MICA: Investigation into the mechanisms that drive cough in health and disease

Coughing is a reflex action started by stimulation of sensory nerves in the lining of the respiratory passages which are the tubes we use to breathe. When a person coughs, there is a short intake of breath and the larynx (the voice box) closes momentarily. The abdominal and chest muscles used for breathing contract, which in turn increases the pressure needed to drive air out the lungs when the larynx re-opens. Cough is a reflex mechanism that helps clear foreign material and secretions from the airways. However, it may also be the first and most persistent symptom of many inflammatory airways diseases, including asthma, COPD, post viral infections, pulmonary fibrosis, bronchiectasis and cough can also be present when a cause cannot be identified. In these situations cough may present as a debilitating symptom and can adversely affect the quality of a patient's life in multiple ways for example by causing exhaustion, self consciousness, insomnia, horseness, musculoskeletal pain, sweating, urinary incontinence and in severe cases patients can break ribs through excessive coughing. Despite these facts, cough is a largely ignored research area and novel anti-tussive agents are lacking. Treatment options are limited and recent meta-analysis concluded that over the counter (OTC) remedies are ineffective plus there is increasing concern about their use in children. Understanding the mechanisms involved in initiating cough will uncover novel therapeutic targets which will impact significantly on patient quality of life and a reduction in associated healthcare costs. The cough reflex is initiated by activation of airway sensory afferent nerves. We hypothesize that agents that inhibit sensory nerve activity will also inhibit the cough reflex. In this proposal we describe pre-clinical data from our laboratory, genetic association data in respiratory disease from the scientific literature and our data from clinical studies implicating certain proteins or ion channels called Transient Receptor Potential (TRP) channels as 'master controllers' of the cough reflex. There are a number of these channels that are expressed in airway sensory nerves and so in this project we will be evaluating their importance using pharmacology (tool compounds that block these targets) or genetically modified mice (which are bred without each of the TRP channels) in isolated nerve experiments (using animal and human tissue) and in animal models of cough. We will investigate their role in the cough response under normal conditions and then in models which are configured to resemble asthma related cough, post-viral cough and that associated with chronic obstructive pulmonary disease (COPD). Finally we will evaluate the role of these channels in patients that demonstrate chronic cough of different aeitiologies (eg. Asthma, COPD, smokers, post-viral, and chronic cough of no known cause).The aim of these studies is to identify possible novel drug targets which can be used as starting points for drug discovery programmes to find novel cough therapies to treat this debilitating symptom. Another output from this grant that we hope to achieve is to establish if the various animal model systems we use to investigate this hypothesis actually represent the human cough and that the systems used to test therapeutics are predictive of anti-tussive activity in patients.

The goal of this collaboration would be to provide insight into the mechanisms that drive cough in health and disease and to understand the similarities and differences in exaggerated cough that is present in specific patient groups. This would provide novel target validation data and inform a translational and predictive screening pathway from high throughput assays to clinical trial design.

(1) Investigate which endogenous mediators (produced in inflammatory diseases) and environmental irritants are able to elicit cough, which fibre type they activate and evaluate their mechanism of action.
(2) Evaluate the utility of selective ligands in cell lines overexpressing the corresponding target protein. Establish which TRP channels are involved in the activation of airway sensory nerves and evoke a cough reflex under 'normal' conditions using selective ligands and vagal tissue from gene deleted animals (eg. TRPV1, TRPV4, TRPA1). If Ad and C-fibre afferents are involved preferentially evaluate the role of NaV channels (in particular NaV1.7). We will perform pharmacokinetic/pharmacodynamic (PK/PD) modelling integrating compound exposure information with in vitro and in vivo data which will aid in the interpretation of the data sets.
(3) Investigate changes in the function and phenotype of airway specific afferents and cough in disease models (eg. allergen, sensitised and challenged guinea-pigs; CS exposed guinea-pigs) as previously described by our lab and others using selective ligands. Develop a model of post viral cough (mirroring the most appropriate clinical phenotype eg. H1N1, rhinovirus).
(4) Perform clinical studies using ion channel specific tussive stimuli (eg. TRPV1, capsaicin; TRPA1, cinnamaldehyde; TRPV4, investigate appropriate stimuli, our pre-clinical studies suggest hypertonic saline may partially activate through TRPV4) across the relevant patient groups (normal, non-smokers, smokers, asthmatics, COPD, idiopathic coughers).

Who will benefit from this research and how?

Researchers: Sensory neurobiologists, respiratory physiologists and pharmacologists and respiratory clinicians will benefit from the proposed project through interaction with the PI's and researchers involved in this project. Interactions at meetings and publications in peer review journals will inform research in other laboratories.

Students (basic science and medical): will learn from the wide range of scientists involved in this project who have basic science, clinical and industrial experience. In particular, at Imperial scientists will be able to learn from top class scientists involved in doing complex electrophysiology and in vivo models.The lack of in vivo physiologists and pharmacologists is still apparent in spite of recent initiatives and so it is still essential that those people that possess these skills train young researchers so as to strengthen the UK in vivo skills base. Birrell and Belvisi train their own staff in these methodologies and together with the named scientists (Eric Dubuis, Sarah Maher) also run practical modules in which they are involved in 'hands on' teaching (BSc, MRes, Phd students) thereby contributing to the training of youngsters in the UK and increasing the research capacity in this area. Outside the UK the group always takes holiday experience placements and visiting fellows from across the globe that will benefit from the expertise and skills they can learn. Outreach events have also been hosted.

Patients:Treatment options are limited and recent meta-analysis concluded that over the counter (OTC) remedies are ineffective plus there is increasing concern about their use in children. Understanding the mechanisms involved in initiating cough will uncover novel therapeutic targets which will impact significantly on patient quality of life and a reduction in associated healthcare costs.

Government and NHS funding bodies: Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. In the UK, over £93 million/year is spent on over the counter anti-tussives of questionable efficacy Cough has a major impact on the UK economy with absenteeism from work, reduced productivity, physician consultations and prescription costs estimated at £1 billion annually. Chronic cough is often associated with an underlying inflammatory condition (eg. lung infections, asthma, COPD, pulmonary fibrosis, bronchiectasis, lung cancer) and can also be iodiopathic in nature with no known cause. Despite these facts, cough is a largely ignored research area and novel anti-tussive agents are lacking.

The European Respiratory Society (ERS) published guidelines on the management of cough. Belvisi and Smith were on this taskforce and Smith is also a member of the American College of Chest Physicians taskforce. The aim was to provide consensus regarding the diagnosis and treatment of cough in both adults and children. In 2004, the ERS produced a practical document, which provides helpful guidance to researchers, clinicians, the pharmaceutical industry and regulatory authorities. This document included recommendations on the following key elements: 1) safe standardised methods of inhalation cough challenge; 2) reliable, reproducible and relevant clinical cough recording and analysis; 3) clinical assessment of cough-related quality of life; 4) appropriate animal models in which to evaluate novel cough treatments; and 5) areas for future research. We believe that this document helped to improved patient care, enhance the quality of cough research and ultimately assist in the development of effective new therapies. Belvisi and Smith remain on these committees and in a key position to influence the field and inform on the cutting edge research they are performing whithin their laboratories. (Eur Respir J. 2004 Sep;24(3):481-92; Eur Respir J. 2007 Jun;29(6):1256-76).