Intratracheal instillation of platelet-activating factor (PAF) in sheep produces bronchoconstriction and airway hyperresponsiveness (AHR) by a two- stage process that involves the initial stimulation of PAF receptors followed by the secondary generation of proinflammatory mediators. Because the biological effects of PAF may be mediated by these proinflammatory metabolites, it is possible that a steroidal anti-inflammatory agent would modify the airway responses of PAF. We measured specific lung resistance (sRL) in sheep (n = 11) before, immediately after, and serially for up to 2 h after intratracheal instillation of PAF (30 μg/kg). Airway responsiveness was measured 2 h post-PAF when sRL had returned to baseline and was expressed as the cumulative provocating dose of carbachol that increased sRL to 4 l · cmH2O · l-1 · s (PD4). PD4 was determined on a control day and on different experiment days without or after treatment with intravenous methylprednisolone (MPS; 1 mg/kg) administered 3 h before (n = 6), 20 min before PAF (n = 7), or 20 min after PAF challenge (n = 7). PAF increased sRL by 222 ± 44% (SE) above baseline and decreased PD4 of carbachol by 44 ± 5% (P < 0.05). Pretreatment (both 3 h and 20 min) with MPS attenuated the PAF- induced increases in sRL, whereas its administration 20 min post-PAF had no effect. Irrespective of the effects on sRL, MPS administration inhibited the PAF-induced AHR. To better define the mechanism by which MPS inhibited the PAF-induced AHR, sheep were treated with the cyclooxygenase inhibitor indomethacin, leukotriene antagonist MK-571, PAF antagonist WEB-2086, and mast cell-stabilizing agent nedocromil sodium 20 min after PAF. Only indomethacin blocked the PAF-induced AHR. These data suggest that PAF-induced AHR in sheep is caused by the secondary generation of cyclooxygenase metabolites and that MPS attenuates this PAF-induced response by inhibiting the synthesis of these products.
- airway hyperresponsiveness
ASJC Scopus subject areas
- Orthopedics and Sports Medicine
- Physical Therapy, Sports Therapy and Rehabilitation