Cell-Specific microRNA Regulation of Ventilation-Induced Lung Injury During Hemorrhagic Shock
Abstract
Peer Reviewed Medical Research Program Topic Areas: Acute Lung Injury and Respiratory Health Military personnel who experience blast injuries, burn injuries, and other traumatic events in the battlefield often experience significant blood loss, a.k.a. hemorrhagic shock, that requires critical care treatment. These patients must be resuscitated and stabilized and frequently need to be placed on life support using a mechanical ventilator. Unfortunately, hemorrhagic shock and resuscitation (HSR) cause significant damage to the lung and even though mechanical ventilation (MV) can be life-saving for these patients, it can also cause further lung injury. As a result, the mortality rate for this condition, known as the acute respiratory distress syndrome (ARDS), is very high (~30%-40%). Currently, the cellular and molecular mechanisms by which the mechanical forces generated during MV exacerbate lung injury during HSR are not known. As a result, there are no effective pharmacological therapies for HSR-induced ARDS. MicroRNAs are an important class of molecules that the body uses to regulate gene expression and represent an innovative way to treat many human diseases. For example, many cancers have been shown to be caused, in part, by malfunctioning microRNAs, and several microRNAs are being investigated as novel therapies for cancer. However, there is little to no information about the role microRNAs play in the development of HSR-induced ARDS. Based on a few recent studies, there is a strong rationale for why two specific microRNAs (miR-146a and miR-155) may represent attractive therapeutic candidates. However, there are no studies that directly test the effectiveness of these microRNAs in systems that mimic the complex physiology associated with HSR and ARDS. Therefore, the overall goal of our Discovery Award proposal is to use novel approaches to demonstrate the therapeutic potential of using miR-146a and miR-155 to reduce MV- and HSR-induced lung damage during ARDS. The use of microRNAs to treat ARDS in general and HSR-induced ARDS in particular is highly innovative and represents an entirely new area of investigation. In addition to investigating a highly innovative idea, this proposal will also use a highly innovative set of experimental tools to establish the importance of microRNAs in HSR-induced ARDS. One such tool is a novel “lung-on-a-chip” device, which is a miniature model of the human lung that is able to perform several of the normal functions of lung cells including the stretching that occurs with breathing. Unlike costly animal studies, this system can be used to efficiently evaluate how delivering miR-146a and miR-155 to specific primary human lung cells alters MV- and HSR-induced lung damage and to determine exactly how these microRNAs work. In addition, this proposal will also use novel drug delivery tools to demonstrate the therapeutic potential of these microRNAs. Specifically, novel nanotechnology tools will be used to deliver miR-146a and miR-155 to specific cells in the lung in order to avoid potential side effects. As a result, this proposal will use innovative technologies to establish a highly novel research area which seeks to develop a potential treatment for patients with HSR-induced ARDS for whom there are currently no effective therapies. The long-term impact of these studies is the development of a new pharmacologic way to prevent and/or treat ARDS in military personnel and therefore reduce the unacceptably high mortality rate of this disease. These studies could also lead to the development of microRNA therapies for other forms of ARDS from causes such as pneumonia and other infections.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910210
Entities
People
- Samir N. Ghadiali
Organizations
- Ohio State University
- United States Army