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Structural - Inflammatory Cell Interactions in Severe Asthma - Division of IIR
Mohib Uddin, Donna E. Davies and Ratko Djukanovic
by Dr. Mohib Uddin
I am working as a Research Fellow in the Allergy and Inflammation Research Group based at the University of Southampton School of Medicine. As a member of Dr Ratko Djukanovic's group, my research currently focuses on understanding the subtle interactions between the airway structural cells such as bronchial epithelial cells and white blood cells like neutrophils, and the consequences this interaction has for lung inflammation, particularly in diseases such as severe asthma.
Asthma is a chronic inflammatory disease of the airways that affects millions of Britons and results in an economic burden amounting to an estimated £850 million annually. In particular, patients with poorly controlled (moderate to severe) asthma account for much of the morbidity, mortality and economic burden of this chronic lung disease. This disease is characterised by a reversible narrowing of the airway tubes in the lungs due to the muscles surrounding the airways going into spasm. Furthermore, it is associated with persistent inflammation and with over-secretion of mucus resulting in airflow limitation. Indeed, it is now appreciated that asthma is a complex disease involving a cascade of cellular events. An important finding in this field of research has been the recognition that inflammatory cells, particularly neutrophils (Picture 1), classically thought to be involved solely in host defence responses against foreign bacteria to also play an active role in the inflammatory reactions associated with more severe forms of asthma.
Neutrophils are the more common white blood cells and provide the first-line protection against invading microbes. these specialised cells act like "foot soldiers" in this defence system where their primary mission is to combat infection by seeking out and destroying microbial invaders. They move towards their targets in an amoeboid motion by a process called "chemotaxis" by sensing inflammatory agents released from the affected tissue. Upon arrival at the affected site, they engulf the foreign agent, eventually destroying it by unleashing a cocktail of toxic free radicals and destructive enzymes (Picture 2).
Once the affected site is disinfected, the now weakened neutrophils begin to self destruct by undergoing a "suicide" mechanism known as apoptosis that exists to ensure the safe removal of these redundant cells from the inflamed tissue. However, in the lungs of severe asthmatics, these cells sometimes become overly aggressive and the same weaponry they deploy to protect the host against microbial invasion gets mis-directed causing inadvertent damage to the lung tissue. Hence, the activation of neutrophils, while vital for the host defence system against infections can also contribute to the inflammatory processes in severe asthma.
The lining of the airways, referred to as the bronchial epithelium, acts as the main protective barrier against air-bourne particles and irritants. Repair of this barrier tends to occur quite rapidly after injury, but is often compromised in chronic diseases like severe asthma. it is now clear that the damaged epithelium can secrete a wide range of pro-inflammatory chemicals that can orchestrate the trafficking of neutrophils into the lungs. this accumulation into the inflamed airways can enhance both the function and lifespan of neutrophils, thereby actually promoting inflammation by allowing these cells to remain longer in the lungs and to release their toxic contents near the delicate tissues (Picture 3).
Our research is focused primarily on understanding such mechanisms by which the intimate associations between the neutrophils and the bronchial epithelium bring about the overall enhancement of neutrophil actions in an asthmatic lung. Specifically, we aim to characterise the precise source and nature of these complementary signals emanating from the bronchial epithelium that act to potentiate neutrophil motility, function and fate. Currently, these aspects are being explored using layers of the bronchial epithelial cell line (16HBE cells) grown in our laboratory, and data obtained from such studies will be extended to assess the role of primary cultures of bronchial epithelial cells derived from consenting normal and asthmatic donors. Hence, detailed investigation of the underlying events regulating the interplay between these two cell types will lead to a better understanding of the pathogenesis of severe asthma. in the long term, we envisage that such understanding may be harnessed for the development of novel therapies to control this distressing lung disease.
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