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

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

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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Oxygen partial pressure (pO2) CF airways in vivo and in thick films of A...
Oxygen partial pressure (pO2) CF airways in vivo and in thick films of ASL on human airway epithelial cultures. (a) pO2 in CF airways. First 30 minutes represents measurement in a nonobstructed region of the airway lumen. The arrow indicates insertion of oxygen probe into a mucopurulent mass. The pO2 returned to basal values after probe retraction from the adherent mass into the nonobstructed airway region. (b) pO2 in nonobstructed CF airway lumens (L) and CF mucopurulent masses (M) in vivo. n = 3 CF subjects; *P = 0.001. (c) Plots of pO2 gradients under thick film conditions at 37°C in NL (squares; eight cultures/five subjects) and CF cultures (circles; six cultures/four subjects). (d) pO2 gradients under thick film conditions measured at 4°C in NL (squares; five cultures/three subjects) and CF cultures (circles; five cultures/three subjects). (e) pO2 gradients in CF mucus that had accumulated for 48 hours on CF culture surfaces and had become stationary due to volume hyperabsorption (inverted triangles). Mucus transport was restored in these cultures by addition of 30 μl PBS, and pO2 gradients remeasured 1–2 hours later (triangles; six cultures; three subjects each). (f) Comparison of pO2 gradients in NL (squares; nine cultures/six subjects) and PCD (diamonds; five cultures/two subjects) cultures under thick film conditions. Data are shown as mean ± SEM. *Significantly different (P < 0.05) from pO2 at the air-liquid interface (0 μm). †Significant difference (P < 0.05) between NL and CF.