Emeritus ProfessorPeterJeffery

Summary

Research Focus
Specific Career Highlights
A Selection of Ten Clinically Relevant Publications

Professor (Emeritus) Peter Key Jeffery FRCPath. DSc.(Med) PhD. MSc. is a Senior research Investigator, Imperial College London and Honorary Consultant, Royal Brompton Hospital (RBH) the campus where he is located. He began his career at the Institute (then Institute of Diseases of the Chest) in 1968 and, apart from a brief period at St George’s Hospital and Chelsea King’s College, UK has been with us since. In 1992, he initiated and directed the Lung Pathology Research Unit and throughout his career divided his research efforts into 3 areas: (1) normal lung microstructure, (2) basic mechanisms of airway inflammation and airway wall remodelling in both chronic and acute phases (i.e. exacerbations) of airway diseases and (3) investigating and testing improved or novel treatments, primarily for asthma and chronic obstructive pulmonary disease (COPD). Professor Jeffery has taught undergraduates and post-graduate lung specialists and, in response to invitation, lectures extensively throughout the world. He has held posts as Scientific Group leader, Head elect of the Cell & Molecular Biology Assembly of the European Respiratory Society and was on the Editorial Board of the European Respiratory Journal for 5 years. He has won several awards, particularly through application of his high resolution images of the lung with which he has illustrated and unravelled the complexities of the lung in health and disease. He has hundreds of publications published in the best respiratory journals world-wide and his chapters on normal lung microanatomy and pathology have become standard reference texts.

Research Focus

The focus of Professor Peter Jeffery’s research has been a critical and quantitative analysis of pulmonary inflammation and the structural alterations (also referred to as remodelling) associated with it. The tissue resource has been bronchial or open lung biopsies taken with ethical approval and informed consent from subjects with asthma, chronic bronchitis, bronchiectasis or fibrosing alveolitis. These studies in humans have been aided by complementary explant or cell culture studies of human airway tissues and, only where necessary, experimental studies of laboratory rodents.

His international recognition and distinction is as a result of research, published works and teaching in the following three main areas of lung pathology:

1. Normal microstructure - As a necessary prerequisite to the study of the alterations which occur in disease, he has undertaken studies of the normal lung in both man and animals and applied the techniques of electron microscopy, immunohistology and molecular biology (ie insitu hybridisation) to determine the complexity of cell types, both structural and inflammatory, which make up the airway wall and to ascertain the localization of genes which are expressed constitutively. The focus on high-resolution techniques has provided exciting novel images of the normal lung. These images have formed the basis for chapters on normal microanatomy of the airways that have become well-respected international reference texts.
2. Pathogenesis – Investigations have been conducted of airway and parenchymal tissues obtained at surgical resection or by flexible fibre-optic or open lung biopsy from adults with inflammatory conditions of the airway and lung and, most recently, wheezy infants and children who have recently developed asthma. Comparison with the norm has provided new data as to the key structural and molecular changes that occur in disease, novel findings that have been published in peer-reviewed international and leading specialist journals. In addition, there is a creative aspect exemplified by the production of a series of highly popular videos that demonstrate, through ‘journeys’ into the lung, the pathology of asthma and chronic obstructive pulmonary (lung) disease (usually known as COPD).
3. Therapy - Based on his findings in diseased lung, there have been investigations in humans to ascertain whether or not and how distinctive classes of drugs may alter (improve) the structure and immunopathology of the airway wall, especially, in asthma and COPD. By the initiation of clinical trials and using bronchial biopsies in humans to ascertain directly the effects of anti-inflammatory agents on the airway tissue itself, interesting differences in responsiveness to inhaled corticosteroid have emerged and novel treatments that target the key inflammatory cells of COPD or asthma have been discovered.

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Specific Career Highlights

The following provides a point-by-point synopsis of Professor Jeffery’s research and major achievements.

(i) Applied transmission and high resolution scanning microscopy to provide novel detailed ultra-structural descriptions of the human airway mucosa in the normal, asthma and in COPD.

