Sheffield Lung Research Tissue Bank

We are interested in different types of lung cell and the triggers that activate these cells. Lung cell activation could contribute to respiratory diseases such as asthma.

We are also interested in establishing mechanisms by which established drugs used for respiratory disorders, such as inhalers, work on cells found in the lung. We are also interested in testing alternative drugs on these cells either to assess how the cells work or because some of these drugs may be of potential therapeutic benefit.

Some of these drugs will, therefore, have been developed by the pharmaceutical industry. Overall, these studies hope to identify (a) how lung cells are activated and (b) novel approaches to treating lung diseases. These studies are supported by the Pharmaceutical Industry, Charities, Research Councils and by Education Ministries.

Current research projects

Role of prostanoids in human lung mast cells and macrophages

The human lung mast cell and macrophage are both recognised as playing important roles in respiratory diseases. In this project the effects of prostaglandin E2 (PGE2) on cell responses is being studied. PGE2 is a naturally occurring molecule that has a wide variety of effects in the body. PGE2 can act at four different receptors and by using molecules that are known to act selectively at each of the receptors we have been able to demonstrate that a particular receptor, the EP2 receptor, regulates mast cell responses whereas the EP4 receptor regulates macrophages. This information could potentially be used to develop compounds that inhibit mast cell and macrophage responses.

Characterization of human lung macrophage phenotype and function

The lung macrophage is known to be crucial in dealing with infections in the lung. However, in certain lung diseases, such as Chronic Obstructive Pulmonary Disease, the macrophage is overly active. In this project we are looking to identify the behaviour of lung macrophages and our findings so far suggest that the macrophage doesn’t behave like macrophages found in other tissues. We are investigating this anomalous behaviour further.

Desensitization of IgE-dependent responses in human lung mast cells

Allergic individuals can be made to tolerate exposure to whatever causes their allergy by a process that is often called clinical desensitization. This involves exposing the allergic individual initially to very low doses of the allergen and then repeatedly administering increasing doses of the allergen over a period of 4 to 24 hours. The mechanism by which desensitization is achieved in the clinic is not fully understood. In this project we are trying to develop a test tube model of clinical desensitization.

Preliminary studies to develop epithelial cell cultures

Epithelial cells line the airways and form an important protective barrier against airborne pathogens. Inappropriate and excessive activation of these cells could be important in the development of a variety of respiratory diseases. In this study, we are trying to isolate epithelial cells from lung tissue and keep them in culture so that their properties and function can be studied in greater detail.

Characterization of histamine receptor expression in respiratory cells

Histamine is a chemical that has long been associated with allergies such as asthma. Indeed, anti-histamines are used to treat certain allergies such as hay fever. However, anti-histamines, which act to block the action of histamine at H1 histamine receptors, are ineffective in asthma. The reason for this might be related to the fairly recent discovery of a new histamine receptor called the histamine H4 receptor. It is possible that the H4 rather than the H1 receptor, is more important in asthma. In this project we are evaluating the role of histamine and histamine receptors in the regulation of respiratory cells.

Orai and TRPC channel expression and function in human lung mast cells

When mast cells are activated by allergens, there is an increase in the concentration of calcium inside the cell. Calcium interacts with certain proteins inside the cell and, as a result, the activity of the cell increases. Orai and TRPC channels are involved in the transport of calcium into a variety of different cells. However, which of these channels is more important in mast cells is not known. The purpose of this project is to identify those channels that control calcium transport in mast cells. Blocking calcium transport could be a way to prevent mast cells from being activated.

SNARE protein expression and function in human lung mast cells

The mast cell can be identified using a microscope because it is packed with granules. These granules are full of chemicals like histamine. When the mast cell is activated it undergoes a process called ‘degranulation’ in which the contents of the granules are released by the cell. The released chemicals cause allergic reactions. The movement of the granules and the release of granule contents are controlled by proteins called SNAREs. This project is involved in trying to understand how SNAREs regulate degranulation. Blocking SNAREs could be a way to prevent mast cells from degranulating.

Activation of human lung mast cells by Stem Cell Factor

Stem Cell Factor (SCF) is a critical growth factor in the development of mast cells but is not really recognised as an activator of mast cells. However, our own recent studies suggest otherwise since SCF was found to be very effective at inducing the generation of leukotrienes and prostaglandins from human lung mast cells. These mediators promote inflammation and cause the airways to narrow. In this project, the mechanism by which SCF causes leukotriene and prostaglandin generation from human lung mast cells is being explored.

Recent research papers

  1. Kay LJ, Suvarna SK, Scola A-M, Rostami-Hodjegan A, Chess-Williams R and Peachell PT (2010). Influence of beta-2-adrenoceptor gene polymorphisms on beta-2-adrenoceptor expression in human lung. Pulmonary Pharmacol Ther 23: 71-77.
  2. Havard S, Scola A-M, Kay LJ, Ishmael SS, MacGlashan DW, Peachell PT (2011). Characterization of syk expression in human lung mast cells: relationship with function. Clin Exp Allergy 41: 378-388.
  3. Hewson CA, Patel S, Calzetta L, Campwala H, Havard S, Luscombe E, Clarke PA, Peachell PT et al (2012). Preclinical evaluation of an inhibitor of cytosolic phospholipase A2alpha for the treatment of asthma. J Pharmacol Exp Ther 340: 656-665.
  4. Lewis A, Baothman B, Monk PN, Suvarna SK, Peachell PT (2013). Heterogeneity in the responses of human lung mast cells to stem cell factor. Clin Exp Allergy 43: 50-59.
  5. Kay LJ, Gilbert M, Pullen N, Skerratt S, Farrington J, Seward EP, Peachell PT (2013). Characterization of the EP receptor subtype that mediates the inhibitory effects of prostaglandin E2 on IgE-dependent secretion from human lung mast cells. Clin Exp Allergy 43: 741-751.

Recent research presentations at scientific meetings

  1. Paradoxical effects of the EP2 agonist, butaprost, on histamine release from human lung mast cells by Kay LJ, Peachell PT presented at the European Histamine Research Society meeting, Durham, 2010 (awarded 2nd prize in the Poster Competition).
  2. Characterization of the EP receptor expressed by human lung mast cells using novel EP receptor antagonists by Kay LJ, Gilbert M, Skerratt S, Pullen N, Peachell PT presented at the European Histamine Research Society meeting, Belfast, 2012 (awarded 3rd prize in the Poster Competition).
  3. Preliminary characterization of histamine receptor expression in human lung mast cells by Kay LJ, Seward EP, Peachell PT presented at the European Histamine Research Society meeting, Lodz, 2013 (awarded 1st prize in the Poster Competition).
  4. Prostaglandin E2 activates EP4 receptors to inhibit pro-inflammatory cytokine release from human lung macrophages by Gill SK, Marriott HM, Peachell PT presented at the American Thoracic Society, San Diego, 2014.
  5. Cycloxygenase-1 catalyses the biosynthesis of prostaglandin D2 in human lung mast cells by Smith JC, Kay LJ, Peachell PT presented at the European Histamine Research Society meeting, Lyon, 2014 (special commendation in the Poster Competition).

Contact

Further details about the Sheffield Lung Research Tissue Bank can be obtained from Roger Thompson (r.thompson@sheffield.ac.uk).

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