Pneumonia After Cecal Ligation and Puncture

Abstract

Sepsis continues to be the primary cause of death among patients in surgical intensive care units. In many cases, death does not result from the initial septic event but rather from subsequent nosocomial infection with pneumonia being the most common etiology. In addition, most deaths in patients with sepsis occur after the first 72 h. By contrast, in most animal models of sepsis, most deaths occur within the first 72 h. The purpose of this study was to develop a clinically relevant "two-hit" model of sepsis that would reflect delayed mortality because of secondary nosocomial infection. The well-accepted and widely used cecal ligation and puncture (CLP) model was used as the "first hit". Pseudomonas aeruginosa or Streptococcus pneumoniae was used to induce pneumonia in mice 72 h after CLP as a "second hit." In this study, mortality in mice undergoing CLP followed by pneumonia was significantly higher than in mice receiving pneumonia or CLP alone. S. pneumoniae pneumonia after CLP resulted in a 95% mortality compared with a 20% mortality for pneumonia alone, P < 0.0001. Similarly, mortality of P. aeruginosa pneumonia after CLP (85%) was significantly higher than P. aeruginosa alone (20%), P < 0.0001. Mice undergoing CLP followed by P. aeruginosa pneumonia also had significantly higher levels of B- and T-cell apoptotic death. Finally, mice undergoing CLP followed by P. aeruginosa or S. pneumoniae pneumonia had significantly decreased concentrations of proinflammatory mediators monocyte chemoattractant protein-1 and interleukin (IL)-6 compared with mice undergoing CLP or pneumonia alone. In conclusion, a primary sublethal infection impairs the immune system thus rendering the host more susceptible to secondary infection and death. Double injury, that is, CLP followed by pneumonia, provides a useful tool in the study of sepsis, creating a prolonged period of infection as opposed to CLP alone. The extended duration of infection may lead to a better understanding of the mechanism of the immune dysregulation seen in clinical sepsis and therefore provides for evaluation of potential therapies that target specific stages of the immune response.

Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes

“…While anti-HMGB1 pAb therapy increased survival in simple endotoxaemia and CLP sepsis, it was unknown whether anti-HMGB1 could potentiate immunosuppression and increased susceptibility to secondary infection. To investigate this, a ‘double-hit’ model of CLP-induced sepsis followed by bacterial challenge was employed, where sepsis survivors exhibit increased susceptibility to Pseudomonas challenge 42 . Anti-HMGB1 pAb-treated septic mice had a survival advantage compared to control mice following secondary infection and treatment was associated with improved antimicrobial responses as mice exhibited increased IL-12 and decreased IL-6 following infection.…”

Alterations in Antigen-Specific Naive CD4 T Cell Precursors after Sepsis Impairs Their Responsiveness to Pathogen Challenge

“…Yet, one weakness of these (and other well-characterized) experimental pathogens is that they are typically not seen as nosocomial infection threats for septic patients. Most septic patients potentially face complications arising from secondary infection by the extracellular pathogens Candida, Pseudomonas , and Staphylococcus (46, 80, 81), and these pathogens have been used most often to examine alterations in animal survival in experimental models of sepsis. It is important to keep in mind that our use of Lm-2W for most of the studies was to take advantage of the wealth of information known regarding the infectivity/pathogenicity of this pathogen, the characteristic CD4 T cell response that it elicits, and the availability of reagents to critically investigate different aspects of this response.…”

Mice Survival and Plasmatic Cytokine Secretion in a “Two Hit” Model of Sepsis Depend on Intratracheal Pseudomonas Aeruginosa Bacterial Load

“…[18], Muenzer et al . [17] and Pène et al . [19] induce pneumonia 24h, 3 days or 8 days after CLP respectively.…”

“…Although most animal models are not directly relevant to investigate human sepsis pathophysiology, appropriate animal models remain crucial either to understand the course of sepsis or to develop new therapies. Among all mice models, the Cecal Ligation and Puncture (CLP), a mouse model of peritonitis, closely replicates the clinical picture encountered in human patients and has become, as a gold standard model, the most frequently used model of sepsis [17–19]. Nevertheless, the way to perform CLP, the possible adjuvant therapeutics as in human sepsis (antibiotics, resuscitation, analgesia), the gender or the strain of the mouse can influence and change the characteristics of the model.…”