Asthma and Allergy
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Dr Garry Walsh eosinophil, airway epithelial cell, adhesion, apoptosis, phagocytosis |
This is an interdisciplinary group elucidating molecular mechanisms underlying the development of, and therapies for, asthma and related allergic disease.
Immune Regulation and Allergy: Dr Graham Devereux and Professor Robert Barker have demonstrated that early life influences, particularly a low maternal intake of dietary antioxidants during pregnancy, affect predisposition to asthma by altering development of regulatory cells. Novel therapy based on an immune evasion mechanism used by EBV is being developed by Dr Mark Vickers, Professor Rob Barker, and recently licensed commercial partners, to enhance allergen-specific regulatory T cell responses.
Dr Garry Walsh: The laboratory has a highly developed programme of work that focuses on the elucidation of the molecular mechanisms controlling the initiation and resolution of the inflammatory processes underlying asthmatic and allergic disease, with an emphasis on the role played by eosinophils and the cells of the bronchial epithelium. An additional major area of study is the anti-inflammatory effects of second-generation antihistamines and their potential side effects.
Current projects:
Airway epithelial cells
Airway epithelial cells (AEC) make a major contribution to the inflammatory processes in the asthmatic airways through the release of cytokines, chemokines and mediators. We are examining the AEC inflammatory secretory phenotype in adults with asthma and in children with asthma or virally induced wheeze using cells from both the upper and lower airways. This project is also elucidating the effect of existing and novel asthma mediations AEC secretory processes.
Eosinophils
Eosinophils are one of the major effector cells found in the lungs in patients with asthma. Their well-documented cytotoxic potential results in damage to the airway epithelium and tissue inflammation while their release of lipid mediators such as cysteinyl leukotrienes can obstruct airflow. Eosinophils are not present in healthy lungs while in asthmatics there are well-documented correlations between eosinophil numbers and disease severity. Thus there is much interest in understanding how eosinophils preferentially accumulate in the asthmatic lung. We are re-examining the processes controlling eosinophil adhesion to the post-capillary endothelium and their subsequent migration into the tissues. We are therefore examining the mechanisms by which eosinophils adhere to recombinant human adhesion proteins or endothelial cells under conditions of shear stress using a state of the art micro flow. A sample movie clip is shown below featuring human eosinophils adhering to vascular cell adhesion molecule-1 under conditions of flow in vitro.
- Video - Low Resolution Version (for slow internet connection < 56 kbps)
- Video - High Resolution Version (for fast internet connection)
Apoptosis
Apoptosis is a kinetic event that can occur through any of several well characterised pathways involving cell surface signals, changes in mitochondrial morphology, and caspase activation, all resulting in DNA fragmentation, membrane perforation and selective clearance of cell debris. Eosinophil infiltration is normally followed by elimination of these cells by apoptosis in conjunction with recognition and phagocytosis by tissue macrophages or resident bronchial epithelial cells (see image below). This project is studying the membrane receptors and intracellular signalling pathways (caspases, mitochondria membrane potential) controlling apoptosis induction in peripheral blood, cultured eosinophils and an eosinophil cell line.
Apoptotic eosinophil disposal
Once eosinophils become apoptotic they are rapidly recognised and cleared by macrophages or airway epithelial cells. We are have demonstrated that bronchial epithelial cells recognise and ingest apoptotic eosinophils using specific membrane receptors and intracellular phagocytic mechanisms. The confocal micrograph below shows phagocytosis of multiple apoptotic eosinophils (red) by a large airway bronchial epithelial cell that has been stained for F-actin using Oregon green phalloidin. We are currently examining the impact of these events on the initiation and resolution of asthmatic inflammation via production of pro-and anti-inflammatory cytokines and chemokines.