Defining IL-4-Activated Monocytes as Viable Cellular Immunotherapy in Acute Lung Injury
Abstract
Acute respiratory distress syndrome (ARDS) is a devastating and often fatal disease. ARDS often occurs as a by-product of the body s response to infection (sepsis), trauma, burns, inhaled chemical irritants (smoke, phosgene or chlorine gas), or other systemic insults. The resulting inflammation, fluid accumulation, and damage in the lungs prevent them from properly getting oxygen to their bloodstream and to vital organs. The current approach to taking care of patients with ARDS is placement on a respirator. Unfortunately, there are still no treatments that can repair the damage created by ARDS, and therefore the disease has a high mortality rate. New strategies that can harness the power of the immune system to halt injury or repair the lungs damaged by ARDS would be a significant advancement for treatment options, and likely reduce mortality. In mice, we have found that administration of a particular protein factor, interleukin-4 or IL-4, can heal and repair lungs damaged by ARDS. IL-4 can change the way the cells of the immune system behave during the disease process. Interleukin-4 works by binding with a receptor on the surface of cells, like a key fitting into a lock. When IL-4 binds to its receptor, a chain reaction of events occurs inside the cell. The result of this chain reaction is that specific genes are turned on in the nucleus of the cell, some of which become proteins that are important for the healing process in the lungs of the mice with ARDS. One type of cell that is strongly activated by IL-4 is called a macrophage, and macrophages that are activated by IL-4 are thought to be helpful by healing wounds, including the damaged lungs. Macrophages that are found in the lung come from two sources: replication within the lung and migration to the lung from the bloodstream where they are known as monocytes. During illnesses like ARDS or others that cause severe inflammation and damage in the lung, a significant percentage of lung macrophages come from the bloodstream monocyte pool. Monocyte movement into the lungs is driven by soluble factors released from the damaged lungs that tell the monocyte to move in a particular direction. Once the monocytes exit the blood and migrate to the lung, they become macrophages. Monocytes are activated by IL-4 in a similar manner as macrophages, and for them to become helpful macrophages, a key protein inside the cell, STAT6, is often needed. STAT6 is one of a few proteins that can transmit the signal from the IL-4 receptor to the nucleus to turn on important genes. Our hypothesis is that blood monocytes are an important source of helpful macrophages that can heal the lungs from ARDS-induced damage and that STAT6 is a critical protein for monocytes activated by IL-4 to promote the lung healing in the mice with ARDS. We think that if we use nanoparticle-sized delivery devices called backpacks that can keep IL-4 adherent to the monocytes, we can make the healing and helpful macrophages last much longer and further enhance the reparative process. In patients with ARDS, we do not know if the monocytes in their blood have characteristics of the helpful macrophages, compared to monocytes from healthy people without ARDS. We would like to use blood monocytes from ARDS patients, treat them with IL-4 to make them wound-healing and helpful, and then reinfuse them into patients as a new treatment option. Before we do this, we have to test whether IL-4 exposure to monocytes from ARDS patients can actually generate a wound-healing helpful macrophage by comparing them to IL-4-exposed monocytes from healthy people. If our experiments in mice with ARDS and among human monocytes support our hypotheses, we may be able to test our therapy in ARDS patients, and if that works, it would be the first successful therapy in ARDS. Therefore, the goals of this proposal are: (1) Determine the importance of blood monocytes for IL-4 to promote lung repair in mice with ARDS. (
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610510
Entities
People
- Neil Aggarwal
Organizations
- Johns Hopkins University
- United States Army