Inhibitory influence of protease-activated receptor 2 and E-prostanoid receptor stimulants in lipopolysaccharide models of acute airway inflammation.
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 LPS-induced 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.
Peters
Terence
T
School of Medicine and Pharmacology, University of Western Australia, Stirling Highway, Nedlands, Australia, 6009. peter.henry@uwa.edu.au
Mann
Tracy S
TS
Henry
Peter J
PJ
D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000633:toxicity*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009842:Oligopeptides / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D012140:Respiratory Tract Diseases / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control
D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D008070:Lipopolysaccharides; D009842:Oligopeptides; D044464:Receptor, PAR-2; D018078:Receptors, Prostaglandin E; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone