High levels of S100A8/A9 proteins aggravate ventilator-induced lung injury via TLR4 signaling

• Published in: PloS one Vol. 8; no. 7; p. e68694
• Main Authors: Kuipers, Maria T, Vogl, Thomas, Aslami, Hamid, Jongsma, Geartsje, van den Berg, Elske, Vlaar, Alexander P J, Roelofs, Joris J T H, Juffermans, Nicole P, Schultz, Marcus J, van der Poll, Tom, Roth, Johannes, Wieland, Catharina W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.07.2013; Public Library of Science (PLoS)
• Subjects: Alveoli; Anesthesiology; Animals; Arthritis; Bacteria; Biology; Breathing; Bronchoalveolar Lavage Fluid - chemistry; Calgranulin A - metabolism; Calgranulin B - adverse effects; Calgranulin B - genetics; Calgranulin B - metabolism; Heart surgery; Histology; Hostages; Humans; Immune system; Immunity; Immunology; Inflammation; Injuries; Innate immunity; Intensive care; Interdisciplinary aspects; Laboratories; Lipopolysaccharides; Lung diseases; Lungs; Mechanical ventilation; Medicine; Mice; Mice, Knockout; Mitogens; Neutrophils; Pathogenesis; Patients; Phagocytes; Pneumonia; Proteins; Respiration; Respiratory distress syndrome; Rodents; Signal Transduction - physiology; Signaling; Statistics, Nonparametric; Studies; Teaching hospitals; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Trachea; Ventilation; Ventilator-Induced Lung Injury - physiopathology; Ventilators; Netherlands; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068694

Bacterial products add to mechanical ventilation in enhancing lung injury. The role of endogenous triggers of innate immunity herein is less well understood. S100A8/A9 proteins are released by phagocytes during inflammation. The present study investigates the role of S100A8/A9 proteins in ventilator-induced lung injury. Pulmonary S100A8/A9 levels were measured in samples obtained from patients with and without lung injury. Furthermore, wild-type and S100A9 knock-out mice, naive and with lipopolysaccharide-induced injured lungs, were randomized to 5 hours of spontaneously breathing or mechanical ventilation with low or high tidal volume (VT). In addition, healthy spontaneously breathing and high VT ventilated mice received S100A8/A9, S100A8 or vehicle intratracheal. Furthermore, the role of Toll-like receptor 4 herein was investigated. S100A8/A9 protein levels were elevated in patients and mice with lung injury. S100A8/A9 levels synergistically increased upon the lipopolysaccharide/high VT MV double hit. Markers of alveolar barrier dysfunction, cytokine and chemokine levels, and histology scores were attenuated in S100A9 knockout mice undergoing the double-hit. Exogenous S100A8/A9 and S100A8 induced neutrophil influx in spontaneously breathing mice. In ventilated mice, these proteins clearly amplified inflammation: neutrophil influx, cytokine, and chemokine levels were increased compared to ventilated vehicle-treated mice. In contrast, administration of S100A8/A9 to ventilated Toll-like receptor 4 mutant mice did not augment inflammation. S100A8/A9 proteins increase during lung injury and contribute to inflammation induced by HVT MV combined with lipopolysaccharide. In the absence of lipopolysaccharide, high levels of extracellular S100A8/A9 still amplify ventilator-induced lung injury via Toll-like receptor 4.