TY - JOUR
T1 - Interleukin 10 overexpression alters survival in the setting of gram-negative pneumonia following lung contusion
AU - Dolgachev, Vladislav A.
AU - Yu, Bi
AU - Sun, Lei
AU - Shanley, Thomas P.
AU - Raghavendran, Krishnan
AU - Hemmila, Mark R.
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - Chest trauma
KW - Inflammation
KW - Lung contusion
KW - Pneumonia
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U2 - 10.1097/SHK.0000000000000123
DO - 10.1097/SHK.0000000000000123
M3 - Article
C2 - 24430542
AN - SCOPUS:84897054803
SN - 1073-2322
VL - 41
SP - 301
EP - 310
JO - Shock
JF - Shock
IS - 4
ER -