title: Regulation of neutrophilic inflammation in lung injury induced by community-acquired pneumonia.
abstract: BACKGROUND
  Community-acquired pneumonia is commonly caused by Streptococcus pneumoniae, which is associated with excessive neutrophilic inflammation. The high-affinity thrombin receptor, proteinase-activated receptor 1 (PAR1), has been implicated in mediating the interplay between coagulation and inflammation. However, its role during S pneumoniae-induced neutrophilic inflammation, and the mechanisms for neutrophil recruitment in this context are poorly understood. We aimed to investigate the role of neutrophilic inflammation and PAR1 in S pneumoniae-induced pneumonia.
  
  
  METHODS
  We used the most clinically advanced PAR-1 antagonist, SCH530348, and performed neutrophil depletion and chemokine neutralisation studies in two murine models. We also did translational studies to examine CXC and CC chemokine receptor expression by flow cytometry on neutrophils in blood and bronchoalveolar lavage fluid (BALF) from mechanically ventilated patients with acute respiratory distress syndrome induced by community-acquired pneumonia.
  
  
  RESULTS
  S pneumoniae infection led to activation of coagulation, increased neutrophil recruitment, and increased PAR-1 expression. By contrast with neutrophil depletion, PAR1 antagonist treatment significantly reduced neutrophil recruitment (mean difference 26·7 × 10(3) cells per mL [SE 4·9] at 4 h, p=0·0002; and 149·3 [41·4] at 24 h, p=0·0032) without being detrimental to host defence. Markers of alveolar leak, coagulation activation, and proinflammatory cytokines and chemokines (interleukin 1β, CXCL1, CCL2, and CCL7) were attenuated. Neutralisation studies demonstrated that interleukin 1β and CCL7, but not CXCL1 and CCL2, had a key role in neutrophil recruitment in this model. In patients with acute respiratory distress syndrome induced by community-acquired pneumonia (n=10), CXCR1 and CXCR2 expression on BALF neutrophils was higher than in controls (n=3) (median difference in mean fluorescence intensity [MFI] 703 arbitrary units [p=0·0699] for CXCR1 and 658·7 [p=0·0280] for CXCR2). The expression of CXCR1 was decreased on neutrophils from BALF compared with blood (median difference in MFI 1337, p=0·0020) and that of CXCR2, CCR1, CCR2, and CCR3 was increased (125·5, p=0·0020; 335·1, p=0·0020; 116, p=0·0068; and 275, p=0·0020; respectively).
  
  
  CONCLUSIONS
  These findings suggest that clinically available PAR1 antagonists might offer a novel therapeutic approach for prevention and management of excessive neutrophilic inflammation and alveolar barrier dysfunction in pneumococcal pneumonia without compromising host defence. Furthermore, these data highlight a role for chemokine receptor switching in acute respiratory distress syndrome induced by community-acquired pneumonia.
  
  
  BACKGROUND
  Wellcome Trust.
authors: Centre for Inflammation and Tissue Repair, University College London, London, UK. Electronic address: r.jose@ucl.ac.uk.
authors: Ricardo
authors: R
authors: José
authors: Centre for Inflammation and Tissue Repair, University College London, London, UK.
authors: Andrew
authors: A
authors: Williams
authors: Centre for Inflammation and Tissue Repair, University College London, London, UK.
authors: Michal
authors: M
authors: Sulikowski
authors: Department of Intensive Care Medicine, University College London Hospital, London, UK.
authors: David
authors: D
authors: Brealey
authors: Centre for Inflammation and Tissue Repair, University College London, London, UK.
authors: Jeremy
authors: J
authors: Brown
authors: Centre for Inflammation and Tissue Repair, University College London, London, UK.
authors: Rachel
authors: R
authors: Chambers