Early and late bronchoconstrictions, airway hyper-reactivity, leucocyte influx and lung histamine and nitric oxide after inhaled antigen: effects of dexamethasone and rolipram.
BACKGROUND
Guinea-pig models can provide the essential features of asthma, including early- (EAR) and late- (LAR) phase asthmatic responses, airway hyper-reactivity (AHR) and inflammatory cell influx; however, these components are rarely demonstrated all in the same model.


OBJECTIVE
The aim of this study was to establish a conscious guinea-pig model with these essential features of asthma and to correlate these with bronchoalveolar lavage fluid (BALF) histamine and nitric oxide (NO) levels. The model would be validated from the susceptibility of these parameters to standard anti-asthmatic agents, the steroid, dexamethasone, and a phosphodiesterase-4 (PDE4) inhibitor, rolipram.


METHODS
Guinea-pigs were sensitized with ovalbumen (OA) (10 microg plus Al2(OH)3 100 mg, intraperitoneal (i.p.)) and 14 days later received inhaled OA (100 microg/mL) or vehicle for 1 h. Airway function was measured by whole-body plethysmography as specific airway conductance (sGaw). Reactivity to inhaled histamine (nose-only, 1 mm, 20 s) was recorded 24 h before and at 6, 12 or 24 h after OA challenge. BALF was obtained to determine the total and differential cell counts, NO and histamine.


RESULTS
Guinea-pigs challenged with OA showed an EAR as a fall in (sGaw) (-54.9+/-10.8%), which resolved by 6 h and was followed by an LAR between 7 and 11 h (-30.2+/-8.8%). No bronchoconstriction to inhaled histamine occurred before OA challenge but at 6, 12 or 24 h afterwards, sGaw fell significantly, indicating AHR. At 1 h after OA, macrophages, eosinophils and neutrophils significantly increased in BALF. Macrophages and eosinophils increased further up to 24 h (3- and 44-fold), but neutrophils declined to control levels. BALF histamine levels increased at 0.25 h after OA challenge and peaked at 6 h. BALF NO levels initially fell (44%) 1 h after OA exposure and then progressively rose above control levels. Dexamethasone (20 mg/kg, i.p.) and rolipram (1 mg/kg, i.p.) administered 24 and 0.5 h before and 6 h after OA challenge inhibited leucocyte influx, AHR and the early deficiency and later excess of NO. Dexamethasone but not rolipram attenuated the LAR.


CONCLUSIONS
This model displays many of the features of human asthma with predictable responses to dexamethasone and evidence of anti-asthmatic activity by the PDE4 inhibitor, rolipram.
Toward
T J
TJ
Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cardiff, UK.
Broadley
K J
KJ
D000280:Administration, Inhalation; D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D003907:Dexamethasone / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000627:therapeutic use*; D006168:Guinea Pigs; D006632:Histamine / Q000032:analysis; D007962:Leukocytes / Q000276:immunology; D008297:Male; D023421:Models, Animal; D009569:Nitric Oxide / Q000032:analysis; D020889:Rolipram / Q000627:therapeutic use*
D000941:Antigens; D005938:Glucocorticoids; D009569:Nitric Oxide; D003907:Dexamethasone; D006632:Histamine; D020889:Rolipram