Mechanisms of regeneration of the large airways
The airways of the lung are in direct contact with the environment and therefore constantly injured by pollution and infections. The airway lining is therefore efficient at repair and regeneration, but our understanding of the mechanisms of this are limited. The airway contains a complex 3D microenvironment, which allows it to perform its critical function in clearing mucus. Diseases that affect the airway all result in mucus pooling, secondary bacterial infections and pneumonias, which can be life threatening. Human airway from a cadaver has been successfully implanted into a patient and is a promising regenerative therapy for airway diseases. But in order to move forward with this bioengineered therapy we need to understand the mechanisms of airway repair to improve the therapy and prevent complications.
Here we propose to bioengineer the human airways in order to study the molecular mechanisms by which the 3D microenvironment influences airway epithelial repair. The overall goal is to create bioengineered airways that are structurally and functionally similar to native human airways and could therefore be used to transplant into patients with diseased airways.
The results of our studies will have a direct impact on the development of a novel bioengineered therapy for airway diseases, such as bronchial stenoses, and will impact other airway diseases with mucus clearance problems, such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis.
In California, 37.38 per 100,000 deaths occur as a result of chronic lung disease. Many of these chronic lung diseases have problems with the accumulation of mucus in the lungs with the development of pneumonia, which can be life threatening. The clearance of mucus from the lungs is an important mechanism to protect people from environmental pollution and infections, but abnormalities of the lung airway and its microenvironment result in excess mucus production and prevent the clearance of mucus. Smoking is the primary risk factor for chronic lung disease, but other risk factors include exposure to air pollution, second-hand smoke and occupational dusts and chemicals, and heredity. Our proposed research is to create 3D bioengineered airways that function like normal airways in clearing mucus. This research will identify the mechanisms of how the microenvironment of the lungs influences normal and abnormal repair of the airways, and ultimately will be used to create normal, new airways that could be used to transplant into patients and to identify novel therapeutic targets for chronic lung diseases. The proposed research will therefore benefit the state of California and its citizens by increasing our understanding of airway repair in chronic lung disease and by developing a novel regenerative therapy for the airways.