Redox sensitive TRP ion channels in the interaction between human lung mast cells and oxidative stress

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Asthma causes more than 1,000 deaths each year in the UK. For many people the currently available treatments do not adequately control their symptoms. There is evidence that a process called oxidative stress is important in this condition. Oxidative stress is a process when there are too many very reactive molecules called reactive oxygen species (ROS) and reactive nitrogen species (RNS) for the body to deal with, and they cause damage to the proteins and DNA inside cells. There are higher concentrations of these molecules produced in the airway of patients with asthma, and these can exacerbate inflammation and narrowing of the airways. Pulmonary fibrosis is another lung disease where ROS are thought to be involved in damaging the lung tissue, and abnormal healing following this damage may result in scarring of the lungs, preventing them from functioning properly.Mast cells are a type of cell that can cause inflammation by releasing chemicals in diseases such as anaphylaxis (a very severe and dangerous allergic reaction), asthma, rhinitis and eczema. These chemicals cause some of the symptoms of allergic diseases such as wheezing, excessive mucus, runny noses, and swelling of tissues. Mast cells also contribute to lung fibrosis. It has been found that ROS are produced in the process leading to release of chemicals by mast cells, and that using drugs that reduce ROS production might reduce the release of these chemicals; this could help to treat the symptoms of allergy and asthma, and also lung fibrosis. Although we know that there is probably too much ROS production in asthma, ROS also have important functions in normal healthy cells and tissues, and inhibiting them might also cause some unhelpful side effects too. That is why we believe it is important to investigate what regulates the production of ROS in inflammatory cells, particularly in mast cells, to help us develop new, effective and safe therapies, including for allergic conditions and fibrosis.In order for cells to be respond appropriately to oxidative stress and possibly regulate ROS production they need to be able to tell if there are too many ROS being produced; they need to be able to sense the presence of oxidative stress. Some proteins called transient receptor potential (TRP) channels are able to do this, and we have preliminary evidence from work performed in our lab, that they may be operating in mast cells from human lungs. We believe that they may be able to regulate human lung mast cell function, the production of ROS, as well as mediating both beneficial and detrimental cell activities in response to oxidative stress. Our research is aimed at testing these ideas to help develop better treatments for lung diseases that involve mast cells and oxidative stress including asthma and pulmonary fibrosis.My goals are to investigate how these channels are involved in mast cell function, including whether they can promote or reduce mast cell activation (mast cells are overactive in some diseases) in conditions of oxidative stress. I will also investigate whether the number of these channels in the bronchial tubes of patients with asthma is different to people without asthma.