Mucus Clearance and Lung Function in Cystic Fibrosis with Hypertonic Saline

Donaldson, Scott H.; Bennett, William D.; Zeman, Kirby L.; Knowles, Michael R.; Tarran, Robert; Boucher, Richard C.

doi:10.1056/nejmoa043891

Cited by 617 publications

(533 citation statements)

References 19 publications

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“…Similar to the blood dip experiments, we immersed the silicone oil-coated endoscopes into porcine mucin solutions with a concentration (17 wt./vol%) typically found in cystic fibrosis patients: a patient population known to have an excess of extremely sticky lung secretions (34,35). Fig.…”

Section: Resultsmentioning

confidence: 99%

Transparent antifouling material for improved operative field visibility in endoscopy

Sunny

Cheng

Daniel

et al. 2016

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

115

125

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Camera-guided instruments, such as endoscopes, have become an essential component of contemporary medicine. The 15–20 million endoscopies performed every year in the United States alone demonstrate the tremendous impact of this technology. However, doctors heavily rely on the visual feedback provided by the endoscope camera, which is routinely compromised when body fluids and fogging occlude the lens, requiring lengthy cleaning procedures that include irrigation, tissue rubbing, suction, and even temporary removal of the endoscope for external cleaning. Bronchoscopies are especially affected because they are performed on delicate tissue, in high-humidity environments with exposure to extremely adhesive biological fluids such as mucus and blood. Here, we present a repellent, liquid-infused coating on an endoscope lens capable of preventing vision loss after repeated submersions in blood and mucus. The material properties of the coating, including conformability, mechanical adhesion, transparency, oil type, and biocompatibility, were optimized in comprehensive in vitro and ex vivo studies. Extensive bronchoscopy procedures performed in vivo on porcine lungs showed significantly reduced fouling, resulting in either unnecessary or ∼10–15 times shorter and less intensive lens clearing procedures compared with an untreated endoscope. We believe that the material developed in this study opens up opportunities in the design of next-generation endoscopes that will improve visual field, display unprecedented antibacterial and antifouling properties, reduce the duration of the procedure, and enable visualization of currently unreachable parts of the body, thus offering enormous potential for disease diagnosis and treatment.

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Section: Resultsmentioning

confidence: 99%

Transparent antifouling material for improved operative field visibility in endoscopy

Sunny

Cheng

Daniel

et al. 2016

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

115

125

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“…35 The observation of a decrease in mucin gel strength is consistent with recent studies which have shown that inhalation of hypertonic saline aids in mucus clearance for cystic fibrosis patients. 36 Observation of the Nearly Critical Gel at pH 4. To ensure that the rheological changes in the gel properties presented above were entirely driven by pH rather than ionic strength, which does vary slightly with the pH of the buffer solution, rheology experiments at varying pH were repeated on samples of identical ionic strength (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Rheology of Gastric Mucin Exhibits a pH-Dependent Sol−Gel Transition

et al. 2007

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Gastric mucin, a high molecular weight glycoprotein, is responsible for providing the gel-forming properties and protective function of the gastric mucus layer. Bulk rheology measurements in the linear viscoelastic regime show that gastric mucin undergoes a pH-dependent sol-gel transition from a viscoelastic solution at neutral pH to a soft viscoelastic gel in acidic conditions, with the transition occurring near pH 4. In addition to pH-dependent gelation behavior in this system, further rheological studies under nonlinear deformations reveal shear thinning and an apparent yield stress in this material which are also highly influenced by pH.

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“…Another drug, Moli1901, works by increasing the activity of non-CFTR chloride channels, and there is evidence of clinical efficacy for these compounds [96]. Inhalation of hypertonic saline preceded by a bronchodilator [97,98] has recently been shown to improve lung function in CF patients with varying severities of lung disease, and as a result, there are now studies underway looking at the efficacy of hypertonic saline in infants with CF. Finally, numerous papers have recently appeared claiming to have identified genetic modifiers that influence the course of CF lung disease and thus are potential targets for clinical interventions [99].…”

Section: Targeting the Consequences Of Defective Cftr Functionmentioning

confidence: 99%

“…Restoration of salt transport Four drugs in phase II or III trials a , encouraging results with Denufosol (P2Y2 receptor agonist) from phase II trial [94,95] Mucus treatment Two established therapies: recombinant human DNase (Pulmozyme ® ) [18,62,65] and hypertonic saline inhalation [97] Non-CFTR-specific interventions…”

Section: Strategymentioning

confidence: 99%

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Campodónico

Gadjeva

Paradis-Bleau

et al. 2008

Trends in Molecular Medicine

100

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Defective expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR) underlies the hypersusceptibility of cystic fibrosis (CF) patients to chronic airway infections, particularly with Pseudomonas aeruginosa. CFTR is involved in the specific recognition of P. aeruginosa, thereby contributing to effective innate immunity and proper hydration of the airway surface layer (ASL). In CF, the airway epithelium fails to initiate an appropriate innate immune response, allowing the microbe to bind to mucus plugs that are then not properly cleared because of the dehydrated ASL. Recent studies have identified numerous CFTR-dependent factors that are recruited to the epithelial plasma membrane in response to infection and that are needed for bacterial clearance, a process that is defective in CF patients hypersusceptible to infection with this organism. Pseudomonas aeruginosa in cystic fibrosisCystic fibrosis (CF) is unique among human genetic disorders in that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein whose primary function described to date has been to regulate conductance of ions in and out of cells and intracellular vacuoles, lead to hypersusceptibility to chronic lung infection. Human diseases wherein individuals homozygous for mutant genes are predisposed to infections serve as a firm foundation for understanding the molecular, cellular, physiologic and immunologic aspects of normal and compromised resistance to infection. CF is not just a prime example of how we can learn about normal and pathologic states; it could, in fact, be the only known human genetically determined disease wherein infection with a single pathogen -Pseudomonas aeruginosa -drives the vast majority of morbidity, clinical deterioration and ultimately life-shortening mortality encountered in this disease. In humans with significant compromises to their immune system, such as advanced AIDS, we would normally expect to see a plethora of pathogens take advantage of this debilitated state, but this is not the case in CF.CF is characterized by the emergence and persistence of (and, ultimately, the inability to clear) chronic infection with a variant of P. aeruginosa (mucoid P. aeruginosa) that overproduces a surface polysaccharide known as alginate. The organism undergoes other significant genetic adaptations and selections within the CF lung, and it is the emergence of mucoid P. aeruginosa that is the primary determinant of the clinical course of this disease [1,2]. In those individuals with either an uncommon but fortuitous protective immune response to specific P. aeruginosa antigens [3,4] Histopathologic basis for defining relevant interactions between P.aeruginosa and the CF airway epitheliumAlthough CF is a multisystem disease characterized by GI and nutritional abnormalities, salt loss syndromes and male urogenital abnormalities, the major clinical problem for CF patients is chronic sinopulmonary disease. Therefore, relying on observations made fr...

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Mucus Clearance and Lung Function in Cystic Fibrosis with Hypertonic Saline

Abstract: In patients with cystic fibrosis, inhalation of hypertonic saline produced a sustained acceleration of mucus clearance and improved lung function. This treatment may protect the lung from insults that reduce mucus clearance and produce lung disease.

Cited by 617 publications

References 19 publications

Transparent antifouling material for improved operative field visibility in endoscopy

Transparent antifouling material for improved operative field visibility in endoscopy

Rheology of Gastric Mucin Exhibits a pH-Dependent Sol−Gel Transition

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

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