Professor John Simpson
Dean of Translational Research & Professor of Respiratory Medicine, Newcastle University
- Email: firstname.lastname@example.org
- Telephone: 0191 208 7770
- Address: 3rd Floor, William Leech Building
Newcastle upon Tyne
I am a member of the Respiratory Medicine Research Group
My research group is principally interested in understanding innate immune dysfunction in the setting of critical illness, with a view to developing biomarkers and novel treatments. Further details are found in the adjacent RESEARCH section. Selected publications are shown in the adjacent PUBLICATIONS section.
My clinical interests are in nosocomial infection (particularly pneumonia), pulmonary embolism and interstitial lung disease. I moved to Newcastle in 2010, having previously worked in the University of Edinburgh / MRC Centre for Inflammation Research, and in the Royal Infirmary of Edinburgh.
Current roles and responsibilities
Dean of Translational Research, Newcastle University
Clinical lead for academic respiratory medicine, Newcastle University
Director of the NIHR Diagnostic Evidence Cooperatives (DEC), Newcastle. DECs were established in order to improve methodological evaluation, and implementation into practice, of in vitro diagnostics (IVDs). The Newcastle DEC welcomes and encourages contact from IVD companies and from academics with an interest in developing IVDs.
I was previously Clinical Director of R&D in Newcastle upon Tyne Hospitals NHS Foundation Trust, 2013-February 2016.
Our group’s work spans basic science, experimental medicine and randomised controlled trials (RCTs). The work focuses principally on innate immunity (with particular reference to neutrophil and monocyte function), and how this is impaired in critical illness.
We have identified biomarkers that effectively exclude ventilator-associated pneumonia in critically ill patients, and we are currently undertaking a multi-centre, randomised controlled trial (VAPRapid) to establish if these biomarkers can usefully influence antibiotic stewardship.
We have identified mechanisms by which neutrophils acquire a defect in phagocytic capacity during critical illness, and we have shown that this defect is independently associated with significantly increased risk of developing nosocomial infection in the intensive care unit (ICU). We have also described novel means by which to restore phagocytosis to normal (for example using GM-CSF), and we recently carried out an RCT (GRiP) of GM-CSF versus placebo in critically ill patients with evidence of impaired neutrophil phagocytosis.
Other related projects in the group include: studies of mitochondrial function during sepsis; regulation of neutrophil degranulation; biological effects of lipopolysaccharide (LPS) “mimics”; innate immune effects of inhaled LPS in human volunteers; and innate immune effects of surgical trauma.
Newcastle upon Tyne Hospitals NHS Charities have funded a project expanding on research in Intravenous Endotoxin Challenge in Healthy Human Volunteers.
We also contribute to clinical research projects related to idiopathic pulmonary fibrosis and pulmonary embolism.
The VAPRapid project involves collaboration with investigators from multiple UK sites (Newcastle, Belfast, Birmingham, Chester, Coventry, Edinburgh, London (Chelsea & Westminster), Manchester, Newcastle, North Tyneside, Preston, Sunderland, Liverpool)
Our group is part of the MRC-funded SHIELD consortium, led by Prof David Dockrell in Sheffield, which seeks to establish mechanisms of bacterial clearance by innate immune cells, and to establish ways of reducing antimicrobial resistance. The consortium brings together groups in Sheffield, Newcastle, Edinburgh and Birmingham
The GRiP project involved collaborations with ICUs in Gateshead, Newcastle and Sunderland
Other key collaborators include:
Professor Danny McAuley, Dr Cecilia O’Kane, Dr Ronan McMullan (Queen’s University Belfast)
Professor David Dockrell, Professor Steve Renshaw (Sheffield University)
Professor Adriano Rossi, Dr Donald Davidson, Dr Nik Hirani (Edinburgh University)
Professor Paul Corris, Dr Tony De Soyza, Dr Ian Forrest, Dr Sophie West, Dr Stephen Bourke, Dr Patrick Kesteven, Professor Matt Collin, Professor John Dark, Dr Simon Baudouin, Dr Stephen Wright, Professor Muzz Haniffa (Newcastle University)
Grants as Lead Applicant (current and selected previous)
Wellcome Trust/Department of Health Health Innovation Challenge Fund (HICF): Rapid detection and treatment of ventilator-associated pneumonia – towards improved antibiotic stewardship
NIHR Diagnostic Evidence Co-operative Award
Sir Jules Thorn Charitable Trust Award for Biomedical Sciences 2003
Acute infective lung injury: towards cell therapy with antiprotease-infected monocytes.
