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Airway reactivity, inflammatory cell influx and nitric oxide in guinea‐pig airways after lipopolysaccharide inhalation
Author(s) -
Toward Toby J,
Broadley Kenneth J
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703589
Subject(s) - bronchoconstriction , lipopolysaccharide , inhalation , nitric oxide , histamine , bronchoalveolar lavage , guinea pig , immunology , airway , chemistry , endocrinology , medicine , pharmacology , asthma , lung , anesthesia
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. Inhaled histamine (1 m M , 20 s), causing no bronchoconstriction before LPS exposure (30 μg 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 m M , 20 s) was attenuated ( P <0.01) i.e. airway hyporeactivity (AHOR). 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±2.3×10 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±0.3×10 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±0.43×10 6 cells per sample, respectively). 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. Inhaled N o ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME: 1.2 and 12 m M , 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). 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.British Journal of Pharmacology (2000) 131 , 271–281; doi: 10.1038/sj.bjp.0703589