Inflammasome-regulated cytokines are critical mediators of acute lung injury

Tamás Dolinay, Young Sam Kim, Judie Howrylak, Gary M. Hunninghake, Chang Hyeok An, Laura Fredenburgh, Anthony F. Massaro, Angela Rogers, Lee Gazourian, Kiichi Nakahira, Jeffrey A. Haspel, Roberto Landazury, Sabitha Eppanapally, Jason D. Christie, Nuala J. Meyer, Lorraine B. Ware, David C. Christiani, Stefan W. Ryter, Rebecca M. Baron, Augustine M.K. Choi

Research output: Contribution to journalArticle

295 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1225-1234
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume185
Issue number11
DOIs
StatePublished - Jun 1 2012

Keywords

  • Acute respiratory distress syndrome
  • Inflammasome
  • Interleukin-18
  • Mechanical ventilation

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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