Pleiotropic effects of interleukin-6 in a “two-hit” murine model of acute respiratory distress syndrome

Julia L. Goldman, Saad Sammani, Carrie Kempf, Laleh Saadat, Eleftheria Letsiou, Ting Wang, Liliana Moreno-Vinasco, Alicia N. Rizzo, Jeffrey D. Fortman, Joe G.N. Garcia

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)280-288
Number of pages9
JournalPulmonary Circulation
Volume4
Issue number2
DOIs
StatePublished - Jun 2014

Keywords

  • Acute respiratory distress syndrome (ARDS)
  • Interleukin-6 (IL-6)
  • Lipopolysaccharide (LPS)
  • Ventilator-induced lung injury (VILI)

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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    Goldman, J. L., Sammani, S., Kempf, C., Saadat, L., Letsiou, E., Wang, T., Moreno-Vinasco, L., Rizzo, A. N., Fortman, J. D., & Garcia, J. G. N. (2014). Pleiotropic effects of interleukin-6 in a “two-hit” murine model of acute respiratory distress syndrome. Pulmonary Circulation, 4(2), 280-288. https://doi.org/10.1086/675991