Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

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.

Leukotriene B4 indicates lung injury and on-going inflammatory changes after severe trauma in a porcine long-term model

“…However, IL-18 demonstrated a clear trend to increased levels after trauma, indicating at findings from others that have represented the importance of IL-18 as a promising biomarkers for predicting morbidity and mortality of ARDS [52]. Similar findings were reported by Dolinay et al (2012), showing that patients with trauma-or sepsis-induced ARDS had increased IL-18 levels, which correlated with increased in-hospital mortality [54]. Additional studies to validate these findings are needed.…”

Role of endogenous IL‐18 in the lung during endotoxin‐induced systemic inflammation

“…Recent studies suggest that inflammasome-related cytokines, including IL-18, play important roles in acute lung injury. 4 Arndt et al reported that IL-18 may play a role in modulating the development of acute lung injury during endotoxemia. 5 As we reported that IL-18 delayed human neutrophil apoptosis in vitro, 6 the effect of IL-18 on neutrophil apoptosis may be a key factor in acute lung injury.…”

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

“…IL-1β was generated presumably by activation of the inflammasome, 19 which has been linked to the pathogenesis of ARDS. 20 This inhibition of proinflammatory cytokines has also been …”