Reduction of Alveolar-Capillary Diffusion after Inhalation of Endotoxin in Normal Subjects

doi:10.1378/chest.102.4.1095

Chest

Volume 102, Issue 4, October 1992, Pages 1095-1098

https://doi.org/10.1378/chest.102.4.1095 Get rights and content

Normal subjects were exposed to an aerosol of Escherichia coli endotoxin. Carbon monoxide diffusion (DCO), spirometry, blood neutrophils, white blood cells, and platelets were determined at various times thereafter. A significant decrease in DCO and an increase in blood neutrophils was found, with a maximum effect 4 to 8 h after exposure. Exposure to distilled water caused a tendency for DCO to decrease and a significant increase in blood neutrophils. No effect on spirometry or body temperature was detected. It is suggested that the changes observed represent an inflammation at the alveolar level that appears at dose levels of endotoxin below those which cause bronchoconstriction and fever.

Section snippets

Test Subjects

The test subjects were eight nonsmoking students of both sexes recruited by advertising. Only subjects without a history of asthma or symptomatic allergy were accepted. No prescreening for airway sensitivity was performed. The subjects were paid for their participation in the study, which was approved by the ethics committee at the medical faculty.

Exposure

The endotoxin used was the commercially available pure preparation of lipoplysaccharide (Escherichia coli 026B6, Difco) that was suspended in

RESULTS

Regarding lung function, the subjects showed slightly higher than predicted values of FEV₁ before the challenge to endotoxin or distilled water (an average of 105 and 103 percent, respectively). The average FVC and FEV₁ values for the eight subjects remained unchanged at all times after the exposures to both endotoxin and water. There were no indications that single values for any particular subject were affected by any of the exposures.

The results from the measurements of DCO are shown in

DISCUSSION

The dose of endotoxin used in these experiments was 100 µg, of which about 70 percent (70 µg) was delivered by the nebulizer. Considering the size of the aerosol, one could estimate that about 50 percent of this (35 µg) was deposited in the airways. In occupational settings, airborne endotoxin values (cell-bound endotoxin) may reach 1 to 2 µg/m³ using the Limulus method, which corresponds to about 50 to 100 µg/m³ of free endotoxin.⁶

No decrease in the FEV₁ was found at the levels used in this

ACKNOWLEDGMENT

The studies were supported by a grant from the Swedish Work Environment Fund (contract 86-0253) and a personal grant from the Swedish Lung ana Heart Association to Maria Carvalheiro during her stay in Gothenburg. Alex Herbert was on sabbatical leave at the Department to conduct the study. The statistical analysis was performed by Anders Odén, Ph.D.

