Grant: Project Grant

Irritant asthma is a form of asthma that is triggered by exposure to a variety of chemicals in high concentrations that cause spasm of the airways in previously healthy subjects. It also includes asthma that is worsened by irritant exposures, often in the workplace but often through use of cleaning fluids and sanitizers. It is estimated that 25% of asthmatic patients suffer from symptoms related to irritant exposure. The airway lining (epithelium) releases chemicals when injured. One of these chemicals is called interleukin-33 (IL-33) and it is protective against the injurious effects of inhaled chlorine gas, which is a frequent irritant exposure that we believe is representative of chemicals causing oxidative injury. We will explore the mechanism by which IL-33 is protective. We will focus on a category of immune cells, called innate lymphoid cells that respond to IL-33 by increasing in number and by producing other cytokines such as IL-13. In addition, IL-33 and innate lymphoid cells interact with cells that are responsible for mediating inflammation in the lung but also resolving inflammation and facilitating repair. These cells are called macrophages and are affected by IL-33 so that they now have a molecule called FoxP3 within them, which is usually associated with T cells that are anti-inflammatory. This molecule defines a novel subset of macrophages that expands after IL-33 treatment. We will explore their function in relationship to the protective effects of IL-33. We anticipate that the proposal will assist in advising on the rational use of the novel biologics that are undergoing clinical trials for asthma.