Proteinase-Activated Receptor-4 Plays a Major Role in the Recruitment of Neutrophils Induced by Trypsin or Carrageenan during Pleurisy in Mice

Abstract

Background/Aims: The activation of proteinase-activated receptors (PARs) has been implicated in the development of important hallmarks of inflammation, including in vivo leukocyte recruitment. Here, we examined the effects of aprotinin, a potent inhibitor of trypsin proteinase and the kallikrein-kinin system, and the PAR-4 antagonist YPGKF-NH₂ (tcY-NH₂) on neutrophil recruitment in response to carrageenan and trypsin in the pleural cavity of mice. Methods: BALB/c mice were intrapleurally injected with trypsin or PAR-4-activating peptide AY-NH₂, pretreated with aprotinin or tcY-NH₂ (1 µg/cavity) prior to an intrapleural injection of trypsin or carrageenan, or pretreated with leukotriene B₄ antagonist U-75302 (3 µg/cavity) prior to a trypsin injection. The number of infiltrating neutrophils was evaluated after 4 h. Results: PAR-4-activating peptide AY-NH₂ and trypsin-induced neutrophil recruitment was inhibited by aprotinin, tcY-NH₂ or U-75302. Aprotinin and tcY-NH₂ also inhibited neutrophil recruitment induced by carrageenan. Conclusion: These data suggest a key role for PAR-4 in mediating neutrophil recruitment in a mouse model of pleurisy induced by the activity of trypsin or trypsin-like enzymes.