Activation of corticotropin-releasing factor receptor-2 causes bronchorelaxation and inhibits pulmonary inflammation in mice.
Urocortins are members of the corticotropin-releasing factor (CRF) family of peptides that bind to two receptors, CRF(1) and CRF(2). While CRF(1) is a high-affinity receptor for CRF, urocortin III binds with much greater affinity to CRF(2). In the present study we investigated the effect of CRF(2) receptor activation with urocortin III on airway smooth muscle tone in vitro and in an acute model of airway inflammation in mice. Urocortin III caused relaxation of methacholine-precontracted mouse tracheal segments. CRF caused similar relaxation, but with reduced potency compared to urocortin III, consistent with the CRF(2) receptor subtype. Relaxation induced by urocortin III was concentration-dependently inhibited by the CRF(2) antagonist, astressin 2B, with an IC(50) in the nanomolar range. These relaxations were potentiated by inhibition of phosphodiesterases but unaffected by inhibition of cyclooxygenase and NO or by removal of the epithelium. Finally, the number of neutrophils retrieved by bronchoalveolar lavage after administration of bacterial LPS (LPS) was reduced by prior intraperitoneal (i.p.) injection of urocortin III. This effect was also suppressed by astressin 2B, implicating CRF(2) receptors. Therefore, CRF(2) agonists appear to have both bronchorelaxant and anti-inflammatory activities and might represent an interesting therapeutic approach to the treatment of inflammatory lung diseases.
Moffatt
James D
JD
The Sackler Institute of Pulmonary Pharmacology, King's College London, Guy's Campus, London, UK. james.moffatt@kcl.ac.uk
Lever
Rebecca
R
Page
Clive P
CP
D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control*; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008171:Lung Diseases / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology*; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D001993:Bronchodilator Agents; C101531:CRF receptor type 2; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; C120841:astressin B; D003346:Corticotropin-Releasing Hormone