title: Inflammasome-regulated cytokines are critical mediators of acute lung injury.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Tamás
authors.initials: T
authors.lastname: Dolinay
authors.forename: Young Sam
authors.initials: YS
authors.lastname: Kim
authors.forename: Judie
authors.initials: J
authors.lastname: Howrylak
authors.forename: Gary M
authors.initials: GM
authors.lastname: Hunninghake
authors.forename: Chang Hyeok
authors.initials: CH
authors.lastname: An
authors.forename: Laura
authors.initials: L
authors.lastname: Fredenburgh
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Massaro
authors.forename: Angela
authors.initials: A
authors.lastname: Rogers
authors.forename: Lee
authors.initials: L
authors.lastname: Gazourian
authors.forename: Kiichi
authors.initials: K
authors.lastname: Nakahira
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Haspel
authors.forename: Roberto
authors.initials: R
authors.lastname: Landazury
authors.forename: Sabitha
authors.initials: S
authors.lastname: Eppanapally
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Baron
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D056704:Adaptive Immunity / Q000276:immunology / Q000502:physiology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D015331:Cohort Studies; D003422:Critical Care / Q000379:methods; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology / Q000502:physiology; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D007362:Intensive Care Units; D020382:Interleukin-18 / Q000097:blood; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D012121:Respiration, Artificial / Q000379:methods; D012128:Respiratory Distress Syndrome / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D016207:Cytokines; D058847:Inflammasomes; D020382:Interleukin-18; D020170:Caspase 1