Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia

Kurahashi, Kiyoyasu; Kajikawa, Osamu; Sawa, Teiji; Ohara, Maria; Gropper, Michael A.; Frank, Dara W.; Martin, Thomas R.; Wiener-Kronish, Jeanine P.

doi:10.1172/jci7124

Cited by 287 publications

(241 citation statements)

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“…Most strains of P. aeruginosa secrete virulence factors by the type III secretion system [6,7]. The role of proteins secreted and translocated across eukaryotic cell plasma membranes by the type III secretion system has been highlighted both in vitro [8,9] and in animal models in recent years [10]. Neutralization of the type III secretion proteins have shown to prevent septic shock and an improved survival in a mouse model of P. aeruginosa infection [10].…”

Section: Introductionmentioning

confidence: 99%

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX‐2

et al. 2007

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Prostanoids generated by COX‐2 are involved in the regulation of inflammation but their exact role in the innate immune response has not been defined. We investigated whether COX‐2 is involved in host defense against Pseudomonas aeruginosa pneumonia. In vitro studies, in a macrophage cell line, showed that cytotoxic strain of P aeruginosa (PA103) induced significant COX‐2 protein expression and enzymatic function. In vivo data showed that infection with PA103 increased COX‐2 protein production in whole lung tissue compared to mice that were infected with mutant bacteria that lack ExoU (ΔU) or ExoU and ExoT (ΔUT). COX‐2–/– mice had accentuated clearance of cytotoxic P. aeruginosa from the lungs. We further tested the effects of COX‐2 products such as prostaglandin E2 on the function of phagocytic cells. Our studies indicate that prostaglandin E2 may be involved through interacting with the EP2 receptors in modulating the host response because treatment of macrophages with prostaglandin E2 suppressed production of reactive oxygen species. Furthermore there was enhanced bacterial clearance in EP2 receptor–/– mice compared to the wild‐type controls. Thus it is possible that inhibition of COX‐2 or EP2 receptors could be an effective adjunctive treatment for severe or resistant P. aeruginosa pneumonia.

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Section: Introductionmentioning

confidence: 99%

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX‐2

et al. 2007

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“…When alveolar type II cells are injured, normal alveolar epithelial fluid transport and removal of alveolar edema fluid are impaired (23). Furthermore, injury to type II cells reduces the production and turnover of surfactant (12) and may also cause intrapulmonary bacterial translocation, leading to sepsis (21).…”

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confidence: 99%

Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome

Ishizaka¹,

Matsuda²,

Albertine³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 286: L1088 -L1094, 2004. First published September 5, 2003 10.1152 10. /ajplung. 00420.2002 is a pulmonary epithelial mucin more prominently expressed on the surface membrane of alveolar type II cells when these cells are proliferating, stimulated, and/or injured. We hypothesized that high levels of KL-6 in epithelial lining fluid and plasma would reflect the severity of lung injury in patients with acute lung injury (ALI). Epithelial lining fluid was obtained at onset (day 0) and day 1 of acute respiratory distress syndrome (ARDS)/ALI by bronchoscopic microsampling procedure in 35 patients. On day 0, KL-6 and albumin concentrations in epithelial lining fluid were significantly higher than in normal controls (P Ͻ 0.001), and the concentrations of KL-6 in epithelial lining fluid (P Ͻ 0.002) and in plasma (P Ͻ 0.0001) were higher in nonsurvivors than in survivors of ALI/ARDS. These observations were corroborated by the immunohistochemical localization of KL-6 protein expression in the lungs of nonsurvivors with ALI and KL-6 secretion from cultured human alveolar type II cells stimulated by proinflammatory cytokines. Because injury to distal lung epithelial cells, including alveolar type II cells, is important in the pathogenesis of ALI, the elevation of KL-6 concentrations in plasma and epithelial lining fluid could be valuable indicators for poor prognosis in clinical ALI. alveolar type II cell; pulmonary edema; microsampling

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“…rhIL-10 was provided by the Schering-Plough Research Institute (Kenilworth, NJ) and stored at Ϫ80°C until used. In our previous study (37), a 50 g/kg dose of the rhIL-10 was found to be effective in blocking the biological effects of TNF-␣ in rabbits with P. aeruginosa pneumonia.…”

Section: Methodsmentioning

confidence: 90%

“…For 125 I-albumin in blood and bacteria in blood, the y-axis was converted to a log10 scale before applying linear regression, and then the times to reach a specific threshold were compared. The thresholds for the 125 I-albumin in blood were analyzed at 10% and 20% of the instilled intrapulmonary dose, which are about the values at 8 h when rabbits are infected with a noncytotoxic strain of P. aeruginosa and a cytotoxic strain, respectively, according to our previous study (37). The threshold for bacteria in blood was analyzed at 1 ϫ 10 2 CFU/ml because this bacterial concentration in blood has been reported in patients with gram-negative bacteremia with high incidence of death (25,69).…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Kurahashi¹,

Sawa²,

Ota³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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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...

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Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia

Cited by 287 publications

References 34 publications

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX‐2

Bacterial clearance of Pseudomonas aeruginosa is enhanced by the inhibition of COX‐2

Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome

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

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