Role of Exostosin-1 in Regulating Hemorrhage-Induced Microvascular Dysfunction and Lung Injury
Abstract
Severe blood loss (“hemorrhage”) after traumatic injury is a leading cause of death both on and off the battlefield. Fluid resuscitation is the primary treatment for individuals with severe blood loss, with the goal being to restore circulating volume and maintain oxygen delivery to vital organs. Despite the lifesaving measures offered by fluid resuscitation, trauma patients who receive massive transfusions have an increased risk of developing acute lung injury (ALI) that is secondary to the initial trauma. A driving factor for the development of ALI after trauma is breakdown of the lining (“endothelium”) of blood vessels inside of the lungs. Damage to the lung endothelium causes the blood vessels to become “leaky,” allowing fluid and inflammatory cells to enter the lungs and cause tissue injury. Therapies that restore the integrity of the endothelium could prevent the development of ALI in trauma patients; however, currently, no therapies exist to repair leaky blood vessels. The overall goal of this work is to study mechanisms that promote damage to the lung endothelium so that targeted treatments can be developed to restore blood vessel integrity and reduce the risk of ALI for injured Soldiers and civilians. The proposed research will evaluate the role of a protein called exostosin-1 (Ext1) in mediating trauma-induced ALI. Ext1 is a protein found in many cell types that is important for the synthesis of heparan sulfate (HS), a type of sugar molecule found on the surface of cells. HS is the primary sugar found in the endothelial glycocalyx (GCX), a matrix-like layer that covers the surface of endothelial cells (EC) lining the inside of blood vessels. In normal conditions, the GCX functions as a physical barrier to protect EC and surrounding tissues from inflammation. However, after trauma-hemorrhage and resuscitation (THR), the GCX is damaged and HS is shed from the surface of EC. Loss of HS from the surface of EC contributes to blood vessel damage that drives the development of ALI in trauma patients. We posit that Ext1 regulates blood vessel damage after THR via its role in regulating HS synthesis. Thus, in the proposed studies, we will test the hypothesis that inhibition of Ext1 activity caused by THR contributes to decreased surface of expression of HS on EC, which compromises the function of the GCX as a physical barrier to maintain blood vessel integrity. We will also evaluate the therapeutic efficacy of sphingosine-1-phosphate (S1P), a fat-like molecule naturally present in blood. We will determine the ability of S1P to up-regulate EC levels of Ext1, increase HS expression, and restore blood vessel integrity after THR. In addition to directly regulating blood vessel integrity by contributing to the physical barrier formed by the GCX, HS may also regulate the production of other proteins that mediate blood vessel integrity. For example, our preliminary data indicate that EC with decreased surface expression of HS produce increased amounts of a protein called angiopoietin-2 (Agpt-2), a protein that causes inflammation and loss of blood vessel integrity. Agpt-2 may also contribute to the development of trauma-induced lung injury since patients with ALI have increased levels of Agpt-2 and inhibiting Agpt-2 in animals decreases the severity of lung injury caused by THR. In the proposed research, we will investigate the role of Ext1 in mediating EC production of Agpt-2 via its role in regulating EC expression of HS. The research in this application will evaluate the role of Ext1 in mediating GCX integrity and Agpt-2 release in the setting of THR, both of which are driving factors for loss of blood vessel barrier function that drives the development of ALI. Completion of these studies will uncover novel mechanisms that regulate blood vessel functionality and introduce new opportunities for targeted therapeutic strategies to prevent the progression of ALI in injured Soldiers and civilians.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010167
Entities
People
- Jillian R Richter
Organizations
- United States Army
- University of Alabama at Birmingham