Abstract
A model of LPS-induced lung inflammation in cynomolgus monkeys was developed to compare the anti-inflammatory activity of bradykinin B1R antagonist to those of a PDE4 inhibitor and dexamethasone.
6 naive cynomolgus monkeys (6 kg) were challenged once a week. In the first week, bronchoalveolar lavage (BAL) was collected from the left lung (flushed with 10 mL PBS solution), using a pediatric bronchoscope under anaesthesia (zoletil, xylazine). In the second week, BAL was performed 12 h after intratracheal LPS nebulization for 5 min (20 µg/kg). In addition, the monkeys received the vehicle (0.5% CMC) orally 1 h before and 6 h after LPS. In weeks 3, 4 and 5, the animals were challenged with LPS and they received at random the test compound orally bid: B1R antagonist (30 mg/kg), PDE4 inhibitor (0.5 mg/kg) or dexamethasone (1 mg/kg). BAL was performed 12 h after LPS challenge. BALF total cell count, differential cell count, BALF protein, and BALF IL-8 were measured.
At 12 h post LPS, BAL cells were elevated (p < 0.05) over baseline (LPS: 20.106 vs naive: 2.106, neutrophils LPS: 77 % vs naive: 1.8 %), BALF protein was increased (p < 0.05) (LPS: 3 mg/ml vs naive: 0.8 mg/ml) and BALF IL-8 was increased (p < 0.05) (LPS: 1.1 ng/ml vs naive: 0.2 ng/ml). All inflammatory parameters returned to baseline level one week after LPS challenge. All treatments, B1R antagonist, PDE4 inhibitor and dexamethasone, reduced (p < 0.05) LPS-induced BAL neutrophilia (80 % inhibition), BALF protein (90 % inhibition) and BALF IL-8 (80 % inhibition).
These data show that the anti-inflammatory activity of the B1R antagonist was similar to the activity of dexamethasone and the PDE4 inhibitor.
- Copyright ©the authors 2016