Sir Jules Thorn Charitable Trust
A randomised controlled trial of monocyte depletion in acute neutrophil-mediated lung injury.
MRC Developmental Clinical Studies (DCS): Does GM-CSF restore effective neutrophil function in critically ill patients?
Abstracts for selected current work
Intravenous endotoxin challenge in healthy human volunteers
Sepsis is a life-threatening condition that arises when the body's response to infection injures its own tissues and organs. Every year the NHS deals with 150,000 cases of severe sepsis, and this results in a staggering 44,000 deaths. Human survival from infection requires an appropriate inflammatory response: an unbalanced, hyperinflammatory response predisposes patients to overwhelming inflammation and death in the early phase of sepsis, while protracted under-activity of the immune system is associated with organ dysfunction and heightened risk of infections and death in the late phase of sepsis.
Individuals can be divided simply into characteristic genetic categories (or haplogroups) based on the genes contained in their mitochondria (mitochondria are energy-producing components of cells, and interestingly they have a unique genetic code that is different from the "standard" genetic code found in nucleus of the cell). Each mitochondrial haplogroup is assigned and identified by a letter of the alphabet. An observational study performed in Newcastle suggested that patients with haplogroup H had a survival advantage in sepsis, and higher fevers, when compared with non-H haplogroups. Recent data from our laboratory suggest that mitochondrial genes regulate the expression of cell surface receptors on human white blood cells (monocytes), which in turn have a key influence on the early inflammatory response to LPS.
Previous research on sepsis has focused on the role of isolated molecules, often based on findings from animal models. This approach is becoming outdated, as it is clear that many cell types and molecules coordinate the response to sepsis, making it unlikely that "targeting" one will lead to useful new treatments. Furthermore, a growing body of research has recently questioned the validity of using mouse models (because the immune response differs fundamentally from the response in humans). Indeed, the human IV LPS model to be used here shows much greater correlation with genetic changes due to inflammatory stresses seen in human disease.
Injection of LPS, a non-infectious bacterial cell-wall product, is a well-recognised, safe, investigational technique that has been used experimentally for over 50 years. The dose used is adjusted to body weight to ensure a standardised reaction in all participants. While we recognise that administration of low dose endotoxin is not a clinical model of sepsis, it does represent a significant improvement in experimental modeling over animal studies. Human endotoxaemia reproduces the earliest features of the pathogenesis of sepsis (which are almost impossible to study in the clinical setting), paving the way to define mechanisms of pathogenesis, and potentially “drugable” targets.
TeachingIn 2009 I received an Edinburgh University Students' Association Teaching Award.
I regularly teach undergraduate medical students at Newcastle University
Current PhD/MD students
I am lead supervisor for
Dr Tom Hellyer
Dr Jim Macfarlane
Dr John Widdrington
Dr Emma Browne
Dr Sarah Wiscombe
Dr Prosenjit Dutta
Dr Wendy Funston
Dr Kate Musgrave
Dr Jason Powell
I assist in the supervision of Dr Ben Prudon, Dr Carlos Echevarria, Dr Laura Jardine
- Scott J, Harris GJ, Pinder EM, Macfarlane JG, Hellyer TP, Rostron AJ, Morris AC, Thickett DR, Perkins GD, McAuley DF, Widdrington JD, Wiscombe S, Baudouin SV, Roy AI, Linnett VC, Wright SE, Ruchaud-Sparagano MH, Simpson AJ. Exchange protein directly activated by cyclic AMP (EPAC) activation reverses neutrophil dysfunction induced by beta(2)-agonists, corticosteroids, and critical illness. Journal of Allergy and Clinical Immunology 2016, 137(2), 535-544.
