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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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
Rosenthal, Martin D; Kamel, Amir Y; Rosenthal, Cameron M et al. (2018) Chronic Critical Illness: Application of What We Know. Nutr Clin Pract 33:39-45
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
Raymond, Steven L; Hawkins, Russell B; Murphy, Tyler J et al. (2018) Impact of toll-like receptor 4 stimulation on human neonatal neutrophil spontaneous migration, transcriptomics, and cytokine production. J Mol Med (Berl) 96:673-684
Davoudi, Anis; Corbett, Duane B; Ozrazgat-Baslanti, Tezcan et al. (2018) Activity and Circadian Rhythm of Sepsis Patients in the Intensive Care Unit. IEEE EMBS Int Conf Biomed Health Inform 2018:17-20
Loftus, Tyler J; Morrow, Megan L; Lottenberg, Lawrence et al. (2018) The Impact of Prior Laparotomy and Intra-abdominal Adhesions on Bowel and Mesenteric Injury Following Blunt Abdominal Trauma. World J Surg :
Loftus, Tyler J; Mira, Juan C; Miller, Elizabeth S et al. (2018) The Postinjury Inflammatory State and the Bone Marrow Response to Anemia. Am J Respir Crit Care Med 198:629-638

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