Cytokine storm in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by diffuse acute inflammatory lung injury, non-cardiogenic pulmonary edema, and severe hypoxemia. Beyond structural damage, ARDS reflects a profound dysregulation of both innate and adaptive immune responses. Uncontrolled activation of inflammatory pathways disrupts the alveolar-capillary barrier and amplifies cytokine release, which may disseminate systemically as a "cytokine storm." This maladaptive immune response worsens pulmonary injury and contributes to the development of multiorgan dysfunction syndrome (MODS), the leading cause of death in ARDS. This review summarizes current understanding of the cellular and molecular mechanisms underlying "cytokine storm," with emphasis on its systemic effects and its relationship to ARDS subphenotypes, particularly the hyperinflammatory subphenotype, characterized by distinct biomarker profiles, differential treatment responses, and worse outcomes. We also discuss clinical implications and therapeutic strategies, ranging from established interventions such as lung-protective ventilation and corticosteroids to emerging immunomodulatory approaches, including inhibition of interleukin (IL)-1 and IL-6 signaling, extracorporeal cytokine removal, cytokine nanosponges, as well as mesenchymal stromal cell (MSC) and MSC-derived extracellular vesicle therapies. Finally, we emphasize the potential of precision medicine, in which biomarker-guided strategies may allow early identification of patients at risk for a cytokine storm and support the selection of targeted therapies. By aligning treatment with individual inflammatory profiles, these approaches aim to limit immune-mediated organ injury and improve clinical outcomes in ARDS, thereby linking mechanistic insights to patient-centered care.