Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia

The pathogenesis of septic shock occurring after Pseudomonas aeruginosa pne umonia was studied in a rabbit model. The airspace instillation of the cyto toxic P. aeruginosa strain PA103 into the rabbit caused a consistent alveol ar epithelial injury, progressive bacteremia, and septic shock. The lung in stillation of a noncytotoxic, isogenic mutant strain (PA103 Delta UT), whic h is defective for production of type III secreted toxins, did not cause ei ther systemic inflammatory response or septic shock, despite a potent infla mmatory response in the lung. The intravenous injection of PA103 did not ca use shock or an increase in TNF-alpha, despite the fact that the animals we re bacteremic. The systemic administration of either anti-TNF-alpha serum o r recombinant human IL-10 improved both septic shock and bacteremia in the animals that were instilled with PA103. Radiolabeled TNF-alpha instilled in the lung significantly leaked into the circulation only in the presence of alveolar epithelial injury. We conclude that injury to the alveolar epithe lium allows the release of proinflammatory mediators into the circulation t hat are primarily responsible for septic shock. Our results demonstrate the importance of compartmentalization of inflammatory mediators in the lung, and the crucial role of bacterial cytotoxins in causing alveolar epithelial damage in the pathogenesis of acute septic shock in P. aeruginosa pneumoni a.