Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

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 i...

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Published in:	American journal of respiratory and critical care medicine Vol. 185; no. 11; pp. 1225 - 1234
Main Authors:	DOLINAY, Tamas, YOUNG SAM KIM, HASPEL, Jeffrey A, LANDAZURY, Roberto, EPPANAPALLY, Sabitha, CHRISTIE, Jason D, MEYER, Nuala J, WARES, Lorraine B, CHRISTIANI, David C, RYTER, Stefan W, BARON, Rebecca M, CHOI, Augustine M. K, HOWRYLAK, Judie, HUNNINGHAKE, Gary M, CHANG HYEOK AN, FREDENBURGH, Laura, MASSARO, Anthony F, ROGERS, Angela, GAZOURIAN, Lee, NAKAHIRA, Kiichi
Format:	Journal Article
Language:	English
Published:	New York, NY American Thoracic Society 01-06-2012
Subjects:	Acute Lung Injury - genetics Acute Lung Injury - metabolism Acute Lung Injury - therapy Adaptive Immunity - immunology Adaptive Immunity - physiology Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Antibodies Biological and medical sciences Biomarkers Biomarkers - metabolism Bronchoalveolar Lavage Fluid - immunology Caspase 1 - immunology Caspase 1 - metabolism Cohort Studies Critical Care - methods Cytokines Cytokines - immunology Cytokines - metabolism Disease Models, Animal Emergency and intensive respiratory care Female Gene expression Humans Illnesses Immunity, Innate - immunology Immunity, Innate - physiology Inflammasomes - immunology Inflammasomes - metabolism Intensive care Intensive care medicine Intensive Care Units Interleukin-18 - blood Lavage Male Medical sciences Mice Mice, Transgenic Microarray Analysis Mortality Plasma Polymerase chain reaction Proteins Real-Time Polymerase Chain Reaction Respiration, Artificial - methods Respiratory distress syndrome Respiratory Distress Syndrome, Adult - genetics Respiratory Distress Syndrome, Adult - physiopathology Respiratory Distress Syndrome, Adult - therapy Sepsis Severity of Illness Index Ventilators Lung disease Intensive care Respiratory disease interleukin-18 Interleukin inflammasome Cytokine acute respiratory distress syndrome Respiratory distress Mechanical ventilation Resuscitation
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Summary:	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. We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS. 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. 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. The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1073-449X 1535-4970
DOI:	10.1164/rccm.201201-0003OC