'FROM DISCOVERY TO RECOVERY'
My areas of research focus largely on the processes that mediate inflammation and repair in inflammatory lung disease. I am particualrly interested in the role of the matrix metalloproteinases (MMPs) in both initiating and perpetuating the process of tissue damage, but also mediating a reparative process allowing recovery. Broad spectrum MMP inhibition has been an unsuccessful therapeutic strategy in a number of inflammatory diseases. We aim to profile the expression of these proteases at different stages of disease and identify which initiate the damage and which regulate the repair process at the given time points. Ultimately the aim of this work is to allow targetted MMP inhibition at specific stages of disease, initially to reduce inflammation, and at later time points to promote normal epithelial repair and inhibit fibrosis.
My clinical specialties are tuberculosis and cystic fibrosis. Both are characterised by chronic infection leading to inflammation and extensive tissue damage. High protease activity has been well-described in tuberculosis, and along with Cliff Taggart and Danny McAuley I am investigating the capacity of anti-proteases to modulate inflammatory damage but also mycobacterial survival. In Cystic Fibrosis we have established models of direct infection of the lung parenchymal and inflammatory cells with typical CF pathogens (in particular Pseudomonas aerugionsa) and are investigating the regulation and effects of MMP secretion in response. We have a further clinical study about to begin examining in vivo exprssion of these proteases and investigating the mechanism that induce airway remodelling or destruction in this disease.
Along with Danny McAuley I work on proteases and inflammatory mediators in acute lung injury (ALI). We have established in vitro models and a human in vivo model of acute lung inflammation and have used these to test potential novel therapuetics in ALI that target inflammation and MMP production (including statins and Keratinocyte Growth Factor), and have progressed these to early clinical trial stage. We have further projects looking at the role of RAGE and Oncostatin M in mediating inflammatory lung disease, and are also investigating the capacity of endogenously produced anti-protease molecules to modulate these responses (particularly SLPI and elafin) in collaboration with Cliff Taggart. We have further collaborations with Birmingham, Edinburgh, UCL, Galway and San Francisco in ALI.
Finally I have an interest in the process of aberrant tissue remodelling that leads to cutaneous fibrosis. Many of the processes that regulate fibrosis in the lungs are common to other organs. I am currently supervising a clinical fellow investigating the mechanisms of skin fibrosis in scleroderma.
External Research Collaborations
Prof John Simpson (Newcastle University)
MMP activity as a biomarker of ventilator associated pneumonia
Prof Andrew Fisher (Newcastle University)
MMPs in the reconditioned human lung
Prof John Laffey (Galway University Hospitals)
Matrix metalloproteinases (MMPs) in ventilator associated lung injury
Dr David Thickett (University of Brimingham and University of Warwick)
Epithelial to mesenchymal transition as a mechanism of fibrosis in ALI
Vit D deficiency and outcomes in treatment of tuberculosis
Prof Michael Matthay (University of California, San Francisco)
Protective role of KGF and anti-microbial peptides in LPS induced acute lung injury
Dr Mark Griffiths (Imperial College London)
Iron-binding molecules and ALI
Prof Chris Denton (University College London)
Role of epithelial to mesenchymal transition in mediating cutaneous fibrosis in scleroderma
Prof Danny Altmann (Imperial College London)
Serological immune responses to Burkholderia species in CF patients
Invited seminar speaker to VA Medical Centre San Francisco June 2009
Review papers for Thorax, European Respiratory Journal, Critical Care Medicine, American Journal of Physiology: Lung Cellular and Molecular Physiology, Journal of Immunology and Archives of Biochemistry and Biophysics.
Expert reviewer for MRC and National Institute for Health Research (NIHR)
Peer review grants for MRC, British Lung Foundation, local Trust and West Midlands Charitable Funds
Contribution to national meetings
Chaired scientific sessions at the annual BTS winter meeting 2009 and 2010
Organisation/chairing of UKALI meetings bi-annually