- To identify the expression of cytokines, growth factors, lipid mediator enzymes, sensory neuropeptides and nitric oxide synthases in asthmatic inflammation.
- To characterise the cell surface receptors on key target cells in the airways that mediate the actions of these mediators and to determine whether these receptors are abnormally expressed in asthma.
- To study common regulatory mechanisms leading to increased expression of "inflammatory" genes in asthma.
- To study the complex interactions between mediators that may lead to amplification of inflammatory signals in asthma.
- To explore the effects of current therapies on these mediator networks.
Asthma is a complex inflammatory disease driven by a network of inflammatory mediators, including lipid mediators, cytokines, neuropeptides and nitric oxide. The mechanisms of increased mediator production in asthma are not well understood. Our primary objective is to elucidate the mechanisms involved in increased mediator production in asthma in order to understand the pathophysiology of this increasingly common condition and to lead to the development of new and more specific therapies. We have adopted a multidisciplinary molecule-to-man approach as the questions and scope of the research is complex and needs to involve several groups. We have brought together leading European research groups in the field of inflammatory mediators to address this objective.
Major research tasks include elucidation of the factors that regulate expression of lipid mediators (leukotrienes, prostaglandins and platelet-activating factor) and their receptors in airway and inflammatory cells, experimental models of asthma and in normal and asthmatic airways. The regulation of expression of lymphokines and chemokines that orchestrate eosinophilic inflammation in asthmatic airways, sensory neuropeptides and their receptors and the enzyme that generates nitric oxide, will be investigated using the same approaches. Establishment of a network of investigators will allow us to study the interactions between different mediators, by taking advantage of the different assays and technologies available amongst the partners. A unifying theme to this project is the idea that there are common molecular mechanisms leading to increased expression of the genes responsible for the synthesis and effects (receptors) of multiple inflammatory mediators. For example, pro-inflammatory cytokines increase the expression of enzymes involved in the arachidonic acid cascade. The role of common transcription factors, such as nuclear factor-kappa B and activator protein-l that are activated by various cytokines, in regulating the increased expression of inflammatory mediators and their receptors in asthmatic airways will also be explored.
The long-term objectives of our project are to develop more specific therapies to control and prevent the inflammation of asthma. This can only be achieved by greater understanding of the molecular basis for asthmatic inflammation. This requires a critical mass of investigators, with a multiplicity of experimental approaches, ranging from molecular biology through to clinical studies of asthmatic patients. This concerted action provides an opportunity to exploit the highly esteemed European research on inflammatory mediators in order to advance our knowledge more rapidly, and to make inroads into the important health and social problems created by asthma within the European Union.