Respiratory Pharmacology

Professor Maria Belvisi, Head of Group and Dr Mark A Birrell

Respiratory Pharmacology is a multidisciplinary team combining industrial and academic experience. This enables us to employ a range of skills and expertise in molecular, biochemical, cellular, pre-clinical and early clinical studies. Through IR Pharma Ltd the Respiratory Pharmacology group can provide the pharmaceutical industry with pre-clinical drug discovery involving short, focused projects and larger, wide ranging system-based discovery programmes. For more information please see the IR Pharma website.

Our research focuses on inflammatory airways diseases, elucidating novel targets and validating their importance in the progression of inflammatory airway diseases, such as asthma, chronic obstructive pulmonary disease (COPD) and cough. Interesting hypotheses formulated in cell-based assays are progressed for further investigation in pre-clinical models with the use of pharmacological tools to assess the importance of various molecules in the disease process. At every stage the relevance of observations is validated by comparison with data generated in human normal and diseased lung tissue obtained from the transplantation programme. Since current treatments for these diseases, such as COPD, are ineffective in most patients, the development of more effective disease-modifying therapies are essential. Our research contributes towards a better understanding of the pathogenesis of these respiratory diseases, promoting the development of effective therapeutic strategies for these conditions through translational research.

The main disease areas our group are currently working on include:

Inflammatory airway diseases:

• Asthma

• Chronic Obstructive Pulmonary Disease (COPD)

Sensory nerve dysfunction:

• Cough

Finally, the group welcomes opportunities for collaborative research and has an array of expertise it can offer potential collaborators.

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Inflammatory airway diseases:

Asthma

The NHS spends in excess of £2 billion a year treating patients with asthma. Half of this resource is spent on just 10% of patients - those with severe asthma. Currently, the majority of patients with airway inflammatory diseases are treated with β2‑adrenoceptor agonists and/or inhaled glucocorticoids. Β2‑adrenoceptor agonists relax the airway smooth muscle thereby leading to bronchodilation. Glucocorticoids are potent anti-inflammatory agents that influence cells and mediators of inflammation in asthma. However, severe asthma patients can be resistant to treatment with glucocorticoids. Our group aims to determine alternative therapies for treating asthma.

COPD

Chronic obstructive pulmonary disease is an inflammatory disease of the lung (associated with cigarette smoking). It is characterised by breathing difficulties which get progressively worse with age. Every hour COPD is estimated to kill 250 people and in the UK 30,000 people die each year from this disease - almost double the European average. As COPD is a steroid resistance disease, there are at present, no successful treatments available. 

Ongoing projects

• Constrictors and dilators
• Danger signals involved in asthma / COPD:
  TOLL receptors
  The inflammasome – exploring the role of the inflammasome in the pathogenesis of asthma COPD
• Lipid mediators: prostanoid – anti inflammatory bronchodilators
• Role of the NF-κB pathway in asthma / COPD

Sensory nerve dysfunction:

Cough

Although cough is a protective reflex in healthy individuals, it is also the most common respiratory complaint for which medical attention is sought. It often presents as the first and most persistent symptom of many inflammatory airways diseases. The most commonly sought treatment for cough is over-the-counter remedies. A recent analysis however, established that there was no good evidence for the effectiveness of such over-the-counter medicines. Therefore, persistent cough presents a major unmet clinical need. 

Ongoing projects:

• Role of TRP family, eg. TRPA1 and TRPV1
• Role of prostanoids in cough
• Models of enhanced cough:
  Cigarette smoke
  Virus

Expertise

The group uses a multi-disciplinary approach, from molecular biology to cell-based assays followed by experimental in vivo models and is internationally renowned in this regard. The group has developed, validated and established reproducible models which mimic various aspects of the disease pathology seen in asthma, COPD and cough. The identification of disease related biomarkers is a central research theme. At every stage of the process observations are validated by comparison with data generated in human normal and diseased lung tissue, and through to clinical studies. Our group has an extensive network of collaborators both in academia and in the pharmaceutical industry. Some of the expertise areas we can offer potential collaborators include:

• Cell based assays: cell lines and primary cells
• Functional bioassays: isolated vagal nerve preparation, tracheal strip organ bath 
• Pre-clinical Inflammatory airway disease model end points
  Asthma
  COPD
• Cough experiments
   Whole body plesmography chamber

Selected publications

Asthma

Birrell MA, De Alba J, Catley MC, Hardaker E, Wong S, Collins M, Clarke DL, Farrow SN, Willson TM, Collins JL, Belvisi MG – Liver X receptor agonists increase airway reactivity in a model of asthma via increasing airway smooth muscle growth. – J Immunol. 2008 Sep 15;181(6):4265-71.

Birrell MA, Hardaker E, Wong S, McCluskie K, Catley M, De Alba J, Newton R, Haj-Yahia S, Pun KT, Watts CJ, Shaw RJ, Savage TJ, Belvisi MG – Ikappa-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma. – Am J Respir Crit Care Med. 2005 Oct 15;172(8):962-71.

COPD

Birrell MA, Wong S, Hardaker EL, Catley MC, McCluskie K, Collins M, Haj-Yahia S, Belvisi MG – IkappaB kinase-2-independent and -dependent inflammation in airway disease models: relevance of IKK-2 inhibition to the clinic. – Mol Pharmacol. 2006 Jun;69(6):1791-800.

Birrell MA, Wong S, Catley MC, Belvisi MG – Impact of tobacco-smoke on key signaling pathways in the innate immune response in lung macrophages. – J Cell Physiol. 2008 Jan;214(1):27-37.

Cough

Maher SA, Birrell MA, Belvisi MG - Prostaglandin E2 mediates cough via the EP3 receptor: implications for future disease therapy. - Am J Respir Crit Care Med. 2009 Nov 15;180(10):923-8.

Birrell MA, Belvisi MG, Grace M, Sadofsky L, Faruqi S, Hele DJ, Maher SA, Freund-Michel V, Morice AH – TRPA1 agonists evoke coughing in guinea pig and human volunteers. - Am J Respir Crit Care Med. 2009 Dec 1;180(11):1042-7

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