Serine Proteases Degrade Airway Mucins in Cystic Fibrosis

Henke, Markus O.; Gorcsan, John; Rheineck, Christina; Chillappagari, Shashi; Naehrlich, Lutz; Rubin, Bruce K.

doi:10.1128/iai.01252-10

Cited by 54 publications

(53 citation statements)

References 46 publications

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“…This ability also explained why the growth rate of the clinical strain was found to be the greatest on the mucin-supplemented SCFM medium where the growth also peaked earlier than in other cultures (Fig 1A and 1B). It has been suggested that serine proteases, elastase-like in particular, are responsible for mucin digestion in the cystic fibrosis lungs [71]. In our study, elastase-like activity was mainly detected in the culture supernatant of the clinical isolate (Fig 3), which may also contribute to mucin degradation [71].…”

Section: Discussionsupporting

confidence: 50%

“…It has been suggested that serine proteases, elastase-like in particular, are responsible for mucin digestion in the cystic fibrosis lungs [71]. In our study, elastase-like activity was mainly detected in the culture supernatant of the clinical isolate (Fig 3), which may also contribute to mucin degradation [71]. Indeed, serine proteases were the dominant protease class secreted by the clinical strain (Fig 2).…”

Section: Discussionmentioning

confidence: 52%

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Secretion of Proteases by an Opportunistic Fungal