Professor Geoffrey Warhurst
Consultant NHS Scientist
Salford Royal NHS Foundation Trust & University of Salford, Hope Hospital
Tel. +44 (0)161 206 4403, e-mail g.warhurst@salford.ac.uk
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Research Interests
Prof. Warhurst is Consultant Scientist in the R&D Directorate of Salford Royal NHS Foundation Trust at Hope Hospital and is developing an integrated biomedical/clinical research programme in collaboration with the Biomedical Research Institute aimed at translating laboratory studies of disease mechanisms into improvements in diagnosis and treatment in the clinic
1. Host-bacterial interactions and immune / inflammatory dysregulation in human disease.
Gut epithelial-bacterial interactions as a “driver” of inflammatory disease.
The gut lumen hosts a complex microbial flora of >10 14 organisms which is critical to human development and function but is also a significant threat in terms of potential to cause disease. The gut epithelial barrier is critically important in regulating the relationship between host and microflora, ensuring that bacteria are contained in the lumen to prevent wholesale activation of inflammatory responses, while facilitating controlled exposure of the immune system to microbial factors. Impairment of this barrier results in increased responsiveness to gut flora and bacterial invasion into host tissues which may underlie several acute and chronic inflammatory diseases. The mechanisms of barrier dysfunction related to two clinically important areas, sepsis in the critically ill and inflammatory bowel disease (IBD) are being studied. Using a range of in vitro and in vivo models, the group has identified novel mechanisms by which commensal bacteria and their antigens translocate across the gut in response to inflammatory and metabolic stress and identified key barrier proteins that regulate interaction with the luminal flora. The interaction between gut parasites and IBD is also being explored in a joint study with Dr Mike Rogan. The aim is to identify new targets for early diagnosis and improved intervention which can be translated eventually into patient benefit in the clinic and the work involves close collaboration with other academic groups (Dr K. Else; Immunology; Prof I. Roberts, Microbiology, Univ. of Manchester, Prof J, Iovanna, INSERM) and clinical colleagues at Hope Hospital (Prof. G. Carlson).
Molecular diagnosis of hospital acquired infection (HCAI) in the critically ill.
Hospital acquired infections (HCAI) is one of the major concerns of modern healthcare. Approximately 10% of all hospitalized patients in the UK develop HCAI and the cost to the NHS is estimated at >£1billion each year. Patients acquire these organisms from the external environment or from sources within the body (e.g. the gut). Recognition of bloodstream infection currently depends on culture which takes 2-3 days and there is a pressing need to develop new techniques which offer a more rapid and reliable detection of pathogens The ability to rapidly and reliably detect multiple pathogens. In collaboration with Roche Diagnostics and the Critical Care Directorate at Hope Hospital (Dr P. Dark, Dr A. Thomas, Prof G. Carlson), real-time PCR techniques able to detect circulating pathogen DNA within 6 hours are being tested and applied to HCAI detection in the critically ill. Preliminary data indicates has shown the feasibility of this approach and clinical benefits associated with early focusing of antibiotic therapy and reduced dependence on broad spectrum antibiotics. A £2 million programme grant to assess the feasibility and cost-effectiveness of introducing this technology into ICU practice has been shortlisted by the Department of Health.
Mechanisms of systemic immune dysregulation and infection in critical illness.
Systemic inflammatory dysregulation results from sterile tissue injury and/or invading pathogens, and represents a complex immune syndrome linked to increased susceptibility to nosocomial infection, multi-organ dysfunction and mortality in the critically ill. Despite the identification of several candidate molecules, therapeutic progress has been disappointing, primarily due to an incomplete understanding of the pathways involved and how they integrate functionally to produce individual responses to injury and infection. Critical illness, therefore, remains a major healthcare challenge internationally. The emergence of new approaches combining high-throughput transcriptomic and phenotypic profiling techniques provides new opportunities to address these questions. A programme is under development with Dr Paul Dark in Critical Care at Hope Hospital which aims to develop a comprehensive understanding of the key “nodes” within the immune-inflammatory system that underpin the response to sterile injury and determines susceptibility to infection and clinical outcome. High-throughput multiplex analysis of circulating and tissue markers in critically ill patients is being undertaken in Dr Warhurst’s laboratory with collaborating expertise in immunology and bioinformatics at the University of Manchester.
Key References
Collett, A., Higgs, N.B. Zeef, L.A. Hayes , A. Salmo, E, Haboubi, N, Carlson, G.L., Warhurst G. Changes in mucosal expression of bacterial response and epithelial repair genes precede altered gut permeability during colitis development in mdr1a (-/-) mice. Inflammatory Bowel Diseases (in press; 2007).
Edwards-Ingram LC, Gitsham P, Warhurst G, Clarke I, Terentjev Y, Hoyle D, Oliver SG and Stateva LI. Genotypic and physiological characterization of Saccharomyces boulardii, the probiotic strain of S. cerevisiae.Applied and Environmental Microbiology, 73:2458-67 (2007).
Gunji, H., S. Scarth, G.L. Carlson, G. Warhurst, R.A. Little, S.J. Hopkins Variability of bacterial translocation and the influence of interleukin-6 following injury P athophysiology 13: 39 -49 (2006)
Mahmood, B., Higgs N., Howl L., G Warhurst Colonic secretion studied in vitro in rats fed polyunsaturated fatty acid s. Bangladesh Med Res Counc Bull 32: 72-77 (2006)
Clark , EC., C Hoare, J. Tanianis-Hughes, CJ Watson, GL. Carlson, G.Warhurst. Interferon-gamma induces translocation of commensal E. Coli across gut epithelial cells via a lipid raft-mediated process Gastroenterology 128: 1258-1267 (2005)
Watson CJ, Hoare C, Garrod DR Carlson GL, G Warhurst Interferon-gamma selectively increases epithelial permeability to large molecules by activating different populations of paracellular pores. Journal of Cell Science 118: 5221-5230 (2005)
Clark, EC, S. Patel, Currie, A., G. Warhurst, G.L. Carlson Acute deprivation of glutamine as a metabolic fuel facilitates TNF- a induced bacterial translocation. Gut 52: 226-232 (2003)
Watson C.J., M. Rowland, Warhurst G Functional modelling of tight junctions in colonic epithelial monolayers using PEG oligomers. Am. J. Physiol 281: C388-C397 (2001)
Hope N., Butt, G., Ross I, Warhurst, G. Arn, M., Grigor, M., Lubcke R., Barbezat G.O. Somatostatin enhances cAMP-dependent short-circuit current in human colon via somatostatin receptor subtype-2. Dig. Dis. Sci. 46: 2499-2503 (2001)
2. Understanding the barriers to oral drug delivery in man: towards the development of more effective medicines
The ability to successfully deliver a drug via the oral route remains crucial to its clinical and commercial success and more drugs fail due to absorption problems than for any other single reason. This is due to the components of the gut barrier, such as tight junctions and efflux transporters which are crucial to human health (see above) being a major obstacle to the efficient delivery of many drug molecules. The group has made a significant contribution to understanding the role of intestinal drug efflux transporters, particularly P-glycoprotein in limiting absorption and mediating drug-drug interactions. The ethos has been to develop in vitro models based on the use of human cell lines and human tissues which can be used to predict potential absorption problems prior to testing in man. This work is facilitated by strong links with one of the largest GI Surgical Units in the region (Prof Gordon Carlson) and interactions with the pharmaceutical industry including AstraZeneca and Pfizer. These models also have potential to assess the effects of disease on drug absorption, an area which although crucially important is little understood.
Key References
Collett A, Stephens RH, Harwood M, Humphrey M, Dallman L, Bennett J, Carlson GL, Warhurst G. Investigation of regional mechanisms responsible for poor oral absorption in man of a controlled release preparation of the a -adrenoreceptor antagonist, UK-338,003: the rational use of ex vivo intestine to predict in vivo absorption. Drug Metabolism and Disposition (in press 2007)
Collett, A. J. Tanianis-Hughes, GL Carlson, M. Harwood, G. Warhurst Comparison of P-glycoprotein-mediated drug interactions in Caco-2 with human and rodent intestine: relevance to in vivo prediction. European J. Pharmaceutical Sciences 26: 386-393 (2005)
Collett A, J. Tanianis-Hughes, D. Hallifax, G. Warhurst Predicting P-glycoprotein effects on oral absorption: correlation of transport in Caco-2 with drug pharmacokinetics in wild type and mdr1a (-/-) mice in vivo. Pharmaceutical Research 21: 819-826 (2004)
Collett A, J. Tanianis-Hughes, G. Warhurst Rapid induction of P-glycoprotein expression by high permeability compounds in colonic cells in vitro: a possible source of transporter mediated drug interactions? Biochemical Pharmacology 68: 783-790 (2004)
Emery P.T., N.B. Higgs, A.C. Warhurst, G.L. Carlson, G. Warhurst Antisecretory properties of non-peptide somatostatin receptor agonists in isolated rat colon: luminal activity and interaction with p-glycoprotein. Br. J. Pharmacol. 135: 1443-1448 (2002)
Stephens, R.H., O’Neill, C.A., Humphrey, M.J. Henry, B, Rowland, M, G. Warhurst Resolution of p-glycoprotein and non-P-glycoprotein mediated drug efflux using intestinal tissues from mdr1a (-/-) mice. Br. J. Pharmacol. 135: 2038-2046 (2002)
Stephens, R.H., N.B. Higgs, J. Tanianis-Hughes, M. Humphrey, G. Warhurst Region-dependent modulation of intestinal permeability by drug efflux transporters: in vitro studies in mdr1a (-/-) mouse tissues. J. Pharm. Exp. Ther. 303: 1095-1101 (2002)