Mechanisms underlying end-organ injury in sleep apnea

OSA is a prevalent chronic condition characterized by repetitive upper airway collapse that promotes the occurrence of gas exchange abnormalities reflected as intermittent hypoxia (IH) along with heightened risk for the occurrence of end-organ morbidity. Here, we examine the molecular and cellular mechanisms driving OSA-induced morbidity. We describe the maladaptive responses to chronic IH, including stress programs, primarily driven by bursts of reactive oxygen species (ROS) that overwhelm antioxidant defenses and trigger robust, NF-κB-mediated inflammatory cascades (<i>e.g.</i> TNF-α, IL-6). These responses, strikingly different from the adaptive responses to sustained hypoxia, lead to systemic consequences, including endothelial dysfunction, hypertension, and profound metabolic dysfunction with insulin resistance. Understanding this pathophysiology is complicated by marked cellular and tissue heterogeneity, with different cell populations (<i>e.g.</i> endothelium, adipose tissue or different brain regions) exhibiting divergent, context-dependent responses to IH (<i>i.e.</i> inflammation <i>versus</i> repair). Traditional bulk-tissue analyses and clinical metrics, such as the AHI or hypoxic burden, fail to capture in their entirety this cellular and tissue heterogeneity and the critical kinetics of IH, particularly during reoxygenation. Critical knowledge gaps remain, including the need to standardize IH exposure metrics (capturing cycle frequency, hypoxic depth, and reoxygenation kinetics), integrate circadian context and other OSA-related stressors (<i>e.g.</i> episodic hypercapnia, fragmented sleep), account for key biological modifiers (sex, age, genetic background, comorbidities), and determine the potential reversibility of IH-induced injury. Addressing these gaps will be essential to advance OSA diagnostic and therapeutic approaches. Integrating multi-omics profiling and physiological modeling within standardized IH paradigms offers a pathway toward patient-tailored interventions.