title: Regulation of neutrophilic inflammation by proteinase-activated receptor 1 during bacterial pulmonary infection.
abstract: Neutrophils are key effector cells of the innate immune response to pathogenic bacteria, but excessive neutrophilic inflammation can be associated with bystander tissue damage. The mechanisms responsible for neutrophil recruitment to the lungs during bacterial pneumonia are poorly defined. In this study, we focus on the potential role of the major high-affinity thrombin receptor, proteinase-activated receptor 1 (PAR-1), during the development of pneumonia to the common lung pathogen Streptococcus pneumoniae. Our studies demonstrate that neutrophils were indispensable for controlling S. pneumoniae outgrowth but contributed to alveolar barrier disruption. We further report that intra-alveolar coagulation (bronchoalveolar lavage fluid thrombin-antithrombin complex levels) and PAR-1 immunostaining were increased in this model of bacterial lung infection. Functional studies using the most clinically advanced PAR-1 antagonist, SCH530348, revealed a key contribution for PAR-1 signaling in influencing neutrophil recruitment to lung airspaces in response to both an invasive and noninvasive strain of S. pneumoniae (D39 and EF3030) but that PAR-1 antagonism did not impair the ability of the host to control bacterial outgrowth. PAR-1 antagonist treatment significantly decreased pulmonary levels of IL-1β, CXCL1, CCL2, and CCL7 and attenuated alveolar leak. Ab neutralization studies further demonstrated a nonredundant role for IL-1β, CXCL1, and CCL7 in mediating neutrophil recruitment in response to S. pneumoniae infection. Taken together, these data demonstrate a key role for PAR-1 during S. pneumoniae lung infection that is mediated, at least in part, by influencing multiple downstream inflammatory mediators.
authors.affiliation: Centre for Inflammation and Tissue Repair, University College London, London WC1E 6JF, United Kingdom.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: José
authors.affiliation: Centre for Inflammation and Tissue Repair, University College London, London WC1E 6JF, United Kingdom.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Williams
authors.affiliation: Centre for Inflammation and Tissue Repair, University College London, London WC1E 6JF, United Kingdom.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Mercer
authors.affiliation: Centre for Inflammation and Tissue Repair, University College London, London WC1E 6JF, United Kingdom.
authors.forename: Michal G
authors.initials: MG
authors.lastname: Sulikowski
authors.affiliation: Centre for Inflammation and Tissue Repair, University College London, London WC1E 6JF, United Kingdom.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Brown
authors.affiliation: Centre for Inflammation and Tissue Repair, University College London, London WC1E 6JF, United Kingdom r.chambers@ucl.ac.uk.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chambers
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D010539:Permeability; D018410:Pneumonia, Bacterial / Q000097:blood / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D044463:Receptor, PAR-1 / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000276:immunology; D010975:Platelet Aggregation Inhibitors
chemical_list: D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D044463:Receptor, PAR-1; D010975:Platelet Aggregation Inhibitors