Inhibitory effects of synthetic somatostatin receptor subtype 4 agonists on acute and chronic airway inflammation and hyperreactivity in the mouse.
Somatostatin released from activated capsaicin-sensitive afferents of the lung inhibits inflammation and related bronchial hyperreactivity presumably via somatostatin 4 receptors (sst(4)). The aim of this study was to examine the effects of TT-232, a heptapeptide sst(4)/sst(1) receptor agonist and J-2156, a high affinity sst(4) receptor-selective peptidomimetic agonist in airway inflammation models. Acute pneumonitis was evoked by intranasal lipopolysaccharide 24 h before measurement. Chronic inflammation was induced by ovalbumin inhalation on days 28, 29 and 30 after i.p. sensitization on days 1 and 14. Semiquantitative histopathological scoring was based on perivascular/peribronchial oedema, neutrophil/macrophage infiltration, goblet cell hyperplasia in the acute model and eosinophil infiltration, mucosal oedema, mucus production and epithelial cell damage in chronic inflammation. Myeloperoxidase activity of the lung was measured spectrophotometrically to quantify granulocyte accumulation and the broncoalveolar lavage fluid was analysed by flow cytometry. Carbachol-induced bronchoconstriction was assessed by unrestrained whole body plethysmography and its calculated indicator, enhanced pause (Penh) was determined. TT-232 and J-2156 induced similar inhibition on granulocyte recruitment and histopathological changes in both models, although macrophage infiltration in LPS-induced inflammation was unaltered by either compounds. Both agonists diminished inflammatory airway hyperresponsiveness. Since their single administration after the development of the inflammatory reactions also inhibited carbachol-induced bronchoconstriction, somatostatin sst(4) receptor activation on bronchial smooth muscle cells is likely to be involved in their anti-hyperreactivity effect. These results suggest that stable, somatostatin sst(4) receptor-selective agonists could be potential candidates for the development of a completely novel group of anti-inflammatory drugs for the treatment of airway inflammation and hyperresponsiveness.
Elekes
Krisztián
K
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7624 Pécs, Szigeti u. 12., Hungary.
Helyes
Zsuzsanna
Z
Kereskai
László
L
Sándor
Katalin
K
Pintér
Erika
E
Pozsgai
Gábor
G
Tékus
Valéria
V
Bánvölgyi
Agnes
A
Németh
József
J
Szuts
Tamás
T
Kéri
György
G
Szolcsányi
János
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D002073:Butanes / Q000494:pharmacology* / Q000627:therapeutic use; D002217:Carbachol / Q000008:administration & dosage; D002478:Cells, Cultured; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D010047:Ovalbumin; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D018410:Pneumonia, Bacterial / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000378:metabolism; D019141:Respiratory System Agents / Q000494:pharmacology* / Q000627:therapeutic use; D013004:Somatostatin / Q000031:analogs & derivatives; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D016085:Bronchoconstrictor Agents; D002073:Butanes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009281:Naphthalenes; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; D019141:Respiratory System Agents; D013450:Sulfones; C098681:somatostatin receptor subtype-4; C094462:TT2-32; D013004:Somatostatin; D002217:Carbachol; D010047:Ovalbumin; C499293:(1'S, 2S)-4-amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4''-methyl-1''-naphthalenesulfonylamino)butanamide; D013755:Tetradecanoylphorbol Acetate