Blockade of protease-activated receptor 2 attenuates allergen-mediated acute lung inflammation and leukocyte recruitment in mice

Protease-activated receptor (PAR)2 has been implicated in mediating allergic airway inflammation. We investigate the role of PAR2 in lung inflammation and neutrophil and eosinophil recruitment into the lungs in a mouse model of short-term acute allergic inflammation. Allergic lung inflammation was induced in sensitized BALB/c mice through intranasal instillations of ovalbumin (OVA), and mice were pretreated with the PAR2 antagonist ENMD1068 or with the PAR2-activating peptide (PAR2-AP) 1 hour before each OVA challenge. Bronchoalveolar lavage fluid (BALF) was collected, and the lungs, trachea and lymph nodes were removed after the last challenge to analyze the airway inflammation. PAR2 blockade reduced OVA-induced eosinophil and neutrophil counts, CXCL1, CCL5, amphiregulin, and interleukin (IL)-6 and 13 levels. Moreover, PAR2 blockade reduced OVA-induced PAR2 expression in cells present in BALF 2 hour after OVA challenge, and PAR2-AP acted synergistically with OVA promoting eosinophil recruitment into BALF and increased IL-4 and IL-13 levels in lymph nodes. Conversely, PAR2 blockade increased IL-10 levels when compared with OVA-treated mice. Our results provide evidence for a mechanism by which PAR2 meditates acute lung inflammation triggered by multiple exposures to allergen through a modulatory role on cytokine production and vascular permeability implicated in the lung diseases such as asthma.