Pulmonary pharmacology最新文献

Summary: Rolipram, a phosphodiesterase type 4 (PDE4)-selective inhibitor, has been demonstrated to inhibit antigen-induced pulmonary eosinophilia in guinea pigs and monkeys, suggesting that PDE4-selective inhibitors could be useful for treating asthma. Although the rat is used extensively in preclinical drug development, a pulmonary antiinflammatory effect of PDE4 inhibition has not been demonstrated in this species. Therefore, we examined the effects of rolipram, CI-930 (PDE3-selective inhibitor), zaprinast (PDE5-selective inhibitor) and aminophylline on antigen-induced pulmonary inflammatory cell influx in Brown Norway rats. Two weeks after sensitization rats were exposed to aerosolized ovalbumin and 24 h later bronchoalveolar lavage (BAL) was performed for determinations of total cell counts and cell type differentials. The resulting 10-fold increase in total cell counts was due primarily to an increase in eosinophils (from 0.06 to 11.0 × 10⁶) and neutrophils (from 0.02 to 12 × 10⁶). Rolipram, CI-930 and aminophylline, given p.o. before and after antigen challenge, each completely inhibited eosinophil influx, with B.I.D. ED₅₀ values of 0.5, 0.4 and 39 mg/kg, respectively. Rolipram, CI-930 and aminophylline each completely inhibited neutrophil influx as well, with B.I.D. ED₅₀ values of 0.1, 0.5 and 20 mg/kg, respectively. Denbufylline and milrinone (10 mg/kg p.o.) also inhibited eosinophil and neutrophil influx, consistent with PDE4 and PDE3 inhibition as the mechanisms of action of rolipram and CI-930, respectively. In contrast, zaprinast was inactive at 0.3-30 mg/kg. However, the β₂ agonist salbutamol greatly inhibited antigen-induced pulmonary eosinophilia and neutrophilia, with p.o. B.I.D. ED₅₀ values of 2.1 and 2.3 mg/kg, respectively, indicating that drugs which increase intracellular cAMP levels by one of several mechanisms can inhibit antigen-induced pulmonary inflammation in rats. In conclusion, these results demonstrate that PDE4 inhibitors produce pulmonary antiinflammatory effects in rats. Furthermore, these results suggest that PDE3 inhibitors also can produce pulmonary antiinflammatory effects in vivo.

Summary: It has been generally demonstrated that sensitization process and/or specific antigen challenge causes an increase in the responsiveness of airway smooth muscle preparations to contractile agonists. However, there is no report elucidating such modifications in vascular preparations. In this study, we examined the influence of ovalbumin sensitization and challenge on the reactivity of guinea-pig pulmonary arteries to various vasoactive agents. Guinea-pigs were actively sensitized to ovalbumin (10 mg/kg) by i p injections on days 1, 3 and 5. Beginning 21 days after the last injection, animals were challenged with ovalbumin either in vitro or in vivo. The effects of sensitization process and challenge were studied on endothelium-dependent and -independent responses of guinea-pig pulmonary arteries.

Ovalbumin challenge but not sensitization process significantly reduced the endothelium-dependent relaxant responses to acetylcholine and histamine. Similar reductions were also observed in the responses of calcium ionophore, A 23187. However, no alteration was observed in the responses to glyceryl trinitrate and potassium chloride which excludes an abnormality in the relaxant and contractile capacities of pulmonary artery smooth muscle following sensitization and challenge. In addition, an enhancement was observed in the contractile effect of phenylephrine after ovalbumin sensitization and challenge different from U 46619, a thromboxane analogue, and potassium chloride induced contractions. Incubation of the sensitized arteries with the mast cell stabilizer, disodium cromoglycate but not with the free radical scavenger superoxide dismutase protected the reduced responsiveness to endothelium-dependent vasodilators following challenge.

We conclude that ovalbumin challenge causes an abnormality in endothelial cell reactivity of pulmonary vasculature possibly due to destructive enzymes released from mast cells.

Summary: Aerosolized unfractionated heparin GM1060 significantly inhibited allergen-induced eosinophil infiltration into the airways of guinea-pigs (as assessed both histologically and by bronchoalveolar lavage, or BAL) at doses of 160 and 1600 U/ml. Similarly aerosolized unfractionated heparin, Multiparin was effective at reducing eosinophil levels in the BAL fluid at 1000, 2000 and 5000 U/ml, but this reduction was statistically significant only at the highest dose used.

Additionally, Fragmin (a low molecular weight heparin) significantly inhibited allergen-induced eosinophil infiltration into BAL fluid at a dose of 500 U/ml, an effect that was lost at the higher doses of 1000 and 2000 U/ml.

Allergen-induced eosinophil infiltration was unaffected by dermatan sulphate. However, the glycosaminoglycans chondroitin sulphate A, chondroitin sulphate C and heparan sulphate were able to influence the extent of allergen-induced eosinophil infiltration into BAL fluid.

These results suggest that heparin and some related glycosaminoglycans can inhibit allergen-induced eosinophil infiltration when administered directly to the airways.