Oxidative Stress in ARDS: Mechanisms and Therapeutic Potential

Fengyun Wang^1*Ruiqi Ge²Yun Cai¹Mingrui Zhao¹Zhen Fang¹Jingguo Li¹Chengzhi Xie¹Mei Wang¹Wanyue Li¹Xiaozhi Wang¹

• ¹Second Affiliated Hospital of Hainan Medical University, Haikou, China
• ²Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, China

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 genderspecific 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.