Inflammasome-regulated cytokines are critical mediators of acute lung injury

Rationale: Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distresssyndrome(ARDS).Theinflammasome/caspase-1pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation. Objectives:We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS. Methods: We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid. Measurements and Main Results: In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18-neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response tomechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B,andIL18)wereincreasedinperipheralblood. In samples fromfour clinical centers, IL-18was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality. Conclusions: The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.