Translational Studies of Mast Cell Crosstalk with Structural Cells in Chronic Respiratory Diseases

Chronic inflammatory diseases of the lung, are the second largest cause of mortality worldwide. A significant proportion of patients with asthmatic diseases have symptoms and decreased quality of life despite conventional therapy. Although the inflammatory response observed in the airway mucosa has been studied for decades, detailed understanding of the driving mechanisms remains limited. 

Mast cells have long been recognized as key cells in the allergic response in asthma. In this process, the mast cell and the pro-inflammatory mediators released from this cell play an important role. Evidence for their role in anaphylaxis and asthma is the localisation in or near structures involved in asthma pathophysiology such as smooth muscle, glands and epithelium. It is believed that another main component in the development of asthma is an abnormal epithelial airway barrier which produce excessive amounts of pro-inflammatory mediators in response to infections and allergens, resulting in a cycle of early and permanent lung damage, and ultimately asthma. It is established that the airway epithelium undergoes dramatic remodelling in asthmatic disease. Asthmatic patients also have an impaired anti-viral capacity with an defective anti-viral response, although the mechanism behind this is unclear. Respiratory infections early in life have also been associated with asthma development in children as well as in causing severe worsening of asthmatic disease. However, how the epithelium interacts with immune cells during the cause of an allergic inflammation or viral infection is largely unknown.

In recent genome-wide association studies, three of the top ten genes that were differentially expressed in asthmatic epithelium compared to healthy controls were mast cell specific genes. Within the epithelium, mast cells are ideally situated to react on various harmful substances and to exert an immunological response to allergens. This indicates a strong association of intraepithelial mast cells in asthmatic disease, however very little is known regarding the cross-talk between these two cells and its implication in respiratory disease progression.

Aim and Hypothesis

Interactions between structural cells and mast cellsare likely to be major drivers of the development and progression of chronic airway diseases. 

The main aim of this research programme is to define the interaction between mast cells and structural cells such as epithelial and smooth muscle cells in the pathobiology of chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). The long-term goal is to elucidate the mechanisms behind these diseases and to create better and more personalised therapies. 

Specific research questions investigated in patients with different asthma phenotypes and COPD patients:  

I)             How is the anti-viral and bacterial defence of the epithelium affected by mediators released from mast cells?

II)           How are mast cell mediators affecting functional aspects of wound healing and barrier function of the airway epithelium?

III)         How does differentially activated mast cells affect airway smooth muscle cell phenotype and function in asthmatic patients? 

My research has unique potential to answer these questions by combining studies of human experimental models and investigations in volunteers and patients with different sub-phenotypes of asthma and COPD.The overall purpose of the research programme is to define mechanisms that may be applied to improve and specify diagnosis and treatment of different phenotypes of asthma and COPD.