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, budesonide. The effect of aerosolized budesonide administered to the lower airways 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. suum antigen. Budesonide was administered once, 1 h prior to A. suum challenge and airway reactions and mediator release were observed for 8 h after allergen challenge. 2. In the budesonide aerosol group (n = 6), 10.2 +/- 1.2 micrograms kg-1 budesonide was given locally and in the budesonide infusion group (n = 5), 5 micrograms kg-1 was given intravenously. The area under the plasma concentration curve for budesonide during the experiment was 11.4 +/- 1.2 and 10.3 +/- 1.2 nM h in the budesonide aerosol and 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 budesonide vehicle as an infusion prior to A. suum challenge. 3. Total lung resistance (RL) increased acutely (maximal response within 15 min) in the budesonide aerosol, budesonide infusion and budesonide vehicle groups (by 91 +/- 40, 150 +/- 86 and 80 +/- 27%, respectively). The acute reaction partially resolved at about 1 h and was followed by a late increase in RL in the budesonide infusion and budesonide vehicle groups (by 251 +/- 148 and 281 +/- 136% at 8 h, respectively). However, no late change in RL was seen in the budesonide aerosol group (7 +/- 24%). 4. Aerosolized budesonide had a protective effect in that it attenuated the late changes in arterial blood gas and pH as well as the late elevation of plasma catecholamines. Budesonide given as an infusion did not protect against the late changes in these parameters. However, budesonide aerosol or infusion did not inhibit the late vasodilation in the bronchial circulation. 5. Histamine and cysteinyl-leukotrienes were released during the acute reaction as measured by urinary concentration of methylhistamine and leukotriene E4 respectively. There was no release of histamine during the late reaction. A late increase in leukotriene E4 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 RL (P < 0.05, r = -0.53, n = 10), whereas budesonide concentration 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 administered budesonide can inhibit the late allergic reaction in the pig lower airways. If budesonide was given as an intravenous infusion in a dose yielding a plasma concentration similar to that seen after the aerosol treatment, the protective effect of budesonide was poor. It may be suggested that the tissue-bound portion of budesonide affects local mechanisms involved in the development of late changes in the airways (RL), although it does not affect the late increase in bronchial blood flow. We conclude that the inhibitory effect of budesonide on the allergen-induced late reaction in the pig airways relates to tissue-bound steroid, and that the systemic component is of less importance.
Fornhem
C
C
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Dahlbäck
M
M
Kumlin
M
M
Lundberg
J M
JM
Alving
K
K
D000280:Administration, Inhalation; D000287:Administration, Topical; D000402:Airway Obstruction / Q000139:chemically induced; D000485:Allergens; D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000947:Antigens, Helminth; D017165:Ascaris suum; D001794:Blood Pressure / Q000187:drug effects; D019819:Budesonide; D005938:Glucocorticoids; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000378:metabolism / Q000652:urine; D007275:Injections, Intravenous; D017999:Leukotriene E4 / Q000652:urine; D008168:Lung / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D011282:Pregnenediones / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D014655:Vascular Resistance / Q000187:drug effects
D000485:Allergens; D000893:Anti-Inflammatory Agents; D000947:Antigens, Helminth; D005938:Glucocorticoids; D011282:Pregnenediones; D019819:Budesonide; D017999:Leukotriene E4; D006632:Histamine