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Am J Respir Crit Care Med. 2012 Jun 1;185(11):1225-34. doi: 10.1164/rccm.201201-0003OC. Epub 2012 Mar 29.

Inflammasome-regulated cytokines are critical mediators of acute lung injury.

Author information

1
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Abstract

RATIONALE:

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.

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 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.

Comment in

PMID:
22461369
PMCID:
PMC3373064
DOI:
10.1164/rccm.201201-0003OC
[Indexed for MEDLINE]
Free PMC Article

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