There is a fundamental gap in the understanding between syndecan-1 (sdc-1) shedding and mortality in severely injured patients in hemorrhagic shock (HS). Additionally, our knowledge of the precise cellular and molecular mechanisms responsible for reduced mortality by the early use of fresh frozen plasma (FFP) after HS is limited. While the long term goal is to understand the molecular link between HS-induced sdc-1 shedding and vascular instability, the objective of the current application is to identify how sdc- shedding contributes to vascular instability after HS and how shed sdc-1 is reconstituted by FFP. The central hypothesis is that 1) HS induces sdc-1 shedding from the endothelium;2) sdc-1 shedding leads to vascular instability and organ injury;and 3) FFP based resuscitation repairs vascular instability and organ injury by restoring sdc-1 expression. This hypothesis is based on preliminary data which demonstrates the feasibility of studying syndecan biology in a model of HS. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Examine HS-induced sdc-1 ectodomain shedding and restitution;2) Investigate the mechanism of sdc-1 shedding and restitution after HS;and 3) Investigate the specific contribution of endothelial syndecan-1 to restoration of vascular stability after HS. The approaches are innovative because they focus for the first time on shedding of sdc-1 after hemorrhagic shock and its restitution by FFP based resuscitationon. The proposed research is significant because it is expected to advance the understanding of HS-induced sdc-1 shedding and vascular hyperpermeability and to provide a mechanistic foundation to guide the use of FFP. The conclusions from this work are expected to not only help guide current therapies, but facilitate the development of novel strategies to reduce HS-related deaths after severe injury.

Public Health Relevance

The proposed research is relevant to public health because it will provide insight into how FFP restores endothelial syndecan-1 and vascular stability, thus repairing the injured endothelium and potentially reducing death after hemorrhagic shock in injured patients. The proposed research is relevant to NIH's mission pertaining to the application of knowledge that will enhance health and reduce the burden of illness.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Somers, Scott D
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University of Texas Health Science Center Houston
Schools of Medicine
United States
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Wu, Feng; Kozar, Rosemary A (2018) Fibrinogen Protects Against Barrier Dysfunction Through Maintaining Cell Surface Syndecan-1 in-vitro. Shock :
Pati, Shibani; Peng, Zhanglong; Wataha, Katherine et al. (2018) Lyophilized plasma attenuates vascular permeability, inflammation and lung injury in hemorrhagic shock. PLoS One 13:e0192363
Wu, Feng; Peng, Zhanglong; Park, Pyong Woo et al. (2017) Loss of Syndecan-1 Abrogates the Pulmonary Protective Phenotype Induced by Plasma After Hemorrhagic Shock. Shock 48:340-345
Kozar, Rosemary A (2017) Re: ADAM-17: A potential therapeutic target to prevent organ injury after hemorrhagic shock? J Trauma Acute Care Surg 82:976-977
Peng, Zhanglong; Ban, Kechen; LeBlanc, Anthony et al. (2016) Intraluminal tranexamic acid inhibits intestinal sheddases and mitigates gut and lung injury and inflammation in a rodent model of hemorrhagic shock. J Trauma Acute Care Surg 81:358-65
Peng, Zhanglong; Pati, Shibani; Fontaine, Magali J et al. (2016) Lack of species-specific difference in pulmonary function when using mouse versus human plasma in a mouse model of hemorrhagic shock. J Trauma Acute Care Surg 81:S171-S176
Kozar, Rosemary A; Pati, Shibani (2015) Syndecan-1 restitution by plasma after hemorrhagic shock. J Trauma Acute Care Surg 78:S83-6
Ban, Kechen; Peng, Zhanglong; Pati, Shibani et al. (2015) Plasma-Mediated Gut Protection After Hemorrhagic Shock is Lessened in Syndecan-1-/- Mice. Shock 44:452-7
Peng, Zhanglong; Pati, Shibani; Potter, Daniel et al. (2013) Fresh frozen plasma lessens pulmonary endothelial inflammation and hyperpermeability after hemorrhagic shock and is associated with loss of syndecan 1. Shock 40:195-202
Peng, Zhanglong; Ban, Kechen; Sen, Aritra et al. (2012) Syndecan 1 plays a novel role in enteral glutamine's gut-protective effects of the postischemic gut. Shock 38:57-62

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