(ii) Elucidated mechanisms of goblet cell hyperplasia in experimental bronchitis in 1981.

(iii) Initiated in the UK, ultrastructural and immunohistological studies of bronchial biopsies in asthma. The study published in abstract form in 1987 and as a full paper in 1989 represented one of the first two worldwide studies of bronchial biopsies obtained by use of the flexible fibre-optic bronchoscope.

(iv) Provided early observations and evidence that highlighted a role for the lymphocyte in the control of inflammation in chronic asthma. This represented, in 1989, and 1990 a landmark shift in emphasis to the understanding and treatment of lymphocytic inflammation in asthma.

(v) Initiated in 1990 in collaboration with the department of Allergy & Clinical Immunology, molecular (in situ hybridisation) studies of interleukin 5 in the airways of asthmatics, now recognized, to be a key cytokine influencing the participation of the eosinophil in the inflammation of asthma.

(vi) Determined, in 1992, the comparative affects of inhaled -agonist or corticosteroid on airway inflammation using analyses of bronchial biopsies in asthma. These were among the first studies in humans to demonstrate clearly the way in which inhaled corticosteroids can markedly reduce inflammatory cell number. It established bronchial biopsies as the gold standard by which one determines anti-inflammatory efficacy.

(vii) In 1992, conducted the first of comparative studies of inflammation in asthma, COPD, cystic fibrosis and fibrosing alveolitis.These demonstrated a striking difference in the nature of the inflammation in COPD which, interestingly, and unlike asthma, has now been shown to respond poorly to inhaled steroids.

(viii) In 1992 and 1993, explored the up-regulation and role of adhesion molecules in experimental neutrophil-dependent lung injury in vivo. The effects of viral infection in human airway epithelial cells has been determined in vitro using novel high resolution techniques which have proved to be highly sensitive and provide a way to analyse single cells, previously not possible.

(ix) Localized in 1997 eotaxin protein and gene expression, a key eosinophil attractant, in airway tissue challenged with allergen and demonstrated how structural cells (eg, airway epithelium, bronchial smooth muscle and endothelial cells) take part in the inflammatory reaction by their production of eotaxin.

(x) Demonstrated the importance of the bronchial myofibroblast and "synthetic myocyte" as a novel source of the newly acquired airway smooth muscle which appears in life-threatening asthma. In this, there are interesting parallels with the changes that occur in vascular disease (eg.atheroma).

(xi) In 1997/1998 reported the original finding that the profile of T-cell subsets was distinct in smokers with COPD as compared with non-smokers with asthma. Initiated new molecular (in situ hybridisation) studies in asthma, chronic bronchitis and fibrosing alveolitis to determine which cytokines are unique to each condition.

(xii) 1999-2001 described and quantified gene expression for IL4, IL5, eotaxin, MCP4, RANTES and 15LO in chronic bronchitis and COPD in association with exacerbations of bronchitis. With his team, conducted double labelling experiments to identify the source of these cytokines in COPD.

(xiii) 2000-2001 demonstrated the effects of therapy using bronchial biopsies: salmeterol in asthma, cysLT receptor antagonists in asthma, fluticasone in COPD and cilomilast (Ariflo, a selective PDE4 inhibitor) in COPD. Initiated studies of the changing pattern of inflammation in severe exacerbations of COPD and of asthma.

(xiv) 2001-2004 initiated studies of bronchial biopsies in children (in collaboration with the Dept. of Paediatrics) and more recently in wheezy infants (in collaboration with the University of Helsinki) and pre-school asthmatic children. These studies demonstrate that the key structural change in asthma is already present and maximal in children of median age 10 years, not present in infants of 12 months but begin to develop at median age of 29 months. These findings have important implications for treatment, possible prevention and prediction of the likelihood of developing future asthma.

