There is increasing recognition that the management of post-surgical and post-trauma sepsis is improving, and the incidence of both multiple organ failure (MOF) and in-hospital mortality are decreasing. Although these trends are generally favorable, there is a dark side to the reduced in-hospital mortality. Associated with this is the appearance of a new phenotype of chronically, critically ill (CCI) patients that we have termed PICS (persistent inflammation/immunosuppression and catabolism syndrome). This project seeks to identify the underlying mechanism(s) that result in the development of PICS. Our overarching hypothesis is that sepsis drives the expansion of myeloid-derived suppressor cells (MDSCs) (Specific Aim #1), and it is the activity of these suppressor cells which contributes to the development of PICS in patients with CCI (Specific Aims #2,3). We have three specific aims:
Specific Aim #1 : to determine whether CCI is associated with the early and sustained expansion of MDSC populations (>15% of total leukocyte population) in sepsis patients. We anticipate that patients with sepsis who have an uncomplicated hospital course will have an early rise in the numbers of MDSCs, but these will resolve rapidly with time. In contrast, patients who develop CCI will experience a sustained and heightened rise in MDSCs with both an increased suppressor and inflammatory phenotypes.
Specific Aim #2 : to determine whether the persistent expansion of MDSCs is an essential requirement for morbid outcomes and an ongoing inflammatory, immunosuppressive and catabolic response (PICS) in CCI patients. We hypothesize that the persistent expansion of MDSCs is an essential requirement for morbid outcomes and the development of PICS in patients with CCI. MDSC expansion and a detailed analysis of PICS will be conducted in patients with CCI and associated with long-term outcomes (survival and complete functional dependence) determined in Project #1.
Specific Aim #3 : to determine in a murine model of polymicrobial sepsis (cecal ligation and puncture) whether blockade of MDSC expansion prevents the development of PICS and supports protective immunity. To explore a causal relationship between MDSC expansion and the development of PICS, we will use two independent methods to block the expansion of MDSCs, and examine whether PICS develops, and protective immunity is either suppressed or maintained. The overall goal of Project #2 is to test the hypotheses that 1) sepsis drives the initial expansion of MDSCs, and 2) the chronic and continued expansion of the MDSC population is required for the PICS phenotype, and dismal long-term outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
1P50GM111152-01
Application #
8740720
Study Section
Special Emphasis Panel (ZGM1)
Project Start
2014-09-01
Project End
2019-05-31
Budget Start
2014-09-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
DUNS #
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Sartelli, Massimo; Kluger, Yoram; Ansaloni, Luca et al. (2018) Raising concerns about the Sepsis-3 definitions. World J Emerg Surg 13:6
Loftus, Tyler J; Rosenthal, Martin D; Croft, Chasen A et al. (2018) Effect of Time to Operation on Value of Care in Acute Care Surgery. World J Surg 42:2356-2363
Loftus, Tyler J; Efron, Philip A; Bala, Trina M et al. (2018) The impact of standardized protocol implementation for surgical damage control and temporary abdominal closure after emergent laparotomy. J Trauma Acute Care Surg :
Loftus, Tyler J; Mira, Juan C; Stortz, Julie A et al. (2018) Persistent Inflammation and Anemia among Critically Ill Septic Patients. J Trauma Acute Care Surg :
Efron, Philip A; Mohr, Alicia M; Bihorac, Azra et al. (2018) Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery. Surgery 164:178-184
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Loftus, Tyler J; Mohr, Alicia M; Moldawer, Lyle L (2018) Dysregulated myelopoiesis and hematopoietic function following acute physiologic insult. Curr Opin Hematol 25:37-43
Bihorac, Azra; Ozrazgat-Baslanti, Tezcan; Ebadi, Ashkan et al. (2018) MySurgeryRisk: Development and Validation of a Machine-learning Risk Algorithm for Major Complications and Death After Surgery. Ann Surg :
Loftus, Tyler J; Kannan, Kolenkode B; Carter, Christy S et al. (2018) Persistent injury-associated anemia in aged rats. Exp Gerontol 103:63-68
Stortz, Julie A; Mira, Juan C; Raymond, Steven L et al. (2018) Benchmarking clinical outcomes and the immunocatabolic phenotype of chronic critical illness after sepsis in surgical intensive care unit patients. J Trauma Acute Care Surg 84:342-349

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