After an infiltration of local anesthetic, a tracheotomy was performed, and an endotracheal tube [4.0-in. ng/ml) were higher in the depleted rabbits. The concentration of IL-10 in liver of the macrophage-depleted rabbits was significantly lower than in normal rabbits at 5 h. Treatment of macrophage-depleted rabbits with intravenous IL-10 reduced plasma proinflammatory cytokine concentrations and reduced the decline in blood pressure and cardiac output. These results show that macrophages in the reticuloendothelial system have critical roles in controlling systemic bacteremia and reducing systemic inflammation, Rabbit polyclonal to NPSR1 thereby limiting the systemic effects of a severe pulmonary bacterial infection. Keywords:counterregulatory response, bacterial clearance, macrophages nosocomial pneumonia occursin 25% of mechanically ventilated patients (13,39).Pseudomonas aeruginosais now one of the most common (18,33) and most lethal (6,15,19) pathogens causing nosocomial pneumonia. One possible reason for the high mortality associated withP. aeruginosapneumonia is the fact that pneumonia due toP. aeruginosaoften leads to bacteremia (12,14,21). Clinical isolates ofP. aeruginosathat are positive for type III secretion system cause more cytotoxicity to macrophage cell lines than those strains (S)-3,5-DHPG that are unfavorable for type III secretion system (3). The intrapulmonary instillation ofP. aeruginosastrains that produce ExoU, a toxin secreted via the type III secretion system, promotes entry of bacteria (S)-3,5-DHPG into the circulation as well as the transport of inflammatory mediators from the infected air spaces into the circulation, leading to lethal hypotension and acidosis (37). Local as well as systemic defense mechanisms are therefore important in the responses to intrapulmonaryP. aeruginosa. The reticuloendothelial system provides important defenses against systemic bacteremia. A number of early studies showed that intravenously administered bacteria, includingEscherichia coli(2),Staphylococcus aureus(2),Salmonella enteritidis(5),Listeria monocytogenes(42), andStreptococcus pneumoniae(11), are rapidly taken up by the reticuloendothelial system. However, the effect of the reticuloendothelial system in the host response to localized contamination has not been studied in detail. In addition to scavenging bacteria, phagocytes in the reticuloendothelial system secrete inflammatory mediators in response to bacterial contact or cytokines that have leaked from the primary sites of contamination. Fox-Dewhurst et al. (22) showed using anE. colipneumonia model that when the bacterial inoculum in the air space exceeds the capacity of the pulmonary defense system, compartmentalization fails and severe systemic inflammation occurs, suggesting that this reticuloendothelial system might have an important role in severe local pulmonary infections. The aims of this study (S)-3,5-DHPG were to determine the role of the reticuloendothelial system in the early physiological and inflammatory response to localized contamination in the lungs caused byPseudomonaspneumonia. We depleted phagocytes in the reticuloendothelial system of anesthetized rabbits using liposome encapsulated dichloromethylene diphosphonate (clodronate-liposomes) and then instilledP. aeruginosainto the air spaces to produce pneumonia. We evaluated lung injury, the number of circulating bacteria, hemodynamic and blood gas changes, and cytokines in the blood, liver, and spleen. Because IL-10 is an important immunomodulatory cytokine produced by mononuclear cells of the reticuloendothelial system, we measured IL-10 levels in the clodronate-treated animals and then treated the animals with human recombinant IL-10 (rhIL-10). The IL-10 levels were lower and inflammatory responses were greater in the clodronate-treated animals, and treatment with rhIL-10 reduced inflammation and improved inflammatory responses. These results (S)-3,5-DHPG provide novel evidence about the role of phagocytes in the reticuloendothelial system in localized bacterial pneumonia and suggest that the reticuloendothelial system contributes not only to the clearance of systemic bacteria, but also to the pathogenesis of the systemic anti-inflammatory response syndrome that accompanies localized bacterial pneumonia. == MATERIALS AND METHODS == == Reagents. == rhIL-10 was provided by the Schering-Plough Research Institute (Kenilworth, NJ) and stored at 80C until used. In our previous study (37), a 50 g/kg dose.