(xv) 2004-2006 initiated studies of the effects of smoking in asthmatics in collaboration with colleagues at the London Chest Hospital. Reported the importance of CXCL5 and CXCR2 in exacerbations. Reported the expression of cysLT1 receptor gene and protein expression in stable asthma, in exacerbations, in children and in patients with COPD. Concluded a 2 year multi-centre double-blind randomised clinical trial in COPD in which biopsy and sputum have demonstrated a broad spectrum of anti-inflammatory effects by Seretide (combination of long-acting beta agonist and steroid by inhalation) administered over 13 weeks.

(xvi) 2006-2007. Initiated a placebo-controlled trial in asthma comparing variable, as needed combination, treatment vs high dose fixed combination of inhaled Symbicort on eosinophilic inflammation and remodelling (i.e. RBM thickness). The results of this new treatment have been published. Initiated studies of bronchial mucosal dendritic cells (DCs) that showed a reduction of the numbers of mature DCs in asthmatics that smoke and also in current smokers with COPD.

(xvii) 2008. In collaboration with the Depts. of Paediatrics and Gene Therapy, completed studies of airway smooth muscle mass increase in children with asthma and other chronic inflammatory conditions of the lung, demonstrating that this aspect of remodelling has also already begun by median age 11 years.

(xviii) 2009. Completed a clinical (biopsy) trial in which the anti-inflammatory potential of a novel treatment for the inflammation of COPD has been assessed.

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A Selection of Ten Clinically Relevant Publications

1. Jeffery, P.K., Wardlaw, A.J., Nelson, F.C., Collins, J.V. and Kay, A.B., "Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity" Am. Rev. Respir. Dis. (1989) 140: 1745 1753.
2. Jeffery, P.K., Godfrey, R.W.A., Adelroth, E., Nelson, F., Rogers, A. and Johansson, S A., "Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma: a quantitative light and electron microscopic study" Am. Rev. Respir. Dis. (1992) 145: 890 899.
3. Gizycki, M.J., Adelroth, E., Rogers, A.V., O'Byrne, P.M. and Jeffery, P.K., "Myofibroblast involvement in the allergen induced late response in mild atopic asthma" Am. J. Respir. Cell Mol. Biol. (1997) 16: 664 673.
4. O'Shaughnessy, T.C., Ansari, T.W., Barnes, N.C. and Jeffery, P.K., "Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1" Am. J. Respir. Crit. Care Med. (1997) 155: 852 857.
5. Gizycki MJ, Hattotuwa KL, Barnes N, & Jeffery PK “The effects of fluticasone propionate on inflammatory cells in COPD: an ultrastructural examination of endobronchial biopsies” Thorax (2002) 57: 799-803
6. Gamble, E., Grootendorst DC, Brightling CE, Troy S, Qiu Y, Zhu J et al & Jeffery PK. Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. (2003) 168:976-982.
7. Jeffery PK, Holgate S, Wenzel S “Methods for the assessment of endobronchial biopsies in clinical research: application to studies of pathogenesis and the effects of treatment (a consensus statement). Am J Respir Crit Care Med (2003) 168: S1-S17
8. Barnes NC, Qiu YS, Pavord ID, Parker D, Davis PA, Zhu J, Johnson M, Thomson NC, Jeffery PK. Anti-inflammatory effects of Salmeterol/Fluticasone Propionate in Chronic Obstructive Lung Disease. Am. J. Respir. Crit. Care Med. (2006) 173: 736-743
9. Pavord ID, Jeffery PK, Qiu Y, Zhu J, Parker D, Carlsheirner A, Naya I Barnes NC. Airway inflammation in patients with asthma with high-fixed or low-fixed plus as-needed budesonide/formoterol. J Allergy Clin Immunol (2009) 123: 1083-1089
10. Ramsay CF, Suillivan P, Gizycki M, Wang D, Swern AS, Barnes NC, Reiss TF, Jeffery PK. Montelukast and bronchial inflammation in asthma: a randomiosed, double-blind placebo-controlled trial. Resp Med (2009) 103: 995-1003

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