The thiazolidinedione ciglitazone reduces bacterial outgrowth and early inflammation during Streptococcus pneumoniae pneumonia in mice

Objective. Thiazolidinediones (TZDs) are synthetic agonists for the peroxisome proliferator-activating receptor-gamma receptor and are currently in use as oral glucose-lowering drugs. TZDs have immune-modulating effects in vitro and in vivo. Because patients with type 2 diabetes have an increased risk for pneumonia, we evaluated the influence of ciglitazone, a TZD, on markers of inflammation and outcome during pneumonia caused by Streptococcus pneumoniae. Design: In vivo animal study and in vitro study. Setting: University research laboratory. Subjects. Female C57BI/6 mice and murine alveolar macrophage-like MH-S cells. Interventions. C571BI/6 mice were inoculated with 10(5) colony-forming units of S. pneumoniae intranasally. The following interventions were studied: 1) vehicle at t = 0; 2) ciglitazone 5 mg/kg intraperitoneally at t = 0; and 3) ciglitazone 5 mg/kg intraperitoneally at t = 0 and 24 hours. Mice were killed at either 24 or 48 hours after infection. Additionally, phagocytosis and killing of S. pneumoniae by MH-S cells were assessed in vitro. Measurements and Main Results: Single treatment with ciglitazone reduced bacterial loads at 24 hours but not at 48 hours, whereas repeated ciglitazone treatment did diminish bacterial loads at 48 hours. After 24 hours, cytokine levels in lung homogenate were lower in single-dose ciglitazone-treated mice; however, after 48 hours, there was no difference in lung cytokines between any of the experimental groups. Repeated ciglitazone treatment was associated with less pulmonary inflammation, as judged by histologic examination. On both time points, there was no difference in plasma cytokine levels or lung myeloperoxidase levels between experimental groups. In an additional experiment, ciglitazone treatment (given once daily) tended to reduce mortality. Ciglitazone did not influence phagocytosis or killing of S. pneumoniae by murine alveolar macrophages. Conclusions: Ciglitazone reduces bacterial outgrowth and local inflammation at least during the early stage of S. pneumoniae pneumonia in mice. (Crit Care Med 2009; 37:614-618)