Mechanisms underlying end-organ injury in sleep apnoea

Obstructive sleep apnoea is a prevalent chronic condition characterised by repetitive upper airway collapse that promotes the occurrence of gas exchange abnormalities reflected as intermittent hypoxia along with heightened risk for the occurrence of end-organ morbidity. Here, we examine the molecular and cellular mechanisms driving obstructive sleep apnoea-induced morbidity. We describe the maladaptive responses to chronic intermittent hypoxia, including stress programmes, primarily driven by bursts of reactive oxygen species that overwhelm antioxidant defences and trigger robust, NF-κB-mediated inflammatory cascades (e.g. tumour necrosis factor-α, interleukin-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 (e.g. endothelium, adipose tissue or different brain regions) exhibiting divergent, context-dependent responses to intermittent hypoxia (i.e. inflammation versus repair). Traditional bulk-tissue analyses and clinical metrics, such as the apnoea-hypopnoea index and hypoxic burden, fail to capture in their entirety this cellular and tissue heterogeneity or the critical kinetics of intermittent hypoxia, particularly during reoxygenation. Critical knowledge gaps remain, including the need to standardise intermittent hypoxia exposure metrics (capturing cycle frequency, hypoxic depth and reoxygenation kinetics), integrate circadian context and other obstructive sleep apnoea-related stressors (e.g. episodic hypercapnia, fragmented sleep), account for key biological modifiers (sex, age, genetic background, comorbidities) and determine the potential reversibility of intermittent hypoxia-induced injury. Addressing these gaps will be essential to advance obstructive sleep apnoea diagnostic and therapeutic approaches. Integrating multi-omics profiling and physiological modelling within standardised intermittent hypoxia paradigms offers a pathway towards patient-tailored interventions.