Lung disease will contribute to the death of 1 in 5 people. Many people suffer from chronic lung disease that impacts on their ability to function on a daily basis. Many chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and bronchiectasis are characterised by the presence of excessive numbers of white blood cells or leukocytes that are recruited to the lung from the blood stream.
In particular, the white blood cells, called neutrophils, are recruited at the earliest signs of lung damage. In small numbers, these neutrophils are essential to fight infection, but in larger numbers, or in more activated forms, they may cause damage to the lung, especially if they deploy their anti-microbial activity before they cross into the airspace.
Before reaching the airspace in which inhaled pathogens are encountered, the neutrophils must pass across the airway epithelium and then they come into contact with the layer of airway mucus that protects the airway from infection. We propose that the epithelial-mucus barrier acts as a checkpoint to prime neutrophil function in health, so that neutrophils are only fully activated once they have passed across the epithelium, thereby limiting collateral damage.
However, patients with IPF have higher numbers of neutrophils in their broncho-alveolar lavage (BAL) fluid and this also correlates with severity of disease. Furthermore, a genetic mutation that increases the amount of Muc5B, one of the airway mucins, has been identified as a risk factor for developing IPF (either sporadic or familial). Muc5B has been implicated in inducing neutrophils to expel fibres of DNA called neutrophil extracellular traps (NETs) and in our preliminary data, is a strong chemoattractant for neutrophils.
Dr Jagdeep Sahota has applied to the Medical Research Council to carry out a project will allow us to identify factors that alter the behaviour of neutrophils as they migrate through the lungs to eradicate infection and the role of MUC5B and TGF beta (a profibrotic cytokine implicated in the development of IPF). Dr Sahota has been able to develop preliminary data using funding from Breathing Matters. Her ultimate aim is to develop novel targeted therapies to reduce neutrophil mediated lung damage whilst maintaining effectiveness against infection. These therapies may be applicable to other chronic lung diseases.