TY - JOUR
T1 - Inflammasome-regulated cytokines are critical mediators of acute lung injury
AU - Dolinay, Tamás
AU - Kim, Young Sam
AU - Howrylak, Judie
AU - Hunninghake, Gary M.
AU - An, Chang Hyeok
AU - Fredenburgh, Laura
AU - Massaro, Anthony F.
AU - Rogers, Angela
AU - Gazourian, Lee
AU - Nakahira, Kiichi
AU - Haspel, Jeffrey A.
AU - Landazury, Roberto
AU - Eppanapally, Sabitha
AU - Christie, Jason D.
AU - Meyer, Nuala J.
AU - Ware, Lorraine B.
AU - Christiani, David C.
AU - Ryter, Stefan W.
AU - Baron, Rebecca M.
AU - Choi, Augustine M.K.
PY - 2012/6/1
Y1 - 2012/6/1
N2 - 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.
AB - 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.
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U2 - 10.1164/rccm.201201-0003OC
DO - 10.1164/rccm.201201-0003OC
M3 - Article
C2 - 22461369
AN - SCOPUS:84861785677
SN - 1073-449X
VL - 185
SP - 1225
EP - 1234
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 11
ER -