Aerosolized Lipopolysaccharide Increases Pulmonary Clearance of<sup>99m</sup>Tc-DTPA in Rabbits

Brown, Mark A.; Lantz, R. Clark; Sobonya, Richard E.; Devine, Linda C.; Lentz, L. Amanda; Lemen, Richard J.

doi:10.1164/ajrccm/146.6.1462

Cited by 14 publications

(8 citation statements)

References 7 publications

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“…However, at this early time point, i.e. 4 h after LPS exposure, there was no change in vascular permeability, in agreement with a previous study showing that aerosolised P. aeruginosa-derived LPS increased airway epithelial paracellular permeability in rabbits in a timedependent manner (4-8 h after LPS nebulisation) without changes in vascular permeability at this early stage [21]. Inflammatory cells involved in lung injury and pulmonary oedema include macrophages and neutrophils, which release inflammatory mediators, including proteases, oxygen radicals and cytokines.…”

Section: Discussionsupporting

confidence: 92%

LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK

Eutamène¹

2005

European Respiratory Journal

104

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The respiratory system is directly exposed to low levels of lipopolysaccharide (LPS), present as a contaminant on airborne particles. In cystic fibrosis, the prevailing data identify structural changes of the airway epithelium, as well as tight junction dilatation. This study was aimed at determining the contribution of myosin light chain kinase to maintaining airway epithelium barrier integrity in the lung inflammatory response to LPS in rats.The effects of the selective myosin light chain kinase inhibitor, 5-iodonaphthalene-1-sulphonylhomopiperazine (ML-7), were evaluated: 1) on pulmonary inflammation and airway epithelium barrier permeability alterations induced by intra-tracheal LPS from Pseudomonas aeruginosa; and 2) on levels of the phosphorylated form of the myosin light chain, which is increased in a human airway epithelial cell line (NCI-H292) and tracheal tissue after LPS exposure.The results show that LPS increased airway epithelium barrier paracellular permeability and lung inflammation, and that pre-treatment with ML-7 inhibited both effects. This effect of ML-7 was associated with the inhibition of phosphorylated myosin light chain in both NCI-H292 cells and tracheal tissue.The data, obtained using in vivo and in vitro approaches, demonstrate a key role for myosin light chain kinase in lung inflammation, and suggest that myosin light chain kinase could be a potential target for novel drugs intended for relief of lung injury.

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Section: Discussionsupporting

confidence: 92%

LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK

Eutamène¹

2005

European Respiratory Journal

104

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“…Whole lung DTPA absorption has been previously used as a gauge of alveolar epithelial permeability [16–19]. In the CF airways, epithelial injury and increases in tight junction permeability associated with infection and inflammation would be expected to increase baseline permeability [11,12].…”

Section: Discussionmentioning

confidence: 99%

Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway

Corcoran¹,

Thomas²,

Myerburg³

et al. 2009

European Respiratory Journal

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Biomarkers providing in vivo quantification of the basic elements of cystic fibrosis (CF) lung disease are needed. A study was performed to determine whether the absorption of a small radiolabelled hydrophilic molecule (Indium-111 (In-)DTPA) would be increased in CF airways. DTPA clearance has been used previously to assess epithelial permeability and may also be useful for quantifying liquid absorption.The absorptive clearance rate of DTPA was quantified in 10 CF and 11 control subjects using a novel aerosol technique. Subjects inhaled an aerosol containing nonabsorbable technetium-99m sulfur colloid (Tc-SC) particles and In-DTPA. Tc-SC clearance from the lung is exclusively mucociliary, while In-DTPA is cleared by both absorption and mucociliary clearance. The difference between the In-DTPA and Tc-SC clearance rates estimates In-DTPA absorption.Tc-SC (mucociliary) clearance was similar in central and peripheral zones in CF and non-CF lungs. Total In-DTPA clearance was increased in both zones in CF lungs. The absorptive component of In-DTPA clearance was increased in the airway-dominated central lung zones in CF (42%?h -1 versus 32%?h -1 , p50.03).The absorption of In-DTPA is increased in the CF airway. Further study is needed to understand the relative roles of fluid absorption, inflammation and other mechanisms potentially affecting epithelial permeability and DTPA absorption.

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“…This discrepancy between AMs from IPF patients and healthy persons may be explained by the effects of priming compounds, e.g. cytokines, in inflammatory diseases [3,29,38].…”

Section: Discussionmentioning

confidence: 99%

Production of oxidants in alveolar macrophages and blood leukocytes

Haugen¹,

Skjonsberg²,

Kähler³

et al. 1999

Eur Respir J

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Increased production of oxidants subsequent to phagocyte stimulation has been associated with tissue damage in lung inflammatory disorders. The overall oxidative burden of the lung may vary with inflammatory cell composition.Flow cytometry using three different dyes, dihydroethidium (DHE), dichlorofluorescein diacetate (DCFH-DA) and dihydrorhodamine 123 (DHR), all compounds that by interaction with oxidants are transformed to fluorescent products, was used to examine the production of intracellular oxidants in alveolar macrophages (AMs), including size-defined subpopulations, monocytes (Ms) and polymorphonuclear neutrophils (PMNs) during in vitro incubation in the presence or absence of phorbol myristate acetate (PMA).PMA stimulation led to slightly increased (two-fold) (p<0.05) DHE-induced fluorescence in AMs, whereas it was greatly increased in Ms and PMNs (13-fold and 113-fold, respectively). The levels of DCFH-DA-and DHR-induced fluorescence were significantly (p<0.05) increased (four-fold and 110-fold, respectively) by PMA stimulation of PMNs, but not of AMs and Ms. Significant differences (p<0.05) in the levels of DHE-and DCFH-DA-induced fluorescence in small and large AMs were also demonstrated.The results show that the potential to increase the generation of various oxidants upon stimulation was: PMNs> Ms>AMs, suggesting that the total oxidative burden of the lungs is dependent on the type of inflammatory cells present, as well as on their state of activation.

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Aerosolized Lipopolysaccharide Increases Pulmonary Clearance of^99mTc-DTPA in Rabbits

Cited by 14 publications

References 7 publications

LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK

LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK

Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway

Production of oxidants in alveolar macrophages and blood leukocytes

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Aerosolized Lipopolysaccharide Increases Pulmonary Clearance of99mTc-DTPA in Rabbits

Cited by 14 publications

References 7 publications

LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK

LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK

Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway

Production of oxidants in alveolar macrophages and blood leukocytes

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Aerosolized Lipopolysaccharide Increases Pulmonary Clearance of^99mTc-DTPA in Rabbits