Reduced Three-Dimensional Motility in Dehydrated Airway Mucus Prevents Neutrophil Capture and Killing Bacteria on Airway Epithelial Surfaces

Matsui, Hirotoshi; Verghese, Margrith W.; Kesımer, Mehmet; Schwab, Ute; Randell, Scott H.; Sheehan, John K.; Grubb, Barbara R.; Boucher, Richard C.

doi:10.4049/jimmunol.175.2.1090

Cited by 129 publications

(104 citation statements)

References 52 publications

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“…Further, our data add to an understanding of how concentrated, dehydrated CF mucus impairs the host defense. Previous studies have shown that the reduced mesh pore size produced by mucus concentration reduces the effectiveness of neutrophils to penetrate and kill P. aeruginosa residing in concentrated, but not ''normal,'' mucus gels (37). The present study demonstrates that the activity of a soluble host defense factor, i.e., lactoferrin, is also degraded in concentrated, CF-like gels.…”

Section: Discussionsupporting

confidence: 50%

A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms

Matsui¹,

Wagner

Hill³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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217

228

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A vexing problem in cystic fibrosis (CF) pathogenesis has been to explain the high prevalence of Pseudomonas aeruginosa biofilms in CF airways. We speculated that airway surface liquid (ASL) hyperabsorption generates a concentrated airway mucus that interacts with P. aeruginosa to promote biofilms. To model CF vs. normal airway infections, normal (2.5% solids) and CF-like concentrated (8% solids) mucus were prepared, placed in flat chambers, and infected with an Ϸ5 ؋ 10 3 strain PAO1 P. aeruginosa. Although bacteria grew to 10 10 cfu/ml in both mucus concentrations, macrocolony formation was detected only in the CF-like (8% solids) mucus. Biophysical and functional measurements revealed that concentrated mucus exhibited properties that restrict bacterial motility and small molecule diffusion, resulting in high local bacterial densities with high autoinducer concentrations. These properties also rendered secondary forms of antimicrobial defense, e.g., lactoferrin, ineffective in preventing biofilm formation in a CF-like mucus environment. These data link airway surface liquid hyperabsorption to the high incidence of P. aeruginosa biofilms in CF via changes in the hydration-dependent physical-chemical properties of mucus and suggest that the thickened mucus gel model will be useful to develop therapies of P. aeruginosa biofilms in CF airways.mucus ͉ rheology C ystic fibrosis (CF) lung disease reflects the chronic bacterial infection of intrapulmonary airways with Pseudomonas aeruginosa biofilms (1, 2). P. aeruginosa biofilms have mostly been studied in flow chambers (3-7) that are good models for the biofilms that form on venous or urethral catheters under conditions of high flow rates and relatively high oxygen tensions. However, biofilms in CF airways form in thickened (concentrated) mucus gels that are relatively hypoxic and adherent to airway surfaces (see Fig. 1A) (8, 9). Recently, Sriramulu et al. (10) investigated the role autoregulators and amino acids play in the tightness of biofilm formation in a mucus stimulant of constant hydration. For the present study, we designed a culture system to investigate whether dehydration of the CF mucus environment may predispose to P. aeruginosa biofilm formation.A key aspect of the model was the selection of mucus concentrations that mimic normal and CF mucus. Although measurements of mucus concentration, i.e., the percentage of solids content, from CF subjects before infection have not been reported, estimates from cell cultures (11) and sputum (12-18) suggest that CF mucus is at least three or four times more concentrated than normal. Therefore, mucus was obtained from well differentiated human airway cultures and was isotonically concentrated (1) to produce mucus of normal (2.5% solids wt/wt) and CF-like (8%) concentrations (Fig. 1B). Aliquots of each were deposited in (i) an open chamber to model a mucus plaque adherent to CF airway surfaces with a residual lumen allowing airflow and (ii) a closed chamber to mimic a mucus plug occluding a CF airway (Fig. 1 A). P....

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Section: Discussionsupporting

confidence: 50%

A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms

Matsui¹,

Wagner

Hill³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

217

228

View full text Add to dashboard Cite

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“…Most studies addressing the mechanisms of CF airway disease pathogenesis have focused on epithelial cells and neutrophils (4,(45)(46)(47)(48)(49)(50). These cell types are important contributors to the altered airway environment.…”

Section: Discussionmentioning

confidence: 99%

Aspergillus fumigatus Generates an Enhanced Th2-Biased Immune Response in Mice with Defective Cystic Fibrosis Transmembrane Conductance Regulator

Allard

Poynter

Marr

et al. 2006

The Journal of Immunology

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Cystic fibrosis (CF) lung disease is characterized by persistent airway inflammation and airway infection that ultimately leads to respiratory failure. Aspergillus sp. are present in the airways of 20–40% of CF patients and are of unclear clinical significance. In this study, we demonstrate that CF transmembrane conductance regulator (CFTR)-deficient (CFTR knockout, Cftrtm1Unc-TgN(fatty acid-binding protein)CFTR) and mutant (ΔF508) mice develop profound lung inflammation in response to Aspergillus fumigatus hyphal Ag exposure. CFTR-deficient mice also develop an enhanced Th2 inflammatory response to A. fumigatus, characterized by elevated IL-4 in the lung and IgE and IgG1 in serum. In contrast, CFTR deficiency does not promote a Th1 immune response. Furthermore, we demonstrate that CD4+ T cells from naive CFTR-deficient mice produce higher levels of IL-4 in response to TCR ligation than wild-type CD4+ T cells. The Th2 bias of CD4+ T cells in the absence of functional CFTR correlates with elevated nuclear levels of NFAT. Thus, CFTR is important to maintain the Th1/Th2 balance in CD4+ T cells.

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“…Since CFTR exhibits a chloride channel activity, it was speculated that water absorption in the mucus present on epithelial cells of the respiratory tract is altered, which may result in a reduced mucociliary clearance and a reduced ability to eliminate P. aeruginosa [5, 6]. The increased viscosity of the mucus may also affect the ability of neutrophils to migrate to and kill bacteria in the respiratory tract.…”

Section: Inflammation In Cystic Fibrosismentioning

confidence: 99%

“…The increased viscosity of the mucus may also affect the ability of neutrophils to migrate to and kill bacteria in the respiratory tract. However, although in vitro experiments suggested the concept of reduced mucociliary clearance in cystic fibrosis [5], in vivo studies on cystic fibrosis patients failed to demonstrate a significant and uniform reduction of the mucociliary clearance in these individuals [6]. …”

Section: Inflammation In Cystic Fibrosismentioning

confidence: 99%

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

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Sphingolipids and in particular ceramide have been shown to be critically involved in the response to many receptor-mediated, but also receptor-independent, mainly stress stimuli. Recent studies demonstrate that ceramide plays an important role in the pathogenesis of cystic fibrosis, a hereditary metabolic disorder caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator. Patients with cystic fibrosis suffer from chronic pulmonary inflammation and microbial lung infections, in particular with Pseudomonas aeruginosa. Chronic pulmonary inflammation in these patients seems to be the initial pathophysiological event. Inflammation may finally result in the high infection susceptibility of these patients, fibrosis and loss of lung function. Recent studies demonstrated that ceramide accumulates in lungs of cystic fibrosis mice and causes age-dependent pulmonary inflammation as indicated by accumulation of neutrophils and macrophages in the lung and increased pulmonary concentrations of Interleukins 1 and 8, death of bronchial epithelial cells, deposition of DNA in bronchi and high susceptibility to Pseudomonas aeruginosa infections. Genetic or pharmacological inhibition of the acid sphingomyelinase blocks excessive ceramide production in lungs of cystic fibrosis mice and corrects pathological lung findings. First clinical studies confirm that inhibition of the acid sphingomyelinase with small molecules might be a novel strategy to treat patients with cystic fibrosis.

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Reduced Three-Dimensional Motility in Dehydrated Airway Mucus Prevents Neutrophil Capture and Killing Bacteria on Airway Epithelial Surfaces

Cited by 129 publications

References 52 publications

A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms

A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms

Aspergillus fumigatus Generates an Enhanced Th2-Biased Immune Response in Mice with Defective Cystic Fibrosis Transmembrane Conductance Regulator

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

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