Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Dolinay, T., Kim, Y. S., Howrylak, J., Hunninghake, G. M., An, C. H., Fredenburgh, L., Massaro, A. F., Rogers, A., Gazourian, L., Nakahira, K., Haspel, J. A., Landazury, R., Eppanapally, S., Christie, J. D., Meyer, N. J., Ware, L. B., Christiani, D. C., Ryter, S. W., Baron, R. M., Choi, A. M. 2012; 185 (11): 1225-1234

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.

View details for DOI 10.1164/rccm.201201-0003OC

View details for Web of Science ID 000304384600016

View details for PubMedID 22461369