Inflammasome-regulated cytokines are critical mediators of acute lung injury

T Dolinay, YS Kim, J Howrylak… - American journal of …, 2012 - atsjournals.org
T Dolinay, YS Kim, J Howrylak, GM Hunninghake, CH An, L Fredenburgh, AF Massaro…
American journal of respiratory and critical care medicine, 2012atsjournals.org
Rationale: Despite advances in clinical management, there are currently no reliable
diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The
inflammasome/caspase-1 pathway regulates the maturation and secretion of
proinflammatory cytokines (eg, 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 …
Rationale: Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway 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 to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was 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.
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