Interplay of the extracellular matrix and immune cells in lung pathology: key role for chitinase-like proteins

点击翻译按钮获取中文摘要

BackgroundAsthma is a complex inflammatory disease, and as such research has focussed on understanding and treating airway inflammation. In some asthma sufferers, anti- inflammatory agents work well to control symptoms and exacerbations. However, these drugs don't always improve lung function and in severe asthma, some patients fail to see any improvement after anti-inflammatory treatments. The asthmatic airway also undergoes pathological changes that result in airway remodelling. Remodelling results in the extracellular matrix components (e.g. collagens) being deposited and reorganised within the lung architecture making the lungs stiff and rigid, ultimately reducing the ability of the lungs to function. Current research suggests remodelling may occur separately from inflammation, explaining why anti-inflammatories don't always improve lung function in asthma. We have shown that chitinase-like proteins (CLPs), molecules that are highly produced in the lungs of people with asthma, contribute to remodelling responses. The higher the concentration of CLPs, the more severe the asthma and remodelling. Using mouse models, we have shown that inhibiting CLPs can reverse asthma remodelling. However, we still need to understand how CLPs work and what causes remodelling to occur in the first place, in order to come up with new therapies that will successfully treat asthma and improve lung function.Questions we will ask during this project:1) How do CLPs, inflammatory cells and tissue structural cells communicate with each other to trigger remodelling? 2) What does inhibiting CLPs do to cells/molecules to breakdown the matrix and reverse remodelling?3) When remodelling occurs, does it change the way the lungs can respond to inflammatory challenges like allergens?How will we answer these questions?Some of the work will use a mouse model that involves giving mice a cocktail of allergens (dust mites, fungi, pollen) frequently encountered by people. Importantly, this mouse model shares common features with severe asthma in people and can be used to study disease pathways in ways that cannot be done in people. We will measure how the lung matrix changes after exposure to aero-allergens, focusing on the location of initial remodelling events and the inflammatory or tissue cells accumulate around these areas. As CLPs contribute to the initiation of remodelling, we will investigate whether interfering with CLPs changes the behaviour of cells important for initiating lung remodelling.Next, we will investigate how to reverse remodelling and hence improve lung function, asking questions about how CLPs breakdown the matrix. Using the mouse allergen model, in addition to isolated mouse and human lung cells, we will determine what pathways, cells and molecules that degrade the matrix are changed when CLPs are inhibited. This research will allow us to identify future targets for making drugs that can reverse remodelling in asthma.Lastly, we will investigate the consequences of lung remodelling during asthma. Inflammatory cells need to navigate their way through the matrix before entering the lung. If the matrix changes, like it does in asthma, it will alter the way cells get into the lung. Using mouse models, and cultures of human and mouse cells, we can manipulate cells/matrix to determine how asthma remodelling influences lung inflammation and ultimately the way the lungs can respond to allergens and molecules that trigger inflammatory responses. What do we hope to achieve overall?We will gain an understanding of how lung matrix proteins change in response to asthma triggers, like allergens, and whether these matrix changes dictate the type of airway inflammation a person has or the type of asthma that develops. Critically, we will determine ways in which remodelling can be reversed, and already have a unique lead to investigate this through manipulation of CLPs.