Characterization and modulation of the immunosuppressive phase of sepsis.
Sepsis continues to cause significant morbidity and mortality in critically ill patients. Studies of patients and animal models have revealed that changes in the immune response during sepsis play a decisive role in the outcome. Using a clinically relevant two-hit model of sepsis, i.e., cecal ligation and puncture (CLP) followed by the induction of Pseudomonas aeruginosa pneumonia, we characterized the host immune response. Second, AS101 [ammonium trichloro(dioxoethylene-o,o')tellurate], a compound that blocks interleukin 10 (IL-10), a key mediator of immunosuppression in sepsis, was tested for its ability to reverse immunoparalysis and improve survival. Mice subjected to pneumonia following CLP had different survival rates depending upon the timing of the secondary injury. Animals challenged with P. aeruginosa at 4 days post-CLP had approximately 40% survival, whereas animals challenged at 7 days had 85% survival. This improvement in survival was associated with decreased lymphocyte apoptosis, restoration of innate cell populations, increased proinflammatory cytokines, and restoration of gamma interferon (IFN-gamma) production by stimulated splenocytes. These animals also showed significantly less P. aeruginosa growth from blood and bronchoalveolar lavage fluid. Importantly, AS101 improved survival after secondary injury 4 days following CLP. This increased survival was associated with many of the same findings observed in the 7-day group, i.e., restoration of IFN-gamma production, increased proinflammatory cytokines, and decreased bacterial growth. Collectively, these studies demonstrate that immunosuppression following initial septic insult increases susceptibility to secondary infection. However, by 7 days post-CLP, the host's immune system has recovered sufficiently to mount an effective immune response. Modulation of the immunosuppressive phase of sepsis may aid in the development of new therapeutic strategies.
Muenzer
Jared T
JT
Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. muenzer_j@kids.wustl.edu
Davis
Christopher G
CG
Chang
Kathy
K
Schmidt
Robert E
RE
Dunne
W Michael
WM
Coopersmith
Craig M
CM
Hotchkiss
Richard S
RS
D000818:Animals; D017209:Apoptosis; D001424:Bacterial Infections / Q000276:immunology* / Q000401:mortality; D001769:Blood / Q000382:microbiology; D015169:Colony Count, Microbial; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000276:immunology / Q000401:mortality; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000401:mortality; D018805:Sepsis / Q000276:immunology* / Q000401:mortality; D012720:Severity of Illness Index; D016019:Survival Analysis; D013997:Time Factors
D016207:Cytokines; D016753:Interleukin-10