Inflammasome-regulated cytokines are critical mediators of acute lung injury. Academic Article Article uri icon

Overview

MeSH

  • Adaptive Immunity
  • Animals
  • Biological Markers
  • Bronchoalveolar Lavage Fluid
  • Caspase 1
  • Cohort Studies
  • Critical Care
  • Disease Models, Animal
  • Female
  • Humans
  • Immunity, Innate
  • Intensive Care Units
  • Interleukin-18
  • Male
  • Mice
  • Mice, Transgenic
  • Microarray Analysis
  • Real-Time Polymerase Chain Reaction
  • Respiration, Artificial
  • Severity of Illness Index

MeSH Major

  • Acute Lung Injury
  • Cytokines
  • Inflammasomes
  • Respiratory Distress Syndrome, Adult

abstract

  • 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.

publication date

  • June 1, 2012

has subject area

  • Acute Lung Injury
  • Adaptive Immunity
  • Animals
  • Biological Markers
  • Bronchoalveolar Lavage Fluid
  • Caspase 1
  • Cohort Studies
  • Critical Care
  • Cytokines
  • Disease Models, Animal
  • Female
  • Humans
  • Immunity, Innate
  • Inflammasomes
  • Intensive Care Units
  • Interleukin-18
  • Male
  • Mice
  • Mice, Transgenic
  • Microarray Analysis
  • Real-Time Polymerase Chain Reaction
  • Respiration, Artificial
  • Respiratory Distress Syndrome, Adult
  • Severity of Illness Index

Research

keywords

  • Comparative Study
  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3373064

Digital Object Identifier (DOI)

  • 10.1164/rccm.201201-0003OC

PubMed ID

  • 22461369

Additional Document Info

start page

  • 1225

end page

  • 1234

volume

  • 185

number

  • 11