RT Journal Article
SR Electronic
T1 Inhibitory Influence of Protease-Activated Receptor 2 and E-Prostanoid Receptor Stimulants in Lipopolysaccharide Models of Acute Airway Inflammation
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 424
OP 433
DO 10.1124/jpet.109.163253
VO 335
IS 2
A1 Terence Peters
A1 Tracy S. Mann
A1 Peter J. Henry
YR 2010
UL http://jpet.aspetjournals.org/content/335/2/424.abstract
AB Protease-activated receptors (PARs) are widely expressed throughout the respiratory tract, and PAR2 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 PAR2-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 PAR2-activating peptide f-LIGRL inhibited LPS-induced neutrophilia at 3 and 6 h after inoculation. PAR2-mediated inhibition of LPS-induced neutrophilia was mimicked by prostaglandin E2 (PGE2) and butaprost [selective E-prostanoid (EP2) receptor agonist], and blocked by parecoxib (cyclooxygenase 2 inhibitor) and 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) (EP1/EP2 receptor antagonist). PAR2-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 PAR2-activating peptides nor PGE2 inhibited LPS-induced generation of MIP-2 in cultures of primary murine alveolar macrophages In summary, PAR2-activating peptides and PGE2 suppressed LPS-induced neutrophilia in murine airways, independently of an inhibitory action on MIP-2 generation by alveolar macrophages.