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Neutralization of LPS may be beneficial for the treatment of a number of diseases, and there are indications that several disorders, where BSE were actually beneficial, might be mediated via LPS-induced signal transduction cascades. For example, inhalation of LPS leads to bronchoconstriction [42–44], a change in non-specific airway responsiveness [42,43,45] and to a reduction of alveolar capillary diffusion [46]. A participation of LPS in chronic airway diseases as asthma has been suggested [47].
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Role of indoor endotoxins in asthma symptoms
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Les endotoxines désignent un groupe chimique caractéristique de la paroi externe des bactéries Gram négatif, les lipopolysaccharides (LPS).
Les tests de provocation respiratoire aux endotoxines (50 μg) entraînent chez le sujet sain une réaction bronchospastique pseudo-asthmatiforme à neutrophiles, analogue à celle observée dans l’asthme non atopique. Des doses moins élevées (20 μg) entraînent la même réaction chez les sujets asthmatiques. Des doses faibles (2 μg) n’entraînent ni bronchospasme, ni hyperréactivité bronchique. En milieu professionnel, notamment agricole, l’exposition souvent très élevée aux endotoxines est associée à l’asthme. Les études cliniques montrent que l’exposition aux LPS augmente la sévérité de l’asthme. En revanche, les études épidémiologiques, en milieu agricole et urbain, sont discordantes, certaines montrant une augmentation des symptômes d’asthme, d’autres l’inversent.
Les études longitudinales, pratiquées notamment en milieu agricole, permettront de préciser l’éventuel rôle protecteur des endotoxines sur l’asthme atopique.
Les endotoxines de l’environnement intérieur sont dans l’ensemble des études actuelles plutôt associées à l’asthme. Mais leur rôle définitif devrait être précisé par des études de cohorte actuellement en cours d’enfants suivis depuis la naissance.
Endotoxin is a collective term designating a characteristic group of chemical constituents of the outer membrane of Gram negative bacteria, the lipopolysaccharides (LPS).
LPS provocation tests in healthy subjects (50 μg) induce asthma-like airflow obstruction with a neutrophilic inflammatory influx, similar to reactions observed in non-atopic asthma. Asthmatic subjects show the same reaction with smaller doses of LPS (20 μg), revealing higher sensitivity to LPS than normal subjects. Low levels (2 μg) of LPS do not induce either airflow obstruction or bronchial hyperreactivity. Among exposed workers, particularly in agriculture, endotoxin is the most significant component of the bioaerosol that is associated with airway disease. In clinical studies, exposure to LPS is associated with severe asthma. Conversely, epidemiological studies, in both urban and rural areas, assessing the relationship between exposure to LPS and asthma and asthma-related symptoms are inconsistent.
Longitudinal epidemiological studies, especially in farm children, may confirm the putative protective effects of LPS with respect to atopic asthma.
Exposure to indoor LPS is frequently associated with asthma and asthma-like symptoms in current studies. Their definitive role needs to be confirmed by birth cohort studies currently under way that should define the controversial protective effect of LPS with respect to atopic asthma in farming populations.
Role of indoor endotoxins in asthma symptoms
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Les endotoxines désignent un groupe chimique caractéristique de la paroi externe des bactéries Gram négatif, les lipopolysaccharides (LPS).
Les tests de provocation respiratoire aux endotoxines (50 μg) entraînent chez le sujet sain une réaction bronchospastique pseudo-asthmatiforme à neutrophiles, analogue à celle observée dans l’asthme non atopique. Des doses moins élevées (20 μg) entraînent la même réaction chez les sujets asthmatiques. Des doses faibles (2 μg) n’entraînent ni bronchospasme, ni hyperréactivité bronchique. En milieu professionnel, notamment agricole, l’exposition souvent très élevée aux endotoxines est associée à l’asthme. Les études cliniques montrent que l’exposition aux LPS augmente la sévérité de l’asthme. En revanche, les études épidémiologiques, en milieu agricole et urbain, sont discordantes, certaines montrant une augmentation des symptômes d’asthme, d’autres l’inverse.
Les études longitudinales, pratiquées notamment en milieu agricole, permettront de préciser l’éventuel rôle protecteur des endotoxines sur l’asthme atopique.
Les endotoxines de l’environnement intérieur sont dans l’ensemble des études actuelles plutôt associées à l’asthme. Mais leur rôle définitif devrait être précisé par des études de cohorte actuellement en cours d’enfants suivis depuis la naissance.
Endotoxin is a collective term designating a characteristic group of chemical constituents of the outer membrane of Gram negative bacteria, the lipopolysaccharides (LPS).
LPS provocation tests in healthy subjects (50 μg) induce asthma-like airflow obstruction with a neutrophilic inflammatory influx, similarto reactions observed in non-atopic asthma. Asthmatic subjects show the same reaction with smaller doses of LPS (20 μg), revealing higher sensitivity to LPS than normal subjects. Low levels (2 μg) of LPS do not induce either airflow obstruction or bronchial hyperreactivity. Among exposed workers, particularly in agriculture, endotoxin is the most significant component of the bioaerosol that is associated with airway disease. In clinical studies, exposure to LPS is associated with severe asthma. Conversely, epidemiological studies, in both urban and rural areas, assessing the relationship between exposure to LPS and asthma and asthma-related symptoms are inconsistent.
Longitudinal epidemiological studies, especially in farm children, may confirm the putative protective effects of LPS with respect to atopic asthma.
Exposure to indoor LPS is frequently associated with asthma and asthma-like symptoms in current studies. Their definitive role needs to be confirmed by birth cohort studies currently under way that should define the controversial protective effect of LPS with respect to atopic asthma in farming populations.
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Citation Excerpt :
Several studies have reported the effects of an acute inhalation of pure endotoxin in humans. There are local effects in terms of an increase in the number of neutrophils and levels of the inflammatory marker fibronectin in the airways, a dose-related decrease in pulmonary function, a decreased alveolar-capillary diffusion, and an increased airway responsiveness (Herbert et al., 1992; Rylander et al., 1989; Sandström et al., 1992). There are also systemic effects in terms of an increased number of neutrophils in the blood, an increased amount of tumor necrosis factor-α (TNF-α), myeoloperoxidase, and C-reactive protein indicative of a general inflammatory response (Michel et al., 1996, 2001; Thorn and Rylander, 1998a).
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Endotoxins associated with cyanobacteria and their removal during drinking water treatment
2002, Water Research
The aim of this study was to investigate endotoxin concentrations in cyanobacterial water blooms and strains, and to assess the removal of endotoxins during drinking water treatment. Endotoxin concentrations were measured from 151 hepatotoxic, neurotoxic and non-toxic cyanobacterial water blooms by using Limulus amebocyte lysate (LAL) assay, and the results were compared to bacterial data. Endotoxin activities ranged from 20 to 3.8×10⁴ endotoxin units (EU) per ml. Endotoxicity of the samples correlated with phycobiliprotein concentration that was used to assess cyanobacterial abundance, heterotrophic plate count, and Aeromonas spp. but it did not correlate with the number of coliforms or streptococci. The high endotoxin concentrations occasionally detected in the water bloom samples were probably due to Gram negative bacteria that existed together with cyanobacteria since the 26 axenic cyanobacterial strains from different genera that were studied showed very low endotoxin activity. No differences in endotoxin activity were detected between hepatotoxic, neurotoxic and non-toxic strains. Removal of endotoxins during drinking water treatment was studied at nine waterworks that previously had been associated with high numbers of cyanobacteria and that used different processes for water purification. Endotoxin concentration in raw waters ranged from 18 to 356 EU ml⁻¹. The treatment processes reduced 59–97% of the endotoxin activity; in the treated water the concentration ranged from 3 to 15 EU ml⁻¹. The most significant reduction occurred at the early stages of water treatment, during coagulation, settling and sand filtration. Activated carbon filtration either increased or had no effect on endotoxin concentration. Ozonation and chlorination had little effect on the endotoxin concentrations.
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Reduction of Alveolar-Capillary Diffusion after Inhalation of Endotoxin in Normal Subjects

Section snippets

Test Subjects

Exposure

RESULTS

DISCUSSION

ACKNOWLEDGMENT

FEMS Microbiol Lett

Organic dusts and lung disease.

Am J Ind Med

The role of endotoxin for reactions after exposure to cotton dust.

Am J Ind Med

Cell recruitment into lung wall and airways of conventional and pathogen-free guinea pigs after inhalation of endotoxin.

Am Rev Respir Dis

Effects of endotoxin inhalation challenges in humans.

Pulmonary function and symptoms after inhalation of endotoxin.

Am Rev Respir Dis

Generation of a microaerosol suitable for deposition in the peripheral airways.

Eur J Respir Dis

Spirometric studies in normal subjects, I: forced expirograms in subjects between 7 and 70 years of age.

Acta Med Scand