astressin-b and Inflammation

Endogenous release of CRH in stress has been associated with a dysfunctional reproductive endocrine axis. In the rhesus monkey, an inflammatory-like stress challenge in the luteal phase decreases luteal secretory function. Here, we tested the effectiveness of astressin B, a nonspecific CRH receptor antagonist, in constraining the deleterious impact of a 10-d lipopolysaccharide (LPS) challenge on the menstrual cycle. Two protocols were carried out in nine animals. In the first, the animals, after showing two normal consecutive control cycles, were injected daily for 10 days with LPS (75-125 mug/d) during the luteal phase of the cycle. The animals were followed through the two postchallenge cycles. The second protocol, carried out in the following year, was identical with protocol 1, except that the animals were treated with astressin B (0.45 mg/kg) 1 h before each daily LPS challenge during the luteal phase. Blood samples were obtained daily to document cyclic hormones levels. The LPS challenge significantly decreased luteal progesterone and LH release during the challenge cycle. Inhibition of luteal progesterone extended to the two successive postchallenge cycles. Astressin B treatment prevented luteal LH but not luteal progesterone decrease during the treatment cycle and restored normal progesterone secretion during the two posttreatment cycles. We conclude that the deleterious impact of a short-term inflammatory stress challenge on luteal function is far longer than the stress period itself. Systemic administration of astressin B accelerates the return to normal luteal function, presumably by restoring normal neuroendocrine regulation of gonadotropin secretion.

Topics: Animals; Corpus Luteum; Corticotropin-Releasing Hormone; Eating; Female; Gonadotropins; Hydrocortisone; Inflammation; Injections, Intravenous; Lipopolysaccharides; Luteal Phase; Macaca mulatta; Menstrual Cycle; Peptide Fragments; Receptors, Corticotropin-Releasing Hormone; Recovery of Function; Stress, Physiological; Time Factors

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.

Topics: Animals; Bronchodilator Agents; Corticotropin-Releasing Hormone; Disease Models, Animal; Female; In Vitro Techniques; Inflammation; Isometric Contraction; Lung Diseases; Mice; Mice, Inbred BALB C; Muscle, Smooth; Peptide Fragments; Receptors, Corticotropin-Releasing Hormone; Trachea