Lipopolysaccharide (LPS) inhalation (30 microg ml(-1), 1 h) caused airway hypereactivity (AHR) to
histamine (1 mM, 20 s) 1 h later in conscious guinea-pigs. Bronchoalveolar lavage fluid (BALF) levels of neutrophils,
myeloperoxidase (MPO) and
protein were elevated whereas
nitric oxide (NO) metabolites were reduced 1 h after LPS compared with saline challenge. 24 h after LPS, there was no AHR, but BALF neutrophils, eosinophils, macrophages, MPO,
protein and NO metabolites were all raised.
Budesonide (0.7 mM) and a molar equivalent concentration of the NO-donating
budesonide derivative,
NCX 1020, were inhaled (15 min) at 24 h and 45 min before LPS. The only change produced by
budesonide was to reduce eosinophil influx at 24 h after LPS, compared with vehicle treated animals.
NCX 1020, however, blocked AHR and reduced neutrophils (1 and 24 h) and MPO (1 and 24 h), while NO levels were raised at 1 and reduced at 24 h after LPS. The combined inhalation before LPS of the NO donor, SNAP (1.4 mM), with
budesonide (0.7 mM) blocked the AHR to
histamine and significantly reduced neutrophils (1 and 24 h) and MPO (1 and 24 h), while NO levels were raised at 1 h after LPS. Thus, NO and a
corticosteroid co-administered as
NCX 1020 or
budesonide with a NO donor, have an additive effect against LPS-induced inflammatory responses and may have value in the treatment of neutrophil-driven airways disease such as
COPD.