butaprost and Respiratory-Tract-Diseases

Down-regulation of the E-prostanoid (EP)2 receptor has been reported in aspirin exacerbated respiratory disease (AERD). We aimed to evaluate the expression and activation of EP receptors in AERD and their role in prostaglandin (PG) E2 signalling.. Samples were obtained from nasal mucosa of control subjects (NM-C, n=7) and from nasal polyps of AERD patients (NP-AERD, n=7). Expression of EP1-4 was assessed at baseline. Fibroblasts were stimulated with receptor agonists to measure cAMP levels, cell proliferation and granulocyte-macrophage colony-stimulating factor (GM-CSF) release.. NM-C and NP-AERD samples and fibroblasts expressed EP2, EP3 and EP4 at baseline. Lower expression of EP2 and higher expression of EP4 was observed in NP-AERD compared with NM-C. Stimulation with PGE2 and butaprost caused a higher increase in cAMP in NM-C than in NP-AERD. On the contrary, CAY10598 produced a higher production of cAMP in NP-AERD compared with NM-C. The anti-proliferative effect of PGE2 and butaprost was lower in NP-AERD than in NM-C fibroblasts. Similarly, the capacity of PGE2 and butaprost to inhibit GM-CSF release was lower in NP-AERD than in NM-C.. The altered expression of EP2 in AERD may contribute to reduce the capacity of PGE2 to mediate anti-proliferative and anti-inflammatory effects.

Topics: Alprostadil; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cell Proliferation; Cyclic AMP; Dinoprostone; Disease Progression; Down-Regulation; Female; Fibroblasts; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation; Male; Middle Aged; Nasal Mucosa; Nasal Polyps; Receptors, Prostaglandin E; Respiratory Tract Diseases; Signal Transduction

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.

Topics: Alprostadil; Animals; Bronchoalveolar Lavage Fluid; Cells, Cultured; Chemokine CXCL2; Cyclooxygenase Inhibitors; Cytokines; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Leukocyte Count; Lipopolysaccharides; Macrophages, Alveolar; Mice; Neutrophil Infiltration; Neutrophils; Oligopeptides; Receptor, PAR-2; Receptors, Prostaglandin E; Respiratory Tract Diseases