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Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients
Dieter Worlitzsch, … , Richard C. Boucher, Gerd Döring
Dieter Worlitzsch, … , Richard C. Boucher, Gerd Döring
Published February 1, 2002
Citation Information: J Clin Invest. 2002;109(3):317-325. https://doi.org/10.1172/JCI13870.
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Article

Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients

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Abstract

Current theories of CF pathogenesis predict different predisposing “local environmental” conditions and sites of bacterial infection within CF airways. Here we show that, in CF patients with established lung disease, Psuedomonas aeruginosa was located within hypoxic mucopurulent masses in airway lumens. In vitro studies revealed that CF-specific increases in epithelial O2 consumption, linked to increased airway surface liquid (ASL) volume absorption and mucus stasis, generated steep hypoxic gradients within thickened mucus on CF epithelial surfaces prior to infection. Motile P. aeruginosa deposited on CF airway surfaces penetrated into hypoxic mucus zones and responded to this environment with increased alginate production. With P. aeruginosa growth in oxygen restricted environments, local hypoxia was exacerbated and frank anaerobiosis, as detected in vivo, resulted. These studies indicate that novel therapies for CF include removal of hypoxic mucus plaques and antibiotics effective against P. aeruginosa adapted to anaerobic environments.

Authors

Dieter Worlitzsch, Robert Tarran, Martina Ulrich, Ute Schwab, Aynur Cekici, Keith C. Meyer, Peter Birrer, Gabriel Bellon, Jürgen Berger, Tilo Weiss, Konrad Botzenhart, James R. Yankaskas, Scott Randell, Richard C. Boucher, Gerd Döring

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Figure 1

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P. aeruginosa is localized in intraluminal material of freshly excised C...
P. aeruginosa is localized in intraluminal material of freshly excised CF airways and binds to mucus. (a) Thin section of an obstructed CF bronchus, stained with hematoxalin/eosin. Note the absence of P. aeruginosa on epithelial surface (black arrow) and presence of P. aeruginosa macrocolonies within intraluminal material (white arrows). Blue gap is an artifact due to fixation. (b) P. aeruginosa within macrocolonies in a lung section, stained with rabbit Ab’s against P. aeruginosa. Bars: a, 100 μm; b, 10 μm. (c) Percentage of bacteria detected at a distance of 2-5 μm or 5-17 μm from the epithelial surface of lungs from nine CF patients. Shrinkage artifacts were subtracted from calculated distances. (d) Scanning electron micrograph of mucus-coated spheroid derived from CF respiratory epithelium. P. aeruginosa (white arrow) were enmeshed in mucus (black arrows) following a 2-hour incubation. (e) Immunofluorescent staining of mucins (anti-mucin Ab) bound to P. aeruginosa strain PAO1 in vitro. (f) Spheroid with adherent mucus removed by prewash, then incubated with P. aeruginosa for 2 hours. Note the absence of bacteria on ciliated epithelial cell surfaces. Bars: d, 0.6 μm; e, 4 μm; f, 2.5 μm. Quantitative comparisons of PAO1 binding revealed higher binding to mucus-coated NESfrom normal subjects (21.3 ± 10.6 bacteria/NES) versus non-mucus-coated (washed) NES (7.1 ± 0.1 bacteria/NES) (n = 6; 3 normal subjects; P < 0.05). Importantly, these values were not different for CF NESs (26.4 ± 4.1 bacteria/NES for mucus-coated NESs; 7.7 ± 3.9 bacteria/NES for washed NESs).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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