Therapies to reduce the mortality of sepsis still need to be developed due to the high morbidity and mortality of the disease. We have strong preliminary data indicating that local tissue hypoxia coupled with an increase in extracellular adenosine suppresses the ability of cells to eradicate bacteria. Failure to appropriately control bacteria results in excessive and prolonged inflammation. This proposal will evaluate 2 different modalities to treat sepsis by 1) blocking specific adenosine receptors and 2) providing supplemental oxygen. To increase the applicability of the findings, 4 different murine sepsis models will be studied. The first model is the acute phase of sepsis present in the first four days after cecal ligation and puncture (CLP) and the second model is the chronic phase of sepsis where deaths occur after day five. The third sepsis model evaluates the treatment modalities in a model of trauma (abdominal incision) plus Pseudomonas pneumonia. The fourth will use the recently developed humanized mouse model of sepsis induced by CLP. Our first specific aim will closely study the role of adenosine in sepsis by treating septic mice with specific A2A and A2B receptor antagonists. We will confirm the specificity of these findings using A2A and A2B receptor knockout mice. A novel approach of using biomarkers to direct blockade of the adenosine receptors will also be employed.
The second aim will verify that local hypoxia occurs during sepsis and provide supplemental oxygen to improve outcome.
The third aim will combine adenosine receptor blockade with supplemental oxygen to determine the potential synergistic interactions of the treatments. The fourth specific aim will closely examine the cellular mechanisms of how these treatment strategies improve outcome by determining the augmented pathways that result in improved bacterial clearance. If successful, this application offers both new treatment strategies for sepsis, and the mechanistic knowledge to understand why they are effective.

Public Health Relevance

The project will try and find new ways to treat severe bacterial infections. We believe that providing a small amount of oxygen and blocking receptors on cells will help these cells kill the bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097320-04
Application #
8668080
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2011-09-26
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$302,762
Indirect Cost
$62,762
Name
Boston University
Department
Pathology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Mella, Juan R; Chiswick, Evan; Stepien, David et al. (2017) Antagonism of the Neurokinin-1 Receptor Improves Survival in a Mouse Model of Sepsis by Decreasing Inflammation and Increasing Early Cardiovascular Function. Crit Care Med 45:e213-e221
Kasotakis, George; Galvan, Manuel; King, Elizabeth et al. (2017) Valproic acid mitigates the inflammatory response and prevents acute respiratory distress syndrome in a murine model of Escherichia coli pneumonia at the expense of bacterial clearance. J Trauma Acute Care Surg 82:758-765
Osuchowski, Marcin F; Thiemermann, Christoph; Remick, Daniel G (2017) Sepsis-3 on the Block: What Does It Mean for Preclinical Sepsis Modeling? Shock 47:658-660
Ashley, Scott N; Somanathan, Suryanarayan; Hinderer, Christian et al. (2017) Alternative Start Sites Downstream of Non-Sense Mutations Drive Antigen Presentation and Tolerance Induction to C-Terminal Epitopes. J Immunol 198:4581-4587
Hsieh, Terry; Vaickus, Max H; Stein, Thor D et al. (2016) The Role of Substance P in Pulmonary Clearance of Bacteria in Comparative Injury Models. Am J Pathol 186:3236-3245
Fan, Shu-Ling; Miller, Nancy S; Lee, John et al. (2016) Diagnosing sepsis - The role of laboratory medicine. Clin Chim Acta 460:203-10
Chiswick, Evan L; Mella, Juan R; Bernardo, John et al. (2015) Acute-Phase Deaths from Murine Polymicrobial Sepsis Are Characterized by Innate Immune Suppression Rather Than Exhaustion. J Immunol 195:3793-802
Byrne-Dugan, Cathryn J; Cederroth, Terra A; Deshpande, Anita et al. (2015) The Processing of Surgical Specimens With Forensic Evidence: Lessons Learned From the Boston Marathon Bombings. Arch Pathol Lab Med 139:1024-7
Bauzá, Gustavo; Remick, Daniel (2015) Caffeine Improves Heart Rate Without Improving Sepsis Survival. Shock 44:143-8
Osuchowski, Marcin F; Radermacher, Peter; Remick, Daniel G et al. (2014) The august krogh principle: seeking unity in diversity: reply. Shock 42:480-1

Showing the most recent 10 out of 33 publications