Airway reactivity, inflammatory cell influx and nitric oxide in guinea-pig airways after lipopolysaccharide inhalation.
1. The aim of this study was to investigate the relationship between airway reactivity, leukocyte influx and nitric oxide (NO), in conscious guinea-pigs after aerosolized lipopolysaccharide (LPS) exposure. 2. Inhaled histamine (1 mM, 20 s), causing no bronchoconstriction before LPS exposure (30 microg ml(-1), 1 h), caused bronchoconstriction at 0.5 and 1 h (P:<0.02) after LPS exposure. This airway hyperreactivity (AHR) recovered by 2 h. In contrast, 48 h after LPS exposure, the response from a previously bronchoconstrictor dose of histamine (3 mM, 20 s) was attenuated (P:<0.01) i.e. airway hyporeactivity (AHOR). 3. Investigation of the cellular content of bronchoalveolar lavage fluid (BALF) from these animals revealed a rapid (0.5 h: 691 fold increase) and progressive neutrophil influx after LPS exposure (24 h: 36.3+/-2.3x10(6) cells per sample), that subsided 48 h later. Macrophages and eosinophils also time-dependently increased (0.5 h: 4.6+/-0.4 and 0.1+/-0.05; 48 h: 31.0+/-6.0 and 1.8+/-0.3x10(6) cells per sample, respectively) after LPS, compared to vehicle exposure (24 h: neutrophils, eosinophils and macrophages: 0.28+/-0.19, 0.31+/-0.04 and 4.96+/-0. 43x10(6) cells per sample, respectively). 4. The combined NO metabolites in BALF, after vehicle (1 h), or LPS (1 h: AHR and 48 h: AHOR) exposure, were respectively increased (41%, P:<0.01), decreased (47%, P:<0.01) and further increased (80%, P:<0.001), compared with naïve animals. 5. Inhaled N(o)-nitro-L-arginine methyl ester (L-NAME: 1.2 and 12 mM, 15 min), reduced BALF NO metabolites 2 h later, but did not cause AHR to histamine (P:>0.05). When L-NAME inhalation followed LPS, AHR was prolonged from 1 h to at least 4 h (P:<0.01). 6. In summary, aerosolized LPS inhalation caused neutrophil and macrophage airways infiltration, and an early development of AHR followed 48 h later by AHOR to histamine. AHR and AHOR coincided with a respective reduction and elevation in airways NO (metabolites). Thus, NO may aid recovery from AHR, as inhibition of its production prolongs AHR. However, NO deficiency alone is not responsible for LPS-induced AHR.
Toward
T J
TJ
Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cathays Park, Cardiff, CF10 3XF.
Broadley
K J
KJ
D000280:Administration, Inhalation; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016084:Bronchoconstriction / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester