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Dr Charlotte Summers

Departments

Division of Anaesthesia:
Clinical Lecturer in Critical Care Medicine

Research Interests

My research aims to define the role of neutrophil-endothelial cell interactions in regulating pulmonary inflammation.  Much of our understanding of neutrophil-pulmonary vascular endothelial cell interaction, and the mechanisms underlying the recruitment of leukocytes into the lung, has been extrapolated from studies undertaken in the systemic circulation.  However, substantial differences exist between the pulmonary and systemic circulations, including the site of leukocyte migration (pulmonary capillaries rather than post-capillary venules), the importance of physical entrapment of neutrophils in the lung microcirculation over adhesion/rolling events, and major differences in the repertoire of endothelial ligands expressed.  I have previously demonstrated that the healthy human pulmonary vasculature is able to selectively trap primed neutrophils, facilitate their de-priming and later release them back into the pulmonary circulation in a quiescent state, and furthermore that this homeostatic mechanism fails in patients with acute respiratory distress syndrome (ARDS) leading to neutrophilic pulmonary inflammation (Summers et al, Thorax 2014).  I am currently delineating the critical neutrophil-endothelial cell interactions occurring during these processes using stabilised multi-photon intravital video microscopy of the murine lung.

 

Targeting neutrophil-pulmonary endothelial cell interactions in ARDS may provide the first therapies for this devastating condition, which despite four decades of research, remains without treatment.  We have shown that a novel highly selective TNFR1 antagonist modulates important neutrophil-endothelial interactions/process known to occur in ARDS.   Selective blockade of TNFR1 prevents TNF-induced neutrophil priming alters neutrophil lifespan.  TNFR1 blockade also modulates the expression of ligands for neutrophils on the pulmonary micro-vascular endothelium, ameliorates neutrophil transmigration, and prevents TNF-induced endothelial permeability.  Along with collaborators in Belfast, we have undertaken the first human clinical trial of this novel therapy and demonstrated that it can prevent LPS-induced pulmonary inflammation in healthy volunteers.  We are now commencing Phase II clinical trials in surgical patient populations that have high risks of post-operative ARDS.

Keywords

two-photon microscopy ; de-priming ; pulmonary capillaries ; TNF receptors ; neutrophil-endothelial interactions ; neutrophil kinetics ; endothelium ; pulmonary circulation ; lung ; neutrophil homeostasis ; neutrophils ; tumour necrosis factor ; priming

Topics

  • acute respiratory distress syndrome (ARDS)
  • acute lung injury

Collaborators

Key Publications

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.

[Editor’s Choice paper. See also accompanying editorial pp606-608]

Summers C, Chilvers ER, Peters AM.  Mathematical modelling supports the presence of neutrophil de-priming in vivo.  Physiological Reports 2014; 2:e00241

[Editors Highlighted paper]

Summers C, Rankin SM, Condliffe AM, N Singh, Peters AM, ER Chilvers.  Neutrophil kinetics in health and disease.  Trends Immunol 2010; 31:318-324.

 [See Cover illustration and Featured article]

Singh N, Johnston A, Peters AM, Babar J, Chilvers ER, Summers C.  Acute lung injury results from failure of neutrophil de-priming: a new hypothesis.  Eur J Clin Invest 2012; 42: 1342-1349.

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.

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.

(1)   Two-photon intravital microscopy image of neutrophils (green) in the pulmonary circulation (red) of an mTmG x MRP8 Cre mouse.

(2)   Gamma scintigraphy images showing the distribution of unprimed (A) and ex vivo GM-CSF primed (B) autologous 99mTc-labelled neutrophils in healthy human subjects.

(3)   Cover of Trends in Immunology volume 31, 2010.