As regional trauma systems mature and early interventions improve, severely injured patients who would have previously died, now survive but are at high risk for multiple organ failure (MOF). With advances in intensive care unit (ICU) therapy, the mortality of MOF is decreasing, but.it still remains the leading cause of late ICU deaths and prolonged hospital stays. MOF occurs as a result of a dysfunctional inflammatory response. The gastrointestinal tract is both an instigator and a victim of this response, and the resulting gut dysfunctions contribute to ongoing MOF. A multidisciplinary team of basic and clinical scientists will continue to characterize gut injury and dysfunction in laboratory models of hemorrhagic shock, ischemia/reperfusion (I/R), and sepsis. In this funding cycle, they will test the HYPOTHESIS that therapeutic interventions can modulate gut inflammation and resulting gut dysfunction in critically injured patients to improve outcome. To make meaningful advances a better understanding of the molecular events that regulate gut inflammation is needed. We will therefore characterize cell specific molecular programs that activate pro- and anti-inflammation after mesenteric I/R and investigate how these are modulated by different protective interventions (ischemic preconditioning, hypothermia, alpha-melanocyte stimulating hormone) to identify common pathways to limit gut injury and/or hasten its repair. Resuscitation is an obligatory intervention that saves lives. The current standard of care is early volume loading with isotonic crystalloids (principally lactated Ringer's) and blood transfusions to limit the severity of the ischemic insult. For severe shock, this approach could be improved by modifying it to minimize iatrogenic gut edema and by altering it to specifically control gut I/R induced inflammation. We will therefore study the factors that cause problematic bowel edema with standard of care isotonic crystalloid resuscitation and how increasing edema affects vital gut functions. We will focus on how alternative resuscitation strategies (hypertonic saline with or without colloids) can favorably modulate gut I/R induced inflammation. Enteral nutrition (EN) is another important aspect of care that improves patient outcome. Unfortunately, gastric injury and dysfunction impair the ability to enterally feed high risk patients as well as mandate the use of expensive and potentially harmful prophylaxis against stress gastritis. We will study how resuscitation, sedatives, and analgesics can modify the inflammatory response in the stomach to limit mucosal injury and improve gastric emptying. We will study how the novel intraluminal interventions can modify inflammation in the stomach and ileum to preserve barrier function. Knowledge from these projects will allow modification of routine care to facilitate gastric feeding and to expand the definition of EN to include intraluminal agents whose role is to limit gut inflammation and dysfunction to enhance EN tolerance. Simultaneously, in our HUMAN SUBJECTS CORE laboratory observations will be tested in focused observational studies to determine their relevance in human pathophysiology. These clinical observations will in turn redirect ongoing laboratory investigations and serve as pilot and feasibility data to leverage funding for larger clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
2P50GM038529-15A1
Application #
6812620
Study Section
Special Emphasis Panel (ZGM1-TB-6 (01))
Program Officer
Somers, Scott D
Project Start
1997-07-01
Project End
2009-05-31
Budget Start
2004-09-06
Budget End
2005-05-31
Support Year
15
Fiscal Year
2004
Total Cost
$1,502,754
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Surgery
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Galvagno Jr, Samuel M; Fox, Erin E; Appana, Savitri N et al. (2017) Outcomes Following Concomitant Traumatic Brain Injury and Hemorrhagic Shock: A Secondary Analysis from the PROPPR Trial. J Trauma Acute Care Surg :
Galvagno Jr, Samuel M; Fox, Erin E; Appana, Savitri N et al. (2017) Outcomes after concomitant traumatic brain injury and hemorrhagic shock: A secondary analysis from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios trial. J Trauma Acute Care Surg 83:668-674
Moore, Frederick A; Moore, Ernest E; Billiar, Timothy R et al. (2017) The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure. J Trauma Acute Care Surg 83:520-531
Deng, Xiyun; Cao, Yanna; Huby, Maria P et al. (2016) Adiponectin in Fresh Frozen Plasma Contributes to Restoration of Vascular Barrier Function After Hemorrhagic Shock. Shock 45:50-54
Matijevic, Nena; Wang, Yao-Wei W; Holcomb, John B et al. (2015) Microvesicle phenotypes are associated with transfusion requirements and mortality in subjects with severe injuries. J Extracell Vesicles 4:29338
Kozar, Rosemary A; Pati, Shibani (2015) Syndecan-1 restitution by plasma after hemorrhagic shock. J Trauma Acute Care Surg 78:S83-6
Hobson, Charles; Singhania, Girish; Bihorac, Azra (2015) Acute Kidney Injury in the Surgical Patient. Crit Care Clin 31:705-23
Adams, Sasha D; Cotton, Bryan A; Wade, Charles E et al. (2013) Do not resuscitate status, not age, affects outcomes after injury: an evaluation of 15,227 consecutive trauma patients. J Trauma Acute Care Surg 74:1327-30
Radwan, Zayde A; Bai, Yu; Matijevic, Nena et al. (2013) An emergency department thawed plasma protocol for severely injured patients. JAMA Surg 148:170-5
Dial, Elizabeth J; Tran, Duy M; Hyman, Ari et al. (2013) Endotoxin-induced changes in phospholipid dynamics of the stomach. J Surg Res 180:140-6

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