TR, Wiener-Kronish JP. Depletion of phagocytes in the reticuloendothelial system causes increased inflammation and mortality in rabbits with Pseudomonas aeruginosa pneumonia. Am J Physiol Lung Cell Mol Physiol 296: L198 -L209, 2009. First published November 21, 2008 doi:10.1152/ajplung.90472.2008.-Phagocytes of the reticuloendothelial system are important in clearing systemic infection; however, the role of the reticuloendothelial system in the response to localized infection is not well-documented. The major goals of this study were to investigate the roles of phagocytes in the reticuloendothelial system in terms of bacterial clearance and inflammatory modulation in sepsis caused by Pseudomonas pneumonia. Macrophages in liver and spleen were depleted by administering liposome encapsulated dichloromethylene diphosphonate (clodronate) intravenously 36 h before the instillation of Pseudomonas aeruginosa into the lungs of anesthetized rabbits. Blood samples were analyzed for bacteria and cytokine concentrations. Lung injury was assessed by the bidirectional flux of albumin and by wet-to-dry weight ratios. Blood pressure and cardiac outputs decreased more rapidly and bacteremia occurred earlier in the clodronate-treated rabbits compared with the nondepleted rabbits. Plasma TNF-␣ (1.08 Ϯ 0.54 vs. 0.08 Ϯ 0.02 ng/ml) and IL-8 (6.8 Ϯ 1.5 vs. 0.0 Ϯ 0.0 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, thereby limiting the systemic effects of a severe pulmonary bacterial infection. counterregulatory response; bacterial clearance; macrophages NOSOCOMIAL PNEUMONIA OCCURS in ϳ25% of mechanically ventilated patients (13,39). Pseudomonas aeruginosa is 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 with P. aeruginosa pneumonia is the fact that pneumonia due to P. aeruginosa often leads to bacteremia (12,14,21). Clinical isolates of P. aeruginosa that are positive for type III secretion system cause more cytotoxicity to macrophage cell lines than those strains that are negative for type III secretion system (3). The intrapulmonary instillation of P. aeruginosa strains that produce ExoU, a toxin secreted via the type III secretion system, promotes entry of bacteria 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 intrapulmonary P. aeruginosa.The reticuloendothe...