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.

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National Institute of General Medical Sciences (NIGMS)
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University of Florida
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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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