EFFECTS OF LOCAL AND SYSTEMIC BUDESONIDE ON ALLERGEN-INDUCED AIRWAY REACTIONS IN THE PIG

1 In this study, an attempt was made to distinguish between local and systemic effects of low doses of the topical glucocorticoid, budesonid e. The effect of aerosolized budesonide administered to the lower airw ays versus intravenously administered budesonide on the acute and late response to nebulized Ascaris suum extract in the lung, was evaluated in the minipig after active sensitization with purified A. sawn antig en. Budesonide was administered once, 1 h prior to A. suum challenge a nd airway reactions and mediator release were observed for 8 h after a llergen challenge. 2 In the budesonide aerosol group (n = 6), 10.2 +/- 1.2 mu g kg(-1) budesonide was given locally and in the budesonide in fusion group (n = 5), 5 mu g kg(-1) was given intravenously. The area under the plasma concentration curve for budesonide during the experim ent was 11.4 +/- 1.2 and 10.3 +/- 1.2 nM h in the budesonide aerosol a nd budesonide infusion group, respectively (no significant difference) . The lung tissue content of budesonide in the two groups was 45.2 +/- 4.9 and 18.4 +/- 3.5 nmol kg(-1) dry tissue, respectively, 8 h after allergen challenge (P < 0.05). For comparison, 6 pigs were given budes onide vehicle as an infusion prior to A. suum challenge. 3 Total lung resistance (R(L)) increased acutely (maximal response within 15 min) i n the budesonide aerosol, budesonide infusion and budesonide vehicle g roups (by 91 +/- 40, 150 +/- 86 and 80 +/- 27%, respectively). The acu te reaction partially resolved at about 1 h and was followed by a late increase in R(L) in the budesonide infusion and budesonide vehicle gr oups (by 251 +/- 148 and 281 +/- 136% at 8 h, respectively). However, no late change in R(L) was seen in the budesonide aerosol group (7 +/- 24%). 4 Aerosolized budesonide had a protective effect in that it att enuated the late changes in arterial blood gas and pH as well as the l ate elevation of plasma catecholamines. Budesonide given as an infusio n did not protect against the late changes in these parameters. Howeve r, budesonide aerosol or infusion did not inhibit the late vasodilatat ion in the bronchial circulation. 5 Histamine and cysteinyl-leukotrien es were released during the acute reaction as measured by urinary conc entration of methylhistamine and leukotriene E(4) respectively. There was no release of histamine during the late reaction. A late increase in leukotriene E(4) was observed in 2 of the budesonide infusion and 3 of the budesonide vehicle pigs, whereas no such increase was seen in any of the budesonide aerosol pigs. 6 Budesonide concentration in lung tissue, but not in plasma at 8 h correlated negatively with the late increase in R(L) (P < 0.05, r = -0.53, n = 10), whereas budesonide con centration in plasma but not in lung tissue correlated negatively with the late decrease in dynamic compliance (P < 0.05, r = -0.67, n = 12) . 7 This study has shown that a single low dose of locally administere d budesonide can inhibit the late allergic reaction in the pig lower a irways. If budesonide was given as an intravenous infusion in a dose y ielding a plasma concentration similar to that seen after the aerosol treatment, the protective effect of budesonide was poor. It may be sug gested that the tissue-bound portion of budesonide affects local mecha nisms involved in the development of late changes in the airways (R(L) ), although it does not affect the late increase in bronchial blood ho w. We conclude that the inhibitory effect of budesonide on the allerge n-induced late reaction in the pig airways relates to tissue-bound ste roid, and that the systemic component is of less importance.