Sepsis remains a serious clinical problem with substantial morbidity and mortality and even after extensive investigation there are important, unresolved issues in our understanding of the basic mechanisms of the disease process. Previous attempts at therapy were mostly directed at globally blunting the inflammatory response to sepsis. We have used the murine model of sepsis induced by cecal ligation and puncture (CLP) to closely examine basic mechanisms and find important differences between the early (first 5 days) and late phase of sepsis (beyond day 5). CLP may be performed in a manner to cause 50% mortality but a challenge has been to predict accurately which mice will live. A CLP model with 50% lethality provides much greater insight compared to a model with 100% lethality since therapies may increase or decrease survival, making the findings more clinically relevant. We have identified biomarkers which accurately predict 5 day sepsis survival. These biomarkers allow studies in mice which were not feasible even a few years ago. Animals may be sacrificed during the first 5 days of sepsis prior to their demise and analyses performed to evaluate mechanisms of subsequent mortality.
Specific aim one will attempt to improve survival by enhancing early recruitment of neutrophils into the peritoneal cavity to help eradicate the focus of infection. Toxicity studies will be performed to address the issue of whether increasing local levels of neutrophils contributes to substantial organ injury.
Specific aim two will look at whether increased levels of naturally occurring IgM antibodies directed against enteric bacteria serve as a primary determinant of outcome. This fits with the hypothesis that a portion of the complexity of the response to sepsis is the presence of circulating antibodies prior to the onset of sepsis which would opzonize bacteria to enhance their phagocytosis and killing by the neutrophils. In the third specific aim we will evaluate individually tailoring therapy in the early stages of sepsis using our novel multiplex format for measuring cytokines during the early phase of sepsis. Our work has identified critical plasma cytokine levels that accurately predict subsequent mortality. Only those cytokines which are elevated in the range associated with lethality will be blocked, rather than globally blunting inflammation such as occurs with high-dose glucocorticoids. The last specific aim will look at the chronic phase of sepsis, that which occurs beyond day 5 after CLP. Some of these mice died with excessive inflammation and some of them died with a blunted inflammatory response. Again using the multiplex approach we will tailor the therapy to the individual animal. Our overarching hypothesis is that the septic inflammatory response is dynamic and optimal therapy needs to be individually tailored or directed to early eradication of bacteria. Lay Language: Many patients still die from severe bacterial infections even when they are treated with the correct antibiotics. It is not clear why these patients die. We will use an animal model to determine how bacteria injure kill patients and how to prevent this.

Public Health Relevance

Many patients still die from severe bacterial infections even when they are treated with the correct antibiotics. It is not clear why these patients die, or the best method to treat the patients. We will use an animal model to help us understand how bacteria kill patients and how to prevent this.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM082962-04
Application #
8223131
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2009-04-01
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$330,478
Indirect Cost
$127,107
Name
Boston University
Department
Pathology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Iskander, Kendra N; Craciun, Florin L; Stepien, David M et al. (2013) Cecal ligation and puncture-induced murine sepsis does not cause lung injury. Crit Care Med 41:159-70
Moitra, Rituparna; Beal, Dominic R; Belikoff, Bryan G et al. (2012) Presence of preexisting antibodies mediates survival in sepsis. Shock 37:56-62
Belikoff, Bryan; Hatfield, Stephen; Sitkovsky, Michail et al. (2011) Adenosine negative feedback on A2A adenosine receptors mediates hyporesponsiveness in chronically septic mice. Shock 35:382-7
Stearns-Kurosawa, Deborah J; Osuchowski, Marcin F; Valentine, Catherine et al. (2011) The pathogenesis of sepsis. Annu Rev Pathol 6:19-48

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