- Nolan TJ, Gadsby N, Hellyer TP, Templeton K, McMullan R, McKenna J, Rennie J, Robb CT, Walsh TS, Rossi AG, Conway Morris A, Simpson AJ. Low-pathogenicity Mycoplasma spp. alter human monocyte and macrophage function and are highly prevalent among patients with ventilator-acquired pneumonia. Thorax 2016, 71(7), 594-600.
- Echevarria C, Steer J, Heslop-Marshall K, Stenton SC, Hickey PM, Hughes R, Wijesinghe M, Harrison RN, Steen N, Simpson AJ, Gibson GJ, Bourke SC. Validation of the DECAF score to predict hospital mortality in acute exacerbations of COPD. Thorax 2016, 71(2), 133-140.
- Hellyer TP, Anderson NH, Parker J, Dark P, Van-Den-Broeck T, Singh S, McMullan R, Agus AM, Emerson LM, Blackwood B, Gossain S, Walsh TS, Perkins GD, Conway-Morris A, McAuley DF, Simpson AJ. Effectiveness of biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic Use (VAPrapid-2): study protocol for a randomised controlled trial. Trials 2016, 17, 318.
- Hellyer TP, Morris AC, McAuley DF, Walsh TS, Anderson NH, Singh S, Dark P, Roy AI, Baudouin SV, Wright SE, Perkins GD, Kefala K, Jeffels M, McMullan R, O'Kane CM, Spencer C, Laha S, Robin N, Gossain S, Gould K, Ruchaud-Sparagano MH, Scott J, Browne EM, MacFarlane JG, Wiscombe S, Widdrington JD, Dimmick I, Laurenson IF, Nauwelaers F, Simpson AJ. Diagnostic accuracy of pulmonary host inflammatory mediators in the exclusion of ventilator-acquired pneumonia. Thorax 2015, 70(1), 41-47.
- Hulse EJ, Davies JOJ, Simpson AJ, Sciuto AM, Eddleston M. Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning Implications for Respiratory and Critical Care. American Journal of Respiratory and Critical Care Medicine 2014, 190(12), 1342-1354.
- Ruchaud-Sparagano MH, Mills R, Scott J, Simpson AJ. MPLA inhibits release of cytotoxic mediators from human neutrophils while preserving efficient bacterial killing. Immunology and Cell Biology 2014, 92(9), 799-809.
- Brittan M, Barr LC, Anderson N, Morris AC, Duffin R, Marwick JA, Rossi F, Johnson S, Dhaliwal K, Hirani N, Rossi AG, Simpson AJ. Functional characterisation of human pulmonary monocyte-like cells in lipopolysaccharide-mediated acute lung inflammation. Journal of Inflammation 2014, 11, 9.
- Simpson AJ. Thrombolysis for acute submassive pulmonary embolism: CON viewpoint. Thorax 2014, 69(2), 105-107.
- Barr LC, Brittan M, Conway Morris A, McAuley DF, McCormack C, Fletcher AM, Richardson H, Connell M, Patel D, Wallace WA, Rossi AG, Davidson DJ, Manson L, Turner M, Hirani N, Walsh TS, Anderson NH, Dhaliwal K, Simpson AJ. A Randomized Controlled Trial of Peripheral Blood Mononuclear Cell Depletion in Experimental Human Lung Inflammation. American Journal of Respiratory and Critical Care Medicine 2013, 188(4), 449-455.
- Morris AC, Anderson N, Brittan M, Wilkinson TS, McAuley DF, Antonelli J, McCulloch C, Barr LC, Dhaliwal K, Jones RO, Haslett C, Hay AW, Swann DG, Laurenson IF, Davidson DJ, Rossi AG, Walsh TS, Simpson AJ. Combined dysfunctions of immune cells predict nosocomial infection in critically ill patients. British Journal of Anaesthesia 2013, 111(5), 778-787.
- Kerrin A, Weldon S, Chung AHK, Craig T, Simpson AJ, O'Kane CM, McAuley DF, Taggart CC. Proteolytic cleavage of elafin by 20S proteasome may contribute to inflammation in acute lung injury. Thorax 2013, 68(4), 315-321.
- Walsh TS, Morris AC, Simpson AJ. Ventilator associated pneumonia: can we ensure that a quality indicator does not become a game of chance?. British Journal of Anaesthesia 2013, 111(3), 333-337.
- Dhaliwal K, Scholefield E, Ferenbach D, Gibbons M, Duffin R, Dorward DA, Morris AC, Humphries D, Mackinnon A, Wilkinson TS, Wallace WA, vanRooijen N, Mack N, Rossi AG, Davidson DJ, Hirani N, Hughes J, Haslett C, Simpson AJ. Monocytes control second-phase neutrophil emigration in established lipopolysaccharide-induced murine lung injury. American Journal of Respiratory and Critical Care Medicine 2012, 186(6), 514-524.
- Wilkinson TS, Morris AC, Kefala K, O'Kane CM, Moore NR, Booth NA, McAuley DE, Dhaliwal K, Walsh TS, Haslett C, Sallenave JM, Simpson AJ. Ventilator-Associated Pneumonia Is Characterized by Excessive Release of Neutrophil Proteases in the Lung. Chest 2012, 142(6), 1425-1432.
- Brittan M, Barr L, Conway Morris A, Duffin R, Rossi F, Johnston S, Monro G, Anderson N, Rossi AG, McAuley DF, Haslett C, Hirani N, Dhaliwal K, Simpson AJ. A novel subpopulation of monocyte-like cells in the human lung after LPS inhalation. European Respiratory Journal 2012, 40(1), 206-214.
- MacKinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, Simpson AJ, Forbes SJ, Hirani N, Gauldie J, Sethi T. Regulation of Transforming Growth Factor-beta 1-driven Lung Fibrosis by Galectin-3. American Journal of Respiratory and Critical Care Medicine 2012, 185(5), 537-546.
- Morris AC, Brittan M, Wilkinson TS, McAuley DF, Antonelli J, McCulloch C, Barr LC, McDonald NA, Dhaliwal K, Jones RO, Mackellar A, Haslett C, Hay AW, Swann DG, Anderson N, Laurenson IF, Davidson DJ, Rossi AG, Walsh TS, Simpson AJ. C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients. Blood 2011, 117(19), 5178-5188.
- Gibbons MA, MacKinnon AC, Ramachandran P, Dhaliwal K, Duffin R, Phythian-Adams AT, Van Rooijen N, Haslett C, Howie SE, Simpson AJ, Hirani N, Gauldie J, Iredale JP, Sethi T, Forbes SJ. Ly6C(hi) Monocytes Direct Alternatively Activated Profibrotic Macrophage Regulation of Lung Fibrosis. American Journal of Respiratory and Critical Care Medicine 2011, 184(5), 569-581.
- Murray MP, Govan JRW, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, Greening AP, Haslett C, Hill AT. A randomised controlled trial of nebulised gentamicin in non-cystic fibrosis bronchiectasis. American Journal of Respiratory and Critical Care Medicine 2011, 183(4), 491-499.
- Conway Morris A, Kefala K, Wilkinson TS, Moncayo Nieto OL, Dhaliwal K, Farrell L, Walsh TS, Mackenzie SJ, Swann DJ, Andrews PJD, Anderson N, Govan JRW, Laurenson IF, Reid H, Davidson DJ, Haslett C, Sallenave JM, Simpson AJ. Diagnostic importance of pulmonary interleukin-1 beta and interleukin-8 in ventilator-associated pneumonia. Thorax 2010, 65(3), 201-207.
- Barlow PG, Cosseau C, Beaumont PE, Mackellar A, Wilkinson TS, Hancock REW, Govan JRW, Haslett C, Simpson AJ, Davidson DJ. The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium. American Journal of Respiratory Molecular and Cell Biology 2010, 43(6), 692-702.
- Lowder BV, Guinane CM, BenZakour NL, Weinert LA, ConwayMorris A, Cartwright RA, Simpson AJ, Rambaut A, Nübel U, Fitzgerald JR. Recent human-to-poultry host jump, adaptation, and pandemic spread of Staphylococcus aureus.. Proceedings of the National Academy of Sciences 2009, 106(46), 19545-19550.
- ConwayMorris A, Kefala D, Wilkinson TS, Dhaliwal K, Rossi AG, Farrell L, Walsh TS, Mackenzie SJ, Reid H, Davidson DJ, Haslett C, Sallenave JM, Simpson AJ. C5a mediates peripheral blood neutrophil dysfunction in critically ill patients. American Journal of Respiratory and Critical Care Medicine 2009, 180(1), 19-28.
- Wilkinson TS, Dhaliwal K, Hamilton TW, Lipka AF, Farrell L, Davidson DJ, Duffin R, Haslett C, Govan JRW, Gregory CD, Sallenave JM, Simpson AJ. Trappin-2 promotes early clearance of pseudomonas aeruginosa through CD14-dependent macrophage activiation and neutrophil recruitment. American Journal of Pathology 2009, 174(4), 1338-1346.
- Conway Morris A, Kefala K, Simpson AJ, Everingham K, Kerslake D, Raby S, Laurenson IF, Swann DJ, Walsh TS. Evaluation of the effect of diagnostic methodology on the reported incidence of ventilator-associated pneumonia. Thorax 2009, 64(6), 516-522.
- Li HN, Barlow PG, Bylund J, Mackellar A, Bjorstad A, Conlon J, Hiemstra PS, Haslett C, Gray M, Simpson AJ, Rossi AG, Davidson DJ. Secondary necrosis of apoptotic neutrophils induced by the human cathelicidin LL-37 is not pro-inflammatory to phagocytosing macrophages. Journal of Leukocyte Biology 2009, 86(4), 891-902.
- Farnworth SL, Henderson NC, Mackinnon AC, Atkinson KM, Wilkinson T, Dhaliwal K, Hayashi K, Simpson AJ, Rossi AG, Haslett C, Sethi T. Galectin-3 reduces the severity of pneumococcal pneumonia by augmenting neutrophil function. American Journal of Pathology 2008, 172(2), 395-405.
- Marriott HM, Jackson LE, Wilkinson TS, Simpson AJ, Mitchell TJ, Buttle DJ, Cross SS, Ince PG, Hellewell PG, Whyte MKB, Dockrell DH. Reactive oxygen species regulate neutrophil recruitment and survival in pneumococcal pneumonia. American Journal of Respiratory and Critical Care Medicine 2008, 177(8), 887-895.
- McElroy AN, O'Dwyer DN, Cooke G, Mawhinney L, Tynan A, O'Reilly C, Doroudian M, McKeon S, Keane MP, Fallon PG, Simpson AJ, Millar AB, McGrath EE, Whyte MK, Hirani N, Hogaboam CM, Armstrong ME, Donnelly SC. Toll- Like Receptor 3 (TLR3) L412F Single Nucleotide Polymorphism as a Causative Factor in Disease Progression in Idiopathic Pulmonary Fibrosis (IPF) During Bacterial Infection in TLR3-defective patients. In: Irish Thoracic Society Annual Scientific Meeting 2016. 2016, Killiney, Co.Dublin: Springer.
- O'Dwyer DN, Armstrong ME, Trujillo G, Cooke G, Keane MP, Fallon PG, Simpson AJ, Millar AB, McGrath EE, Whyte MK, Hirani N, Hogaboam CM, Donnelly SC. The Toll-like Receptor 3 L412F Polymorphism and Disease Progression in Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine 2013, 188(12), 1442-1450.
- Pinder EM, Rostron AJ, Hellyer TP, Ruchaud-Sparagano MH, Scott J, Macfarlane JG, Wiscombe S, Widdrington JD, Allen T, Roy AI, Linnett VC, Baudouin SV, Wright SE, Chadwick T, Fouweather A, Bowett S, Parker J, Corris PA, McAuley DF, Morris AC, Simpson AJ. Randomised Controlled Trial Of Granulocyte Macrophage Colony Stimulating Factor In Critically Ill Patients With Impaired Neutrophil Function. In: American Thoracic Society 2016 International Conference. 2016, San Francisco: American Thoracic Society.