Differential Inflammatory Response to Inhaled Lipopolysaccharide Targeted Either to the Airways or the Alveoli in Man

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.

Effect of Inhaled Endotoxin on Mucociliary Clearance and Airway Inflammation in Mild Smokers and Nonsmokers

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Elevated exhaled leukotriene B4 in the small airway compartment in children with asthma

“…30 In this study, we collected EBC using a capnograph-based method to determine the large airway and small airway or alveolar threshold. The initial separation is more precise for each patient using the plateau phase of the exhaled carbon dioxide concentration compared with a volume-based approach.…”

The Stimulated Innate Resistance Event in Bordetella pertussis Infection Is Dependent on Reactive Oxygen Species Production

“…Although DUOX expression is induced by proinflammatory cytokines, especially gamma interferon (36), the role of TLR4 ligands as triggers of H 2 O 2 production in the airways, as reported here, has not been studied extensively. Recently, Moller and colleagues (37) showed that in healthy human volunteers, the inhalation of micrograms of Salmonella LPS triggers a fast airway response, with a peak of H 2 O 2 production at 2 h poststimulation. According to the technique used, the authors concluded that H 2 O 2 production under these conditions is maximal in the airways, although the alveoli also contribute to the generation of ROS.…”