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Rationale: Ventilator-induced lung injury (VILI) leads to an unacceptably high mortality. In this regard, the antiinflammatory properties of inhaled carbon monoxide (CO) may provide a therapeutic option.Objectives: This study explores the mechanisms of CO-dependent protection in a mouse model of VILI.Methods: Mice were ventilated (12 ml/kg, 1-8 h) with air in the absence or presence of CO (250 ppm). Airway pressures, blood pressure, and blood gases were monitored. Lung tissue was analyzed for inflammation, injury, and gene expression. Bronchoalveolar lavage fluid was analyzed for protein, cell and neutrophil counts, and cytokines.Measurements and Main Results: Mechanical ventilation caused significant lung injury reflected by increases in protein concentration, total cell and neutrophil counts in the bronchoalveolar lavage fluid, as well as the induction of heme oxygenase-1 and heat shock protein-70 in lung tissue. In contrast, CO application prevented lung injury during ventilation, inhibited stress-gene up-regulation, and decreased lung neutrophil infiltration. These effects were preceded by the inhibition of ventilation-induced cytokine and chemokine production. Furthermore, CO prevented the early ventilation-dependent up-regulation of early growth response-1 (Egr-1). Egr-1-deficient mice did not sustain lung injury after ventilation, relative to wild-type mice, suggesting that Egr-1 acts as a key proinflammatory regulator in VILI. Moreover, inhibition of peroxysome proliferator-activated receptor (PPAR)-gamma, an antiinflammatory nuclear regulator, by GW9662 abolished the protective effects of CO.Conclusions: Mechanical ventilation causes profound lung injury and inflammatory responses. CO treatment conferred protection in this model dependent on PPAR-gamma and inhibition of Egr-1. [ABSTRACT FROM AUTHOR]

The contribution of the spleen to protective antiviral T cell memory was studied using the mouse model of infection with respiratory syncytial virus (RSV). Virus-specific CD8+ memory T cells were induced by local (intranasal or intracutaneous) or systemic (intravenous) immunization using RSV or vaccinia virus-recombinants expressing an RSV protein. After all three routes of immunization, the spleen was clearly identified as the main anatomic compartment harbouring virus-specific memory T cells. Surprisingly, however, splenectomy performed 30 days after immunization did not impair the efficacy of the memory T cell response to a subsequent RSV challenge infection. Irrespective of the route of priming, splenectomy did not influence the number or the functional activity of virus-specific memory T cells recruited to the lung following RSV challenge. More importantly, splenectomy did not impair pulmonary virus control by antiviral memory T cells in vivo. These findings were confirmed under experimental conditions where no neutralizing antibodies were induced by the priming infection. Thus, although most memory CD8+ T cells localize to the spleen after viral infections, this important lymphoid organ is dispensable for efficient recall responses. These findings have implications for the immunocompetence of splenectomized patients.