Comparative effects of inhaled budesonide and the NO-donating budesonide derivative, NCX 1020, against leukocyte influx and airway hyperreactivity following lipopolysaccharide challenge.
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.
Nevin
Barra J
BJ
Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cathays Park, Cardiff CF10 3XF, UK.
Broadley
Kenneth J
KJ
D000280:Administration, Inhalation; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019819:Budesonide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte; D006168:Guinea Pigs; D008070:Lipopolysaccharides; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D009566:Nitrates / Q000097:blood; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009573:Nitrites / Q000097:blood; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013997:Time Factors
D001993:Bronchodilator Agents; D008070:Lipopolysaccharides; C492926:NCX 1020; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D019819:Budesonide; D026423:S-Nitroso-N-Acetylpenicillamine