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Regulation of pulmonary neutrophilic inflammation in community-acquired pneumonia

Paixao Jose, RJ; (2015) Regulation of pulmonary neutrophilic inflammation in community-acquired pneumonia. Doctoral thesis , UCL (University College London).

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Abstract

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP). In adults, its incidence increases with age and is associated with high mortality. Although neutrophils play a key role in host defence, excessive neutrophilic inflammation in the lungs may be associated with bystander tissue injury. This thesis aims to (1) investigate the role of the major high affinity thrombin receptor, proteinase-activated receptor 1 (PAR-1), in the development of neutrophilic inflammation in response to S. pneumoniae pulmonary infection, and its effect on host defence; (2) to determine the chemokine receptor expression on neutrophils of patients with CAP-induced acute respiratory distress syndrome (ARDS); and (3) to assesses the effect of ageing on the neutrophilic inflammatory response to S. pneumoniae. The data in this thesis demonstrates that S. pneumoniae pneumonia is associated with increased neutrophilic inflammation that results in alveolar leak. PAR-1 and its downstream mediators, IL-1β, CXCL1 and CCL7 contribute to this response. The inflammatory response to S. pneumoniae is enhanced in aged mice due to reduction in IL-10 levels and associated increase in CCL3 and CCL5 levels. Taken together these data support that PAR-1 may be a potential therapeutic target to prevent exaggerated neutrophilic inflammation and lung injury without compromising host defence. Additionally, data presented in this thesis demonstrate the presence of chemokine receptor switching following neutrophil transmigration to the airspaces, in particular with increased expression of CCR2, and highlights the heterogeneity amongst humans with CAP-induced ARDS and the need for personalised therapeutics that target neutrophil chemokine receptors.

Type: Thesis (Doctoral)
Title: Regulation of pulmonary neutrophilic inflammation in community-acquired pneumonia
Event: University College London
Language: English
Keywords: Streptococcus pneumoniae, community-acquired pneumonia, PAR-1, coagulation, neutrophils, inflammation, ARDS
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1473005
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