Cancer is the most common comorbidity in septic patients with nearly 93,000 cases annually. Importantly, cancer is also the comorbidity associated with the highest risk of death in patients with sepsis. We have created a murine model that replicates the increased mortality seen in septic patients with cancer compared to previously healthy patients who develop sepsis. The first goal of this proposal is to understand possible mechanisms through which pre-existing cancer increases mortality when a host develops sepsis. Based upon preliminary data, both the immune system and gut integrity appear to be involved, so each of these will be examined in detail. Experiments will be performed in multiple models of sepsis with multiple tumor lines to determine whether results are generalizable or specific to either type of sepsis or type of cancer. Additionally, there is extensive data from multiple investigative groups that apoptosis prevention in either lymphocytes or the gut epithelium improves survival in previously health rodents with sepsis. However, when this strategy is used in septic mice with cancer, the precise opposite is found with apoptosis prevention either markedly increasing mortality (lymphocytes) or losing its efficacy (intestine). The proposal seeks to understand why a beneficial therapy that has widespread acceptance as a possible treatment approach for patients turns deadly if sepsis occurs in the setting of cancer. Since efforts are currently being made to translate apoptosis prevention into treatment that can be used at the bedside for septic patients, this proposal could potentially change entry criteria and/or prevent inadvertent mortality in patients undergoing clinical trials of apoptosis prevention in sepsis. Thus, the proposal seeks to understand a subpopulation within sepsis that may require a different therapeutic approach than a """"""""typical"""""""" septic host, and this may have significant implications in a disease that is both very common and highly lethal.

Public Health Relevance

Cancer is the most common comorbidity in septic patients with nearly 93,000 cases annually, and cancer is also the comorbidity associated with the highest risk of death in patients with sepsis. Although apoptosis prevention improves survival in previously health rodents with sepsis, apoptosis prevention markedly increases mortality in septic mice with cancer. Understanding a) why mortality is higher in septic hosts with cancer compared to previously healthy septic hosts and b) why a beneficial therapeutic approach turns deadly if sepsis occurs in the setting of cancer may therefore have significant therapeutic implications in a disease that is both very common and highly lethal.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM104323-01
Application #
8425493
Study Section
Special Emphasis Panel (ZRG1-SBIB-J (02))
Program Officer
Dunsmore, Sarah
Project Start
2013-06-01
Project End
2017-03-31
Budget Start
2013-06-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$296,400
Indirect Cost
$106,400
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
McConnell, Kevin W; Coopersmith, Craig M (2016) Pathophysiology of septic shock: From bench to bedside. Presse Med 45:e93-8
Lyons, John D; Ford, Mandy L; Coopersmith, Craig M (2016) The Microbiome in Critical Illness: Firm Conclusions or Bact to Square One? Dig Dis Sci 61:1420-1
Klingensmith, Nathan J; Yoseph, Benyam P; Liang, Zhe et al. (2016) Epidermal Growth Factor Improves Intestinal Integrity and Survival in Murine Sepsis Following Chronic Alcohol Ingestion. Shock :
Diller, Maggie L; Kudchadkar, Ragini R; Delman, Keith A et al. (2016) Balancing Inflammation: The Link between Th17 and Regulatory T Cells. Mediators Inflamm 2016:6309219
Liu, Danya; Burd, Eileen M; Coopersmith, Craig M et al. (2016) Retrogenic ICOS Expression Increases Differentiation of KLRG-1hiCD127loCD8+ T Cells during Listeria Infection and Diminishes Recall Responses. J Immunol 196:1000-12
Yoseph, Benyam P; Klingensmith, Nathan J; Liang, Zhe et al. (2016) Mechanisms of Intestinal Barrier Dysfunction in Sepsis. Shock 46:52-9
Klingensmith, Nathan J; Coopersmith, Craig M (2016) The Gut as the Motor of Multiple Organ Dysfunction in Critical Illness. Crit Care Clin 32:203-12
Diller, Maggie L; Kudchadkar, Ragini R; Delman, Keith A et al. (2016) Exogenous IL-2 Induces FoxP3+ Th17 Cells In Vivo in Melanoma Patients. J Immunother 39:355-366
Lyons, John D; Mittal, Rohit; Fay, Katherine T et al. (2016) Murine Lung Cancer Increases CD4+ T Cell Apoptosis and Decreases Gut Proliferative Capacity in Sepsis. PLoS One 11:e0149069
Mittal, Rohit; Chen, Ching-Wen; Lyons, John D et al. (2015) Murine lung cancer induces generalized T-cell exhaustion. J Surg Res 195:541-9

Showing the most recent 10 out of 17 publications