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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/L368    most recent 00036.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Moraes, T. J. Articles by Downey, G. P. Search for Related Content PubMed PubMed Citation Articles by Moraes, T. J. Articles by Downey, G. P.

Role of PAR2 in murine pulmonary pseudomonal infection

¹Department of Immunology and ²Division of Respirology, Department of Medicine, University of Toronto, ³Toronto General Hospital Research Institute of University Health Network, and ⁴Division of Respiratory Medicine, Department of Pediatrics, Hospital for Sick Children, Toronto, Canada; and ⁵Department of Immunology, Scripps Research Institute, La Jolla, California

Submitted 23 January 2007 ; accepted in final form 7 December 2007

Proteinases can influence lung inflammation by various mechanisms, including via cleavage and activation of protease-activated receptors (PAR) such as PAR2. In addition, proteinases such as neutrophil and/or Pseudomonas-derived elastase can disarm PAR2 resulting in loss of PAR2 signaling. Currently, the role of PAR2 in host defense against bacterial infection is not known. Using a murine model of acute Pseudomonas aeruginosa pneumonia, we examined differences in the pulmonary inflammatory response between wild-type and PAR2^–/– mice. Compared with wild-type mice, PAR2^–/– mice displayed more severe lung inflammation and injury in response to P. aeruginosa infection as indicated by higher bronchoalveolar lavage fluid neutrophil numbers, protein concentration, and TNF- levels. By contrast, IFN- levels were markedly reduced in PAR2^–/– compared with wild-type mice. Importantly, clearance of P. aeruginosa was diminished in PAR2^–/– mice. In vitro testing revealed that PAR2^–/– neutrophils killed significantly less bacteria than wild-type murine neutrophils. Further, both neutrophils and macrophages from PAR2^–/– mice displayed significantly reduced phagocytic efficiency compared with wild-type phagocytes. Stimulation of PAR2 on macrophages using a PAR2-activating peptide resulted in enhanced phagocytosis directly implicating PAR2 signaling in the phagocytic process. We conclude that genetic deletion of PAR2 is associated with decreased clearance of P. aeruginosa. Our data suggest that a deficiency in IFN- production and impaired bacterial phagocytosis are two potential mechanisms responsible for this defect.

neutrophil; phagocytosis; proteinase; innate immunity; bacterial killing; inflammation