Editors' ChoiceLung Disease

The Inflammasome Pathway: A Formidable Foe in Critically Ill Patients

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Science Translational Medicine  13 Jun 2012:
Vol. 4, Issue 138, pp. 138ec106
DOI: 10.1126/scitranslmed.3004427

There are few targeted therapies for critically ill patients, especially those with sepsis and acute lung injury. About 10 to 15% of patients in intensive care develop acute lung injury, a common complication of critical illness that in its worst form [acute respiratory distress syndrome (ARDS)] has a 40% mortality rate. Although the use of low tidal–volume mechanical ventilation can help patients with ARDS, we still cannot predict or stratify patients for ARDS risk or offer targeted treatments for patients with acute lung injury.

Inflammasomes are important regulators of the innate and adaptive immune system, connecting cell death and inflammatory signals. These intracellular molecular complexes trigger the proinflammatory caspase-1 signal, which then activates interleukin-1β (IL-1β) and IL-18, which are mediators of acute inflammation. They respond to viruses, bacteria, particulate compounds such as asbestos and silica, and dying cells. Because inflammation and cell death occur in ARDS, Dolinay et al. examined the role of inflammasome activity in acute lung injury.

The authors found that mice with ventilator-induced lung injury exhibited enhanced levels of the cytokine IL-18 in the lung and blood, whereas neutralization of IL-18 or genetic deletion of IL-18 or caspase-1 reduced lung injury and inflammation. Mechanical ventilation also increased the number of alveolar cells and alveolar macrophages containing cleaved IL-18. Similarly, in humans with ARDS, inflammasome pathway–related mRNA transcripts (CAP1, IL1B, and IL-18) were increased in peripheral blood. Additionally, IL-18 was elevated in the plasma of patients with ARDS, and higher IL-18 plasma concentrations correlated with increased mortality.

The authors conclude that inflammasome-mediated cytokine responses—in particular, IL-18—may participate in the pathogenesis of acute lung injury and could potentially serve as a biomarker for patients at risk of severe lung injury or mortality, improving their care. In addition, therapies targeted against IL-18 may prove useful in the care of patients with ARDS.

T. Dolinay et al., Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am. J. Respir. Crit. Care. Med. 185, 1225–1234 (2012). [Abstract]

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