title: Pleiotropic effects of interleukin-6 in a "two-hit" murine model of acute respiratory distress syndrome.
abstract: Patients with acute respiratory distress syndrome (ARDS) exhibit elevated levels of interleukin-6 (IL-6), which correlate with increased morbidity and mortality. The exact role of IL-6 in ARDS has proven difficult to study because it exhibits either pro- or anti-inflammatory actions in mouse models of lung injury, depending on the model utilized. In order to improve understanding of the role of this complex cytokine in ARDS, we evaluated IL-6 using the clinically relevant combination of lipopolysaccharide (LPS) and ventilator-induced lung injury (VILI) in IL-6(-/-) mice. Bronchoalveolar lavage fluid (BAL), whole-lung tissue, and histology were evaluated for inflammatory markers of injury. Transendothelial electrical resistance was used to evaluate the action of IL-6 on endothelial cells in vitro. In wild-type mice, the combination model showed a significant increase in lung injury compared to either LPS or VILI alone. IL-6(-/-) mice exhibited a statistically significant decrease in BAL cellular inflammation as well as lower histologic scores for lung injury, changes observed only in the combination model. A paradoxical increase in BAL total protein was observed in IL-6(-/-) mice exposed to LPS, suggesting that IL-6 provides protection from vascular leakage. However, in vitro data showed that IL-6, when combined with its soluble receptor, actually caused a significant increase in endothelial cell permeability, suggesting that the protection seen in vivo was likely due to complex interactions of IL-6 and other inflammatory mediators rather than to direct effects of IL-6. These studies suggest that a dual-injury model exhibits utility in evaluating the pleiotropic effects of IL-6 in ARDS on inflammatory cells and lung endothelium.
authors.affiliation: Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA ; Biological Resources Laboratory, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Julia L
authors.initials: JL
authors.lastname: Goldman
authors.affiliation: Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.affiliation: Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA ; Current affiliation: Division of Pulmonary and Critical Care, Sleep Medicine, Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Kempf
authors.affiliation: Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Laleh
authors.initials: L
authors.lastname: Saadat
authors.affiliation: Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Letsiou
authors.affiliation: Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA ; Current affiliation: Division of Pulmonary and Critical Care, Sleep Medicine, Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.affiliation: Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Alicia N
authors.initials: AN
authors.lastname: Rizzo
authors.affiliation: Biological Resources Laboratory, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Fortman
authors.affiliation: Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA ; Office of the Vice President for Health Affairs, University of Illinois at Chicago, Chicago, Illinois, USA ; Current affiliation: Division of Pulmonary and Critical Care, Sleep Medicine, Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
keywords: acute respiratory distress syndrome (ARDS); interleukin-6 (IL-6); lipopolysaccharide (LPS); ventilator-induced lung injury (VILI)