Glycocalyx Mechanoregulation of Angiopoietin-2 and Post-Traumatic 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 life-saving 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 allows fluid and inflammatory cells to enter the lungs causing tissue injury. The overall goal of this work is to study trauma-related factors that cause damage to the lung endothelium in order to develop a treatment to prevent breakdown of the endothelium and reduce the risk of ALI after trauma. The glycocalyx (GCX) is a matrix-like layer that covers the inner surface of endothelial cells lining the inside of blood vessels. In normal conditions, the GCX functions as a barrier to protect endothelial cells and surrounding tissues from inflammation. The GCX also serves as a sensor of mechanical forces that are imposed by blood flow through the vessels. In response to changes in blood flow, the GCX initiates cellular signaling that allows the endothelial cell to adapt its behavior to the blood flow environment. It is well established that damage to the GCX is a critical mediator of endothelial cell damage and lung injury after trauma. In response to injury and subsequent traumatic-hemorrhage and resuscitation, an enzyme called “heparanase” is activated that degrades the GCX and causes damage to the endothelium. In addition to directly contributing to breakdown of the endothelium, we propose that GCX damage also impairs the ability of endothelial cells to appropriately respond to changes in blood flow caused by hemorrhage and subsequent resuscitation. Our studies will focus on how GCX damage leads to impaired signaling that results in the production of Angiopoietin-2 (Agpt-2), a potent mediator of endothelial cell damage that is a critical factor in the progression of ALI after trauma. The overall hypothesis of this research is that heparanase (activated by traumatic-hemorrhage and resuscitation) causes GCX damage and increased Agpt-2 production leading to endothelial damage and ALI. The proposed research focuses on the Topic Area of “Acute Lung Injury.” We will work to understand how heparanase activity and impaired GCX signaling regulates ALI after traumatic-hemorrhage and resuscitation. We will use a cell culture model of hemorrhage and resuscitation that allows us to study the effects of disturbed flow on the GCX and on GCX-dependent signaling that regulates endothelial cell damage. We will measure heparanase activity in the plasma of trauma patients and evaluate the efficacy of a therapeutic heparanase inhibitor (“Roneparstat”) at preventing GCX damage and maintaining normal endothelial cell function. Finally, we will determine if Roneparstat can be used as a treatment administered during resuscitation to prevent lung injury in mice after trauma-hemorrhage. The proposed studies will investigate post-traumatic ALI from the novel perspective of the endothelial GCX and its role as a mechanoregulator of endothelial cell function. The implications for impaired GCX mechanosignaling in the setting of hemorrhage and resuscitation are previously unexplored. Our work will establish the foundation for new a treatment to reduce endothelial damage caused by trauma, hemorrhage, and resuscitation as a strategy for preventing death from ALI in trauma patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810108
Entities
People
- Jillian R Richter
Organizations
- United States Army
- University of Alabama at Birmingham