Abstract
Endotoxin (Lipopolysaccharide, LPS) is a potent inducer of inflammation and there is various LPS contamination in the environment, being a trigger of lung diseases and exacerbation. The objective of this study was to assess the time course of inflammation and the sensitivities of the airways and alveoli to targeted LPS inhalation in order to understand the role of LPS challenge in airway disease.In healthy volunteers without any bronchial hyperresponsiveness we targeted sequentially 1, 5 and 20 µg LPS to the airways and 5 µg LPS to the alveoli using controlled aerosol bolus inhalation. Inflammatory parameters were assessed during a 72 h time period. LPS deposited in the airways induced dose dependent systemic responses with increases of blood neutrophils (peaking at 6 h), Interleukin-6 (peaking at 6 h), body temperature (peaking at 12 h), and CRP (peaking at 24 h). 5 µg LPS targeted to the alveoli caused significantly stronger effects compared to 5 µg airway LPS deposition. Local responses were studied by measuring lung function (FEV1) and reactive oxygen production, assessed by hydrogen peroxide (H2O2) in fractionated exhaled breath condensate (EBC). FEV1 showed a dose dependent decline, with lowest values at 12 h post LPS challenge. There was a significant 2-fold H2O2 induction in airway-EBC at 2 h post LPS inhalation. Alveolar LPS targeting resulted in the induction of very low levels of EBC-H2O2.Targeting LPS to the alveoli leads to stronger systemic responses compared to airway LPS targeting. Targeted LPS inhalation may provide a novel model of airway inflammation for studying the role of LPS contamination of air pollution in lung diseases, exacerbation and anti-inflammatory drugs.
Highlights
Endotoxin (Lipopolysaccharide, LPS) is a constituent of the outer membrane of Gram-negative bacteria and an important microbial trigger that stimulates innate immunity [1,2]
All were never-smokers and had no history of lung disease. These volunteers sequentially inhaled 1, 5 and 20 mg LPS deposited to the airways and 5 mg LPS deposited to the alveoli with at least 4 weeks between the exposures
Most studies published on human LPS challenge used full breath LPS inhalation and thereby cannot account for differences in defence and immune responses in the different regions of the respiratory tract
Summary
Endotoxin (Lipopolysaccharide, LPS) is a constituent of the outer membrane of Gram-negative bacteria and an important microbial trigger that stimulates innate immunity [1,2]. Recent evidence suggests that LPS signal transduction starts with CD14-mediated activation of one or more Toll-like receptors (TLRs) [3]. One of these receptor–ligand complexes is formed between the mammalian TLR4-MD2-CD14 complex and bacterial lipopolysaccharide (LPS) [4]. Besides TLR4, the LPSbinding protein (LBP) plays a major role. Both LBP and CD14 control ligand presentation to the TLR4 receptor complex and influence the amplitude of LPS responses and LPS-induced type cytokine production
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