Airway function and reactivity, leukocyte influx and nitric oxide after inoculation with parainfluenza-3 virus: effects of dexamethasone or rolipram.
Guinea-pigs were inoculated with parainfluenza type 3 (PI3) virus (5.2 x 10(7)) or medium (125 microl each nostril). The PDE4-inhibitor, rolipram (1 mg kg(-1)), the corticosteroid, dexamethasone (20 mg kg(-1)), or vehicle were administered (i.p.) 24 h and 0.5 h before inoculation and for 4 days thereafter. Respiratory function, recorded in conscious guinea-pigs as specific airways conductance (sGaw) by whole-body plethysmography, was unaffected over 4 days by inoculation with medium or PI3. Inhaled histamine (nose-only, 1 mM, 20 s) 24 h before inoculation produced no response but 4 days after PI3 inoculation, a significant (P<0.001) bronchoconstriction occurred, indicating airway hyperreactivity (AHR). Dexamethasone or rolipram treatment inhibited the AHR. Four days after PI3- or medium-inoculation, animals underwent bronchoalveolar lavage (BAL) for total and differential (macrophages, eosinophils and neutrophils) cell counts and determination of nitric oxide (NO) as nitrite and nitrate. Compared with medium-inoculated animals, BAL fluid removed 4 days after PI3 inoculation had significantly increased macrophages, eosinophils and neutrophils. Dexamethasone or rolipram significantly (P<0.05) reduced the PI3-induced airways influx of macrophages (by 40% and 47%), eosinophils (79% and 84%) and neutrophils (58% and 61%). PI3-inoculation significantly (P<0.05) increased BALF combined NO metabolites (84.8+/-2.2 microM 100 microl(-1)), compared with medium-inoculated (56.0+/-5.8) or naive animals (45.7+/-2.0). Treating the PI3-infected guinea-pigs with dexamethasone or rolipram significantly (P<0.001) reduced the raised NO metabolites by 34% and 37%, respectively. These results support a role for steroids and PDE4-inhibitors in the management of inflammation and airways hyperreactivity arising from viral infection of the airways.
Toward
T J
TJ
Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cathays Park, Cardiff CF10 3XF, UK. toby.toward@abbott.com
Johnson
F J
FJ
Boult
J E
JE
Maillard
J-Y
JY
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000821:virology; D002465:Cell Movement / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D006168:Guinea Pigs; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010224:Parainfluenza Virus 3, Human; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012137:Respiratory System / Q000187:drug effects* / Q000503:physiopathology; D010253:Respirovirus Infections / Q000503:physiopathology*; D020889:Rolipram / Q000494:pharmacology*; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide; D003907:Dexamethasone; D020889:Rolipram