• Am. J. Respir. Crit. Care Med. · May 2011

    Exudate macrophages attenuate lung injury by the release of IL-1 receptor antagonist in gram-negative pneumonia.

    • Susanne Herold, Tannaz Shafiei Tabar, Hermann Janssen, Katrin Hoegner, Maciej Cabanski, Peter Lewe-Schlosser, Jens Albrecht, Frank Driever, Istvan Vadasz, Werner Seeger, Mirko Steinmueller, and Juergen Lohmeyer.
    • Department of Internal Medicine II, University of Giessen Lung Center, Giessen, Germany. susanne.herold@innere.med.uni-giessen.de
    • Am. J. Respir. Crit. Care Med. 2011 May 15;183(10):1380-90.

    RationaleExudate macrophages are key players in host defense toward invading pathogens. Their antiinflammatory and epithelial-protective potential in gram-negative pneumonia, however, remains elusive.ObjectivesWe investigated whether exudate macrophages contributed to preservation of alveolar epithelial barrier integrity and analyzed the molecular pathways involved.MethodsWe evaluated the antiinflammatory and epithelial-protective effects of exudate macrophages in a model of LPS- and Klebsiella pneumoniae-induced lung injury comparing wild-type and CC-chemokine receptor 2 (CCR2)-deficient mice with defective lung macrophage recruitment and in in vitro studies using primary alveolar epithelial cells.Measurements And Main ResultsCCR2(-/-) mice exhibited enhanced alveolar epithelial cell apoptosis and lung leakage on intratracheal LPS treatment, which could be attributed to lack of exudate macrophage recruitment from the circulating pool as demonstrated in a model of wild-type/CCR2(-/-) bone-marrow chimeric mice. Among various antiinflammatory and proliferative mediators analyzed, the endogenous counterpart of resident macrophage-expressed IL-1β, IL-1 receptor antagonist (IL-1ra), was highly up-regulated in flow-sorted exudate macrophages in LPS-treated wild-type mice. LPS/IL-1β-induced impairment of alveolar epithelial cell integrity was antagonized by IL-1ra in vitro. Finally, intratracheal substitution of IL-1ra or intravenous adoptive transfer of IL-1ra(+/+) but not IL-1ra(-/-) blood mononuclear cells attenuated alveolar inflammation, epithelial apoptosis, and loss of barrier function in LPS-challenged or K. pneumoniae-infected CCR2(-/-) mice and enhanced survival after K. pneumoniae infection.ConclusionsWe conclude that recruited lung macrophages attenuate IL-1β-mediated acute lung injury in gram-negative pneumonia by release of IL-1ra.

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