LSC Abstract – Regulation of neutrophilic inflammation in community acquired pneumonia (winner of the LSC 2015 Best Oral Presentation Award)
Ricardo José (London, United Kingdom), Ricardo José, Andrew Williams, Michal Sulikowski, David Brealey, Jeremy Brown, Rachel Chambers
Source: International Congress 2015 – Advances from translational research in respiratory infections
Disease area: Respiratory infections
Abstract Community-acquired pneumonia (CAP) is commonly caused by Streptococcus pneumoniae , and is associated with excessive neutrophilic inflammation. The mechanisms of neutrophil recruitment during pneumococcal pneumonia are not completely understood. We examined the role of the high-affinity thrombin receptor, proteinase-activated receptor (PAR)-1 in mediating neutrophilic inflammation in two models of murine pneumococcal pneumonia (D39 and EF3030) by using the most clinically advanced PAR-1 antagonist, SCH530348. Additionally, we investigated neutrophil chemokine receptor expression in humans with CAP-induced ARDS.S. pneumoniae infection resulted in activation of intra-alveolar coagulation, increased neutrophil recruitment and increased PAR-1 expression. SCH530348 significantly reduced neutrophil recruitment without being detrimental to host defence. Markers of alveolar leak, coagulation activation and pro-inflammatory cytokines and chemokines (IL-1b , CXCL1, CCL2 and CCL7) were attenuated. Intra-pulmonary neutralisation studies demonstrated that IL-1b and CCL7, but not CXCL1 or CCL2, influenced neutrophil recruitment to the airspaces, whereas systemic neutralisation of CXCL1 was required to reduce neutrophil recruitment to the airspaces, suggesting compartmentalisation of the chemokine network. In humans with CAP-induced ARDS, CXCR1 expression decreased, while CXCR2, CCR1, CCR2 and CCR3 expression increased on neutrophils from BALF compared with blood, supporting a role for chemokine receptor switching and CC-chemokines during neutrophil recruitment in humans.These data highlight a role for PAR-1 and chemokine receptor switching in pneumonia with important therapeutic implications.
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Ricardo José (London, United Kingdom), Ricardo José, Andrew Williams, Michal Sulikowski, David Brealey, Jeremy Brown, Rachel Chambers. LSC Abstract – Regulation of neutrophilic inflammation in community acquired pneumonia (winner of the LSC 2015 Best Oral Presentation Award). Eur Respir J 2015; 46: Suppl. 59, 5044
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