Airway reactivity, inflammatory cell influx and nitric oxide in guinea-pigairways 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-pig s after aerosolized lipopolysaccharide (LPS) exposure. 2 Inhaled histamine (1 mM, 20 s), causing no bronchoconstriction before LPS exposure (30 mu g 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 (BA LF) from these animals revealed a rapid (0.5 h: 691 fold increase) and prog ressive neutrophil influx after LPS exposure (24 h: 36.3+/-2.3 x 10(6) cell s per sample), that subsided 48 h later. Macrophages and eosinophils also t ime-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 x 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 x 10(6) cells per sample, respectively) . 4 The combined NO metabolites in BALF, after vehicle (I h), or LPS (1 h: AH R and 48 h: AMOR) exposure, were respectively increased (41%, P<0.01), decr eased (47%, P<0.01) and further increased (80%, P<0.001), compared with nai ve animals. 5 Inhaled N degrees-nitro-L-arginine methyl ester (L-NAME: 1.2 and 12 mM, 1 5 min), reduced BALF NO metabolites 2 h later, but did not cause AHR to his tamine (P>0.05). When L-NAME inhalation followed LPS, AHR was prolonged fro m Ih to at least 4 h (P<0.01). 6 In summary, aerosolized LPS inhalation caused neutrophil and macrophage a irways 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.