Alpha-1 Antitrypsin Augmentation Therapy for Acute Lung Injury
Abstract
Acute lung injury (ALI) is a type of lung failure that occurs mostly due to a build-up of fluid in the lung. As ALI worsens, it becomes known as acute respiratory distress syndrome (ARDS). One out of four people that develop ARDS die, and there is currently no therapy available that is able to cure the disease. Nearly 200,000 Americans develop ALI yearly, and up to 150,000 of these go on to develop ARDS. ARDS is also common among American Soldiers with injuries such as trauma and burns. Patients with ARDS often require breathing support and long stays in hospital and as such present a large financial burden on the healthcare system. Alpha-1 antitrypsin (AAT) is a protein produced by cells in the liver in addition to other cells such as white blood cells. The main function of AAT is to bind and inactivate neutrophil elastase, which is a tissue-damaging enzyme released by white blood cells called neutrophils in the lung during infection. During ARDS, large numbers of neutrophils enter the lung from the bloodstream and secrete neutrophil elastase. Therefore, the ability of AAT to prevent neutrophil elastase from attacking lung tissue means it could be a new treatment option for ARDS. Furthermore, a number of studies have been performed, which have shown AAT as having other beneficial effects such as reducing inflammation and decreasing bacteria during infection. The exact role of AAT in ARDS has not been investigated before nor has its therapeutic action. We aim to approach this research project in three ways. Firstly, we wish to measure AAT in samples obtained from ARDS patients and assess what happens to AAT levels during ARDS. We also wish to identify if the patients have an underlying deficiency in AAT that may increase their risk of either developing ARDS and/or dying from the disease. Secondly, we intend to determine how AAT functions during ARDS by performing a variety of cell-based assays. These assays will test if AAT can increase the ability of another type of white blood cell called macrophages to eat and kill bacteria. Thirdly, we aim to examine the beneficial actions of AAT in a live rat model of ARDS and in lungs taken from live pigs. The purpose of this project is to identify if AAT could be used as a new therapy for ALI and ARDS. This would provide a huge benefit to patients with ARDS for which there is currently no cure. A mortality rate of 1 in 4 people is unacceptable and would be greatly decreased if AAT proves to be an effective treatment. The availability of an effective treatment would result in more hospital beds and less taxpayer’s money being spent on long in-hospital stays. In the military setting, trauma and burn-induced ARDS would no longer be considered a death sentence and affected Soldiers would be more easily treated. It would also greatly advance both the medical and scientific field surrounding ARDS and AAT research. Finally, AAT is a Food and Drug Administration (FDA)-approved therapy for a disease called Alpha-1 Antitrypsin Deficiency (AATD). As a result, AAT would not have to begin the clinical trial process at Phase 1 but would instead go direct to Phase 2. This would mean that AAT would be available to patients much quicker.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010095
Entities
People
- Gerard Curley
Organizations
- Royal College of Surgeons in Ireland
- United States Army