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

Worlitzsch, Dieter; Tarran, Robert; Ulrich, Martina; Schwab, Ute; Cekici, Aynur; Meyer, Keith C.; Birrer, P.; Bellon, G.; Berger, Jürgen; Weiß, Tilo; Botzenhart, K; Yankaskas, James R.; Randell, Scott H.; Boucher, Richard C.; Döring, Gerd

doi:10.1172/jci200213870

Cited by 192 publications

(145 citation statements)

References 27 publications

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“…The oxygen concentration in obstructed airways decreases rapidly with depth (17) and does not penetrate static fluids effectively, resulting in anoxic microenvironments. Anoxia in obstructed CF airways is supported by direct measurements (17), the presence of anaerobes in sputum (18), and by the observation of anaerobic metabolism in laboratory microcosms inoculated with bacterial strains from CF patients (17, 20).…”

Section: Introductionmentioning

confidence: 99%

“…Anoxia in obstructed CF airways is supported by direct measurements (17), the presence of anaerobes in sputum (18), and by the observation of anaerobic metabolism in laboratory microcosms inoculated with bacterial strains from CF patients (17, 20). Anoxia in the lung is counterintuitive, as the principal purpose of a healthy lung is to exchange oxygen.…”

Section: Introductionmentioning

confidence: 99%

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Biogeochemical Forces Shape the Composition and Physiology of Polymicrobial Communities in the Cystic Fibrosis Lung

Quinn

Lim

Maughan

et al. 2014

mBio

110

106

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The cystic fibrosis (CF) lung contains thick mucus colonized by opportunistic pathogens which adapt to the CF lung environment over decades. The difficulty associated with sampling airways has impeded a thorough examination of the biochemical microhabitats these pathogens are exposed to. An indirect approach is to study the responses of microbial communities to these microhabitats, facilitated by high-throughput sequencing of microbial DNA and RNA from sputum samples. Microbial metagenomes and metatranscriptomes were sequenced from multiple CF patients, and the reads were assigned taxonomy and function through sequence homology to NCBI and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database hierarchies. For a comparison, saliva microbial metagenomes from the Human Microbiome Project (HMP) were also analyzed. These analyses identified that functions encoded and expressed by CF microbes were significantly enriched for amino acid catabolism, folate biosynthesis, and lipoic acid biosynthesis. The data indicate that the community uses oxidative phosphorylation as a major energy source but that terminal electron acceptors were diverse. Nitrate reduction was the most abundant anaerobic respiratory pathway, and genes for nitrate reductase were largely assigned to Pseudomonas and Rothia. Although many reductive pathways of the nitrogen cycle were present, the cycle was incomplete, because the oxidative pathways were absent. Due to the abundant amino acid catabolism and incomplete nitrogen cycle, the CF microbial community appears to accumulate ammonia. This finding was verified experimentally using a CF bronchiole culture model system. The data also revealed abundant sensing and transport of iron, ammonium, zinc, and other metals along with a low-oxygen environment. This study reveals the core biochemistry and physiology of the CF microbiome.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biogeochemical Forces Shape the Composition and Physiology of Polymicrobial Communities in the Cystic Fibrosis Lung

Quinn

Lim

Maughan

et al. 2014

mBio

110

106

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“…The most serious clinical problem in CF is lung damage caused by chronic bacterial airway infections. The bacteria in CF airways reside in the mucus, which in normal airways is sterile and mobile (6), suggesting that CF mucus is abnormal both in its ability to be cleared from the airways (7) and in its antimicrobial properties (8). Most airway mucus is thought to arise from submucosal glands (9,10), and in the only direct comparisons ever made of airways with and without glands, airways with glands secreted much more lysozyme and were more resistant to bacterial infections, even though no central innervation of the glands was present (11,12).…”

Section: Introductionmentioning

confidence: 99%

Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis

Choi

Joo²,

Krouse³

et al. 2007

J. Clin. Invest.

111

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Cystic fibrosis (CF) is caused by dysfunction of the CF transmembrane conductance regulator (CFTR), an anion channel whose dysfunction leads to chronic bacterial and fungal airway infections via a pathophysiological cascade that is incompletely understood. Airway glands, which produce most airway mucus, do so in response to both acetylcholine (ACh) and vasoactive intestinal peptide (VIP). CF glands fail to secrete mucus in response to VIP, but do so in response to ACh. Because vagal cholinergic pathways still elicit strong gland mucus secretion in CF subjects, it is unclear whether VIP-stimulated, CFTR-dependent gland secretion participates in innate defense. It was recently hypothesized that airway intrinsic neurons, which express abundant VIP and ACh, are normally active and stimulate low-level gland mucus secretion that is a component of innate mucosal defenses. Here we show that low levels of VIP and ACh produced significant mucus secretion in human glands via strong synergistic interactions; synergy was lost in glands of CF patients. VIP/ACh synergy also existed in pig glands, where it was CFTR dependent, mediated by both Cl -and HCO 3 -, and clotrimazole sensitive. Loss of "housekeeping" gland mucus secretion in CF, in combination with demonstrated defects in surface epithelia, may play a role in the vulnerability of CF airways to bacterial infections.

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“…Transport limitation, neutralization effect, and physiological adaption are often quoted to explain the enhanced antibiotic resistance within the biofilm. The formation of P. aeruginosa biofilm poses a physical barrier to antibiotics [20]. The adsorption of positively charged antibiotics (such as the aminoglycosides) to the negatively charged alginate polymers can retard penetration.…”

Section: Discussionmentioning

confidence: 99%

Effect of Ambroxol on Pneumonia Caused by <i>Pseudomonas aeruginosa</i> with Biofilm Formation in an Endotracheal Intubation Rat Model

Fang¹,

Wang

Hu³

et al. 2011

Chemotherapy

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Background:Pseudomonas aeruginosa, especially the mucoid phenotype, is responsible for most of the morbidity and mortality in ventilator-associated pneumonia. Although ambroxol is widely used in neonatal lung problems as a mucolytic as well as an antioxidant agent, its anti-infective role is not well demonstrated by studies in vivo. Objective: To explore the effect of ambroxol on the biofilms of mucoid P. aeruginosa and on the associated lung infection using a rat model. Methods: We developed a rat model of acute lung infection by endotracheal intubation with a tube covered with mucoid P. aeruginosa biofilm. Then, we studied the effect of ambroxol on the biofilm using saline treatment as a control. Subsequently, we studied the microstructure of the biofilm, bacterial count in the tubes and lungs, pathological changes that occurred in the lungs, and the cytokine response. Results: Alteration of the microstructure of the biofilm with ambroxol treatment was demonstrated by scanning electron microscopy. The bacterial counts on the biofilm-covered tube in the ambroxol-treated group were significantly lower than those in the saline-treated group on both post-bacterial challenge days 4 and 7 (p < 0.05). The bacterial counts in lungs of the ambroxol-treated group and of the saline-treated group on post-bacterial challenge day 7 were not significantly different (p > 0.05). The pathological changes in lungs were milder with the effect of ambroxol. The cytokine responses, namely the level of IFN-γ and the ratio of IFN-γ and IL-10, were also reduced with the effect of ambroxol. Conclusion: We demonstrated that the ambroxol treatment could destroy the structure of the biofilm on the tube used for intubation and decrease the bacterial load. Further, the reduced cytokine response and milder pathological changes in lungs in an endotracheal intubation rat model indicate that ambroxol can attenuate the damage caused by biofilm-associated infection in the lung.

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

Cited by 192 publications

References 27 publications

Biogeochemical Forces Shape the Composition and Physiology of Polymicrobial Communities in the Cystic Fibrosis Lung

Biogeochemical Forces Shape the Composition and Physiology of Polymicrobial Communities in the Cystic Fibrosis Lung

Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis

Effect of Ambroxol on Pneumonia Caused by <i>Pseudomonas aeruginosa</i> with Biofilm Formation in an Endotracheal Intubation Rat Model

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