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
Hobson, Charles; Lysak, Nicholas; Huber, Matthew et al. (2018) Epidemiology, outcomes, and management of acute kidney injury in the vascular surgery patient. J Vasc Surg 68:916-928
Sweeney, Timothy E; Perumal, Thanneer M; Henao, Ricardo et al. (2018) A community approach to mortality prediction in sepsis via gene expression analysis. Nat Commun 9:694
Loftus, Tyler J; Rosenthal, Martin D; Croft, Chasen A et al. (2018) The effects of beta blockade and clonidine on persistent injury-associated anemia. J Surg Res 230:175-180
Horiguchi, Hiroyuki; Loftus, Tyler J; Hawkins, Russell B et al. (2018) Innate Immunity in the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome and Its Implications for Therapy. Front Immunol 9:595
Loftus, Tyler J; Brakenridge, Scott C; Croft, Chasen A et al. (2018) Successful nonoperative management of uncomplicated appendicitis: predictors and outcomes. J Surg Res 222:212-218.e2
Guirgis, Faheem W; Leeuwenburgh, Christiaan; Grijalva, Victor et al. (2018) HDL Cholesterol Efflux is Impaired in Older Patients with Early Sepsis: A Subanalysis of a Prospective Pilot Study. Shock 50:66-70
Mira, Juan C; Nacionales, Dina C; Loftus, Tyler J et al. (2018) Mouse Injury Model of Polytrauma and Shock. Methods Mol Biol 1717:1-15
Loftus, Tyler J; Brakenridge, Scott C; Murphy, Travis W et al. (2018) Anemia and blood transfusion in elderly trauma patients. J Surg Res 229:288-293
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

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