The Summers laboratory is split between the Divisions of Respiratory Medicine and Anaesthesia, and studies the role of the innate immune system in acute and chronic inflammation.
Neutrophils are the principal effectors of the innate immune response and play a crucial role in host defence against invading microbes. Hence, patients displaying a defect in either the number or function of these cells are highly vulnerable to recurrent and often fatal bacterial and fungal infection. To perform their bactericidal functions efficiently neutrophils need to be highly mobile, responsive to the finest of chemotactic trails, and fully ‘armed’ to permit efficient intracellular killing. Mechanisms are also needed to prevent premature or excessive activation, and to allow efficient removal of cells at the termination of the inflammatory response. Failure of any one of these processes can lead to prolonged residency and activation of neutrophils within tissues, and the uncontrolled release of an array of noxious granule proteins and pro-inflammatory mediators. The histotoxic nature of many of these agents has been strongly implicated in inflammatory disorders including acute respiratory distress syndrome (ARDS), bronchiectasis, fatal asthma, ischaemia-reperfusion injury, and chronic obstructive pulmonary disease (COPD).
Neutrophil priming is an event whereby the response of the cell to an activating stimulus is augmented greatly by prior exposure to a priming agent (eg. LPS, TNF) and is a critical determinant of the pathogenic capacity of these cells in vivo. My group revealed for the first time that priming of human neutrophils is reversible in vivo, refuting the view that priming is a terminal event. Using 111-Indium and 99m-Technicium-labelled autologous granulocytes we made the first measurements of single pass neutrophil transit across the lung in humans; these confirmed substantial initial retention of ex-vivo primed cells by the pulmonary circulation followed by slow but complete release, supporting our hypothesis that the healthy pulmonary vasculature can retain primed neutrophils, facilitate their depriming and later release them into the systemic circulation in a quiescent deprimed state.
We have extended our studies using radiolabelled granulocytes to investigate the role of neutrophils in idiopathic pulmonary fibrosis and lung cancer, and monocytes in lung injury and other chronic inflammatory disorders.
To see details of our Critical Care-related research programme please see http://anaesthetics.medschl.cam.ac.uk/ccg/
Burzynski LC, Humphry M, Pyrillou K, Wiggins KA, Chan JNE, Figg N, Kitt LL, Summers C, Tatham KC, Martin PB, Bennett MR, Clarke MCH. The coagulation and immune systems are directly linked through the activation of interleukin-1-alpha by thrombin. Immunity 2019; 50:1033-1042.
Bashant KR, Vassallo A, Herold C, Berner R, Menschner L, Subburayalu J, Kaplan MJ, Summers C, Guck J, Chilvers ER, Toepfner N. Real-time deformability cytometry reveals sequential contraction and expansion during neutrophil priming. J Leukoc Biol 2019, 105:1143-1153.
Farahi N, Loutsios C, Tregay N, Wright AKA, Berair R, Lok LSC, Gillett D, Cullum I, Simmonds RP, Summers C, Wong A, Solanki CK, Buscombe J, Pang PH, Thavakumar A, Peters AM, Brightling CE, Condliffe AM, Chilvers ER. In vivo imaging reveals increased eosinophil uptake in the lungs of obese asthmatic patients. J Allergy Clinic Immunol 2018; 142:1659-1662.
Proudfoot AG, O’Kane CM, Bayliffe A, Serone A, Bareille PJ, Smith S, Brown V, Hamid UI, Wright T, Chen Y, Wilson R, Cordy J, van Wilte R, Morley P, Elborn JS, Hind M, Chilvers ER, Griffiths M, Summers C*, McAuley DF*. A domain antibody to the tumour necrosis factor receptor one (TNFR1) prevents pulmonary inflammation in experimental models of acute respiratory distress syndrome. Thorax 2018, in press. (* these authors contributed equally to this work).
Griffiths SV, Conway DH; POPC-CB Investigators, Sander M, Jammer I, Grocott MPW, Creagh-Brown BC. What are the optimum components in a care bundle aimed at reducing post-operative pulmonary complications in high-risk patients? Perioper Med (Lond) 2018; 7:7.
Summers C, Singh NR, Worpole L, Simmonds R, Babar J, Condliffe AM, Gunning KE, Johnston AJ, Chilvers ER. Incidence and recognition of acute respiratory distress syndrome in a UK intensive care unit. Thorax 2016; 71:1050-1051.
Juss JK, House D, Amour A, Begg M, Herre J Storisteanu DML, Hoenderdos K, Bradley G, Lennon M, Summers C, Hessel EM, Condliffe AM and Chilvers ER. ARDS neutrophils have a distinct phenotype and are resistant to phophoinositide 3-kinase inhibition. Am J Respir Crit Care Med 2016; 194:961-973.
Hoenderdos K, Lodge K, Hirst RA, Chen C, Palazzo SGC, , Emerenciana A, Summers C, Angyal A, Porter L, Juss JK, O’Callaghan C, Chilvers ER, Condliffe AM. Hypoxia up-regulates neutrophil degranulation and potential for tissue injury. Thorax 2016; 71:1030-1038.
Summers C, Singh NR, White JF, Mackenzie IM, Johnston A, Solanki C, Balan KK, Peters AM, Chilvers ER. Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in acute respiratory distress syndrome. Thorax 2014; 69:623-629.
Farahi N, Singh NR, Heard S, Loutsios C, Summers C, Simmonds RP, Solanki CK, Solanki K, Balan KK, Ruparelia P, Peters AM, Condliffe AM, Chilvers ER. Use of 111-Indium-labelled autologous eosinophils to establish the in vivo kinetics of human eosinophils in healthy subjects. Blood 2012; 120: 4068-4071.
McGovern NN, Cowburn AS, Porter L, Walmsley SR, Thompson AA, Summers C, Willcocks LC, Whyte MKB, Condliffe AM, Chilvers ER. Hypoxia inhibits respiratory burst activity and killing of staphylococcus aureus in human neutrophils. J Immunol 2011; 186: 453-463.
Szczepura KR, Ruparelia P, Solanki CK, Balan KK, Newbold P, Summers C, Chilvers ER, Peters AM. Measuring whole-body neutrophil redistribution using a dedicated whole body counter and ultra-low doses of 111Indium (whole body counting). Eur J Clin Invest 2011; 41: 77-83.
Cowburn AS, Summers C, Dunmore BJ, Farahi N, Hayhoe RP, Print CG, Cook SJ, Chilvers ER. GM-CSF causes a paradoxical increase in the BH3-only protein Bim in human neutrophils. Am J Respir Cell Mol Biol 2011; 44: 879-887.
Ruparelia P, Szczepura K, Summers C, Solanki CK, Balan KK, Newbold P, Bilton D, Peters AM, Chilvers ER. Quantification of 111In-neutrophil migration into the lungs of patients with chronic obstructive pulmonary disease. Eur J Nucl Med Mol Imaging 2011; 38: 911-919.
Gooptu B, Miranda E, Nobeli I, Mallya M, Purkiss A, Leigh-Brown SC, Summers C, Phillips RL, Lomas DA, Barrett TE. Crystallographic and cellular characterisation of two mutations stabilising the native fold of alpha1-antitrypsin: implications for rational drug design. J Mol Biol 2009; 387:857-68.