Manipulating the Macrophage Iron-Hepcidin Axis to Prevent Acute Lung Injury-Acute Respiratory Distress Syndrome Secondary to Severe Trauma and Hemorrhagic Shock
Abstract
Topic Area: Our Discovery Award proposal directly addresses the Fiscal Year 2016 Peer Reviewed Medical Research Program area of "Acute Lung Injury." Specifically, our proposal addresses the following area of encouragement within the topic of acute lung injury: "Preventive techniques, novel detection technologies, and therapeutics to reduce the incidence and/or severity of ARDS and/or other lung injury secondary to trauma, transfusion, burns, hemorrhagic shock, and/or oxygen exposure." Central Problem Addressed by This Proposal: Acute traumatic injury (such as from motor vehicle accidents, falls, or injuries sustained in military combat) extract an extremely high cost from our society. Trauma is the commonest cause of death in people below 45 years of age, and accounts for 30% of all "life years" lost in the United States (compared to 16% from cancer and 12% from heart disease) according to the National Trauma Institute. Many trauma victims die at the scene of the trauma from severe blood loss or head injury. Once they are at a hospital, the most common cause of death in these patients is multiple organ failure, or the gradual "shut-down" of vital organs such as the kidneys, liver, and lungs. Injury to the lungs, or trauma-induced acute lung injury, is one of the most important complications leading to worse outcomes in patients with severe injury and blood loss. In spite of intense investigative efforts over many years, we do not have effective biologic targets that we can modify to reduce the risk of developing lung injury. Our Discovery Award proposal will test the hypothesis that one of the most important consequences of injury and blood loss is to increase the iron content of some types of white blood cells, particularly monocytes and macrophages, which are a critical part of the body s response to severe injury and bleeding. These iron-laden cells (or "primed" cells) now become more prone to unleashing a devastating inflammatory response when exposed to a second "hit," such as an infection, leading to trauma-induced acute lung injury. The aim of our study is to decrease the iron in monocytes and macrophages by using iron "chelators" that can decrease the iron content of cells. We believe that if we are successful in decreasing monocyte/macrophage iron content, patients suffering from injury and blood loss will be much less likely to experience acute lung injury as a complication. We will test our hypothesis in a mouse model that includes an initial traumatic insult followed 1 day later by lung injury induced by bacterial endotoxin. This model will allow us to test the effects of using iron chelators after the traumatic injury but before the onset of the "second hit" lung injury. We will use an advanced imaging tool (positron emission tomography, or PET scan) to assess whether trauma increases the metabolic activity of white cells in the lung (which correlates with inflammatory activity) and whether we can reduce the PET scan signal by iron chelation. We will also correlate the PET scan data with biochemical and pathologic evidence of lung injury. Innovation: The inflammatory response is the body s response to multiple forms of injury. It is extraordinarily complex, and efforts to modulate specific signaling pathways in the inflammatory signaling network have not been successful. We believe that our proposal is innovative because (a) it identifies increased cellular iron as a common downstream consequence of acute inflammation. Macrophages are a critical amplifier of the inflammatory response, recruiting other white blood cells called neutrophils to multiply inflammation-induced lung damage. We think that macrophage intracellular iron may be a "lynchpin" of the acute inflammatory response and that targeting this potential lynchpin is a novel approach to acute lung injury. (b) The nature of trauma-induced lung injury (initial priming followed by a "second hit") allows a window of opportunity to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710058
Entities
People
- Aranya Bagchi
Organizations
- Massachusetts General Hospital
- United States Army