Inhibitory Influence of Protease-Activated Receptor 2 and E-Prostanoid Receptor Stimulants in Lipopolysaccharide Models of Acute Airway Inflammation

Abstract

Protease-activated receptors (PARs) are widely expressed throughout the respiratory tract, and PAR 2 has been investigated as a potential drug target for inflammatory airway diseases. The primary focus of this study was to determine the extent to which PAR 2 -activating peptides modulate lipopolysaccharide (LPS)-induced airway neutrophilia in mice and establish the underlying mechanisms. Intranasal administration of LPS induced dose-and time-dependent increases in the number of neutrophils recovered from bronchoalveolar lavage (BAL) fluid of mice. Coadministration of the PAR 2 -activating peptide f-LIGRL inhibited LPS-induced neutrophilia at 3 and 6 h after inoculation. PAR 2 -mediated inhibition of LPS-induced neutrophilia was mimicked by prostaglandin E 2 (PGE 2 ) and butaprost[selective E-prostanoid (EP 2 ) receptor agonist], and blocked by parecoxib (cyclooxygenase 2 inhibitor) and 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) (EP 1 /EP 2 receptor antagonist). PAR 2 -activating peptides also blunted early increases in the levels of the key neutrophil chemoattractants keratinocyte-derived chemokine and macrophage inflammatory protein 2 (MIP-2) in the BAL of LPS-exposed mice. However, neither PAR 2 -activating peptides nor PGE 2 inhibited LPSinduced generation of MIP-2 in cultures of primary murine alveolar macrophages In summary, PAR 2 -activating peptides and PGE 2 suppressed LPS-induced neutrophilia in murine airways, independently of an inhibitory action on MIP-2 generation by alveolar macrophages.

Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE2and HGF Expression via a Positive Feedback Loop

“…A number of PGE 2 -specific receptors have been identified, including EP1, EP2, EP3, and EP4 [17, 18], and it has been reported that macrophages can express both EP2 and EP4 [19]. To determine which receptors are involved in the apoptotic cell-induced PGE 2 signaling pathway, RAW 264.7 cells were pretreated with the EP2 receptor antagonist AH-6809 or the EP4 receptor antagonist GW-627368X for 1 h before apoptotic cells were added.…”

Forced expiration measurements in mouse models of obstructive and restrictive lung diseases

“…LPS was dissolved in sterile saline and administered as a single dose of 3 μg/40 μL/mouse after light anesthesia [15]. The mice were studied at the age of 13 weeks, i.e.…”

Coordinated induction of cyclooxygenase-2/prostaglandin E2 and hepatocyte growth factor by apoptotic cells prevents lung fibrosis

“…[12], the selective PGE 2 receptor EP2 antagonist AH6809 (5 mg/kg, i.p.) [17], or the selective c-Met inhibitor PHA-665752 (25 mg/kg, i.p.) [11] was administrated at the same time as instillation of 10 ϫ 10 6 apoptotic Jurkat cells into bleomycin-stimulated lungs (2 days), and mice were killed 2 h later.…”