The overall hypothesis of this program is that persistent inflammation, immunosuppression and catabolism (PICS) are the hallmarks of pathophysiologic processes leading to decreases in long-term survival and functional capacity in patients with chronic critical illness (CCI). While persistent expansion of myeloid-derived suppressor cells (MDSC;Project #2) is a key underlying mechanism of immunosuppression and inflammation in CCI, this project investigates the mechanism by which kidney damage in sepsis initiates an anti-angiogenic state that augments and perpetuates inflammation, immunosuppression, and catabolism in CCI. During sepsis, infection, via toll-like receptors, and hypoxia leads to activation of hypoxia inducible factor (HIF)-1 and subsequent upregulation of angiogenic factors (erythropoietin (EPO) and vascular endothelial growth factor (VEGF)). We have previously shown that the heterodimeric EPO receptor (consisting of the EPO receptor and ?-common receptor (?cR)) interacts with VEGF receptor 2 (VEGFR-2) to mobilize bone marrow derived angiogenic cells, which can contribute to the endothelial repair. EPO and VEGF can both initiate the anti- angiogenic response of upregulation of soluble VEGR-2 (sFlt-1) and angiopoietin-2 (ANG-2). While sFlt-1 binds VEGF reducing its circulating levels and counteracting its effect, unopposed EPO leads to persistent sFlt-1 and ANG-2 elevation and VEGF suppression. Our hypothesis, is that patients in whom kidney damage in sepsis results in an exaggerated EPO response, relative to VEGF, the stimulation of sFlt-1 leads to a persistence of an anti-angiogenic (low levels of VEGF and elevated ANG-2), inflammatory (elevated EPO) state. The investigators propose to examine kidney damage in septic patients as a predictor of anti-angiogenic imbalance and to determine whether anti-angiogenic balance is associated with increased expansion of MDSCs (as determined in Project #2) and increased likelihood of PICS, characterized by morbid long-term outcome (Project #1). The direct effect of increased EPO production on MDSC expansion will be tested in murine models of chronic sepsis using the ?cR knockout mouse.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
1P50GM111152-01
Application #
8740721
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
Mira, Juan C; Brakenridge, Scott C; Moldawer, Lyle L et al. (2017) Persistent Inflammation, Immunosuppression and Catabolism Syndrome. Crit Care Clin 33:245-258
Alamo, Ines G; Kannan, Kolenkode B; Loftus, Tyler J et al. (2017) Severe trauma and chronic stress activates extramedullary erythropoiesis. J Trauma Acute Care Surg 83:144-150
Loftus, Tyler J; Raymond, Steven L; Sarosi Jr, George A et al. (2017) Predicting appendiceal tumors among patients with appendicitis. J Trauma Acute Care Surg 82:771-775
Mathias, Brittany; Delmas, Amber L; Ozrazgat-Baslanti, Tezcan et al. (2017) Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock. Ann Surg 265:827-834
Mira, Juan C; Cuschieri, Joseph; Ozrazgat-Baslanti, Tezcan et al. (2017) The Epidemiology of Chronic Critical Illness After Severe Traumatic Injury at Two Level-One Trauma Centers. Crit Care Med 45:1989-1996
Loftus, Tyler J; Mira, Juan C; Ozrazgat-Baslanti, Tezcan et al. (2017) Sepsis and Critical Illness Research Center investigators: protocols and standard operating procedures for a prospective cohort study of sepsis in critically ill surgical patients. BMJ Open 7:e015136
Lysak, Nicholas; Bihorac, Azra; Hobson, Charles (2017) Mortality and cost of acute and chronic kidney disease after cardiac surgery. Curr Opin Anaesthesiol 30:113-117
Loftus, Tyler J; Jordan, Janeen R; Croft, Chasen A et al. (2017) Temporary abdominal closure for trauma and intra-abdominal sepsis: Different patients, different outcomes. J Trauma Acute Care Surg 82:345-350
Loftus, Tyler J; Brakenridge, Scott C; Dessaigne, Camille G et al. (2017) Antibiotics May be Safely Discontinued Within One Week of Percutaneous Cholecystostomy. World J Surg 41:1239-1245
Stortz, Julie A; Efron, Philip A (2017) Editorial: Myeloid-derived suppressor cells: a new therapeutic target in sepsis patients. J Leukoc Biol 102:185-187

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