Depletion of phagocytes in the reticuloendothelial system causes increased inflammation and mortality in rabbits withPseudomonas aeruginosapneumonia

Abstract

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...

Mechanisms of phagocytosis and host clearance ofPseudomonas aeruginosa

“…Indeed, this is supported by data linking phagocytosis to bacterial clearance from the host (6,68,76). Animal models that lack phagocytic cells quickly succumb to P. aeruginosa challenge (68,76), and people with defects in phagocytic cell function are highly susceptible to P. aeruginosa infection (6). Thus internalization is utilized by the host for control of invasive P. aeruginosa, and so if the bacterium actively promotes cellular entry, there must be an adaptive benefit that outweighs the cost of potential phagocytic degradation.…”

“…Entry into neutrophils and macrophages is achieved through active phagocytosis by the host cell. Indeed, this is supported by data linking phagocytosis to bacterial clearance from the host (6,68,76). Animal models that lack phagocytic cells quickly succumb to P. aeruginosa challenge (68,76), and people with defects in phagocytic cell function are highly susceptible to P. aeruginosa infection (6).…”

“…Mice, rabbits, and humans that are missing major subsets of phagocytic cells, such as neutrophils or macrophages, or that lack major innate immune response molecules, such as MyD88 (myeloid differentiation primary response gene 88), are highly susceptible to P. aeruginosa infection (6,68,76,97). Additionally, patients with CF are well characterized to generate robust antibody responses against P. aeruginosa; however, this is insufficient for effective host control of infection and for sterilizing immunity (9,115,116).…”

Macrophage Depletion Impairs Corneal Wound Healing after Autologous Transplantation in Mice

“…The delivery of liposome containing dichloromethylene-bisphosphonate has been used popularly to deplete macrophages from liver and spleen [30], kidney [31], lung [32] and cornea [14], [33], [34] in vivo. The method is specific for the depletion of phagocytic cells, since the liposomes can be phagocytosis only by phagocytic cells.…”

Interactions between Neutrophils and Pseudomonas aeruginosa in Cystic Fibrosis

“…In neutropenic mice, a 10 5 -times smaller dose of P. aeruginosa is enough to lead to the same lethal effect in a lung infection model than in mice with normal PMN numbers [48]. Similar effects were shown in rabbits, as well [50]. Airway epithelial control of PMN infiltration has been shown to be crucial to fight P. aeruginosa in murine airways [51,52].…”