID-19-related ARDS, SARS-CoV-2 spike protein amplifies mitochondrial ROS, worsening outcomes. Antioxidant therapies falter due to non-specific ROS suppression, patient heterogeneity (e.g., GSTP1 polymorphisms), and poor bioavailability. We propose a model where oxidative stress drives ARDS stages-early alveolar injury and late systemic dysfunction-suggesting targeted therapies like endothelial-specific nanoparticles or ferroptosis inhibitors. Precision medicine using biomarkers (e.g., mtDNA) and gender-specific approaches (e.g., estrogen-Nrf2 regulation) could enhance outcomes. This review bridges mechanistic gaps, critiques therapeutic failures, and advocates novel strategies like mitochondrial-targeted therapies to improve ARDS management.

Keywords: acute lung injury (ALI); acute respiratory distress syndrome (ARDS); inflammation; oxidative stress; reactive oxygen species (ROS).

FIGURE 1

The mechanism network of oxidative stress in ARDS pathogenesis. ROS from NOX and mitochondria activate NF-κB, MAPK, and NLRP3 pathways, upregulating cytokines (e.g., IL-1β). This drives alveolar damage (ZO disruption), inflammation, PCD (apoptosis, pyroptosis, ferroptosis), and multi-organ dysfunction. Key molecules include NOX2, NF-κB, and Gpx4. Therapeutic targets like PECAM-1 nanoparticles and mitoQ aim to mitigate ROS effects. NOX, NADPH Oxidase; NF-κB, Nuclear Factor-κB; MAPK, Mitogen-Activated Protein Kinase; NLRP3, NOD-like Receptor Protein 3; IL-1β, Interleukin-1β; ZO, Zonula Occludens; PCD, Programmed Cell Death; Gpx4, Glutathione Peroxidase 4; PECAM-1, Platelet Endothelial Cell Adhesion Molecule-1.