Interleukin 10 overexpression alters survival in the setting of gram-negative pneumonia following lung contusion

Vladislav A. Dolgachev*, Bi Yu, Lei Sun, Thomas P. Shanley, Krishnan Raghavendran, Mark R. Hemmila

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Objective: Lung contusion injury produces a vulnerable window within the inflammatory defenses of the lung that predisposes the patient to pneumonia. Interleukin 10 (IL-10) is a known anti-inflammatory mediator produced by macrophages and capable of downregulating acute lung inflammation. We investigated the impact of increased levels of IL-10 within the lung on survival and the host response to trauma in the setting of lung contusion (LC) and gram-negative pneumonia. Design: A bitransgenic, tetracycline-inducible, lung-specific human IL-10 overexpression (IL-10 OE) mouse model and single transgenic (TG-) control mice were used. Mice underwent LC injury or sham injury (sham) at time -6 h. At time 0, animals were inoculated intratracheally with 500 colony-forming units of Klebsiella pneumoniae (pneu). Bronchoalveolar lavage fluid, lung tissue specimens, or purified macrophages were collected. Lung tissue and blood bacteria levels were quantified. Cytokine levels were assayed by enzyme-linked immunosorbent assay, and gene expression levels were evaluated by real-time polymerase chain reaction. Cell-type identification and quantification were done using real-time polymerase chain reaction and flow cytometry. Main Results: Interleukin 10 OE mice demonstrated decreased 5-day survival compared with TG- mice following LC + pneu (0 vs. 30%, P < 0.0001). Interleukin 10 OE mice had significantly higher lung bacteria counts (P = 0.02) and levels of bacteremia (P = 0.001) at 24 h. The IL-10 OE mice recruited more neutrophils into the alveoli as measured in bronchoalveolar lavage fluid compared with TG- mice. Alveolar macrophages from IL-10 OE mice displayed increased alternative activation (M2 macrophages, P = 0.046), whereas macrophages from TG- mice exhibited classic activation (M1 macrophages) and much higher intracellular bacterial killing potential (P = 0.03). Interleukin 6, keratinocyte-derived chemokine, and macrophage inflammatory protein 2 levels were significantly elevated in IL-10 OE LC + pneu animals (P < 0.05). Conclusions: Lung-specific IL-10 overexpression induces alternative activation of alveolar macrophages. This shift in macrophage phenotype decreases intracellular bacterial killing, resulting in a more pronounced bacteremia and accelerated mortality in a model of LC and pneumonia.

Original languageEnglish (US)
Pages (from-to)301-310
Number of pages10
JournalShock
Volume41
Issue number4
DOIs
StatePublished - Apr 2014

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Keywords

  • Chest trauma
  • Inflammation
  • Lung contusion
  • Pneumonia

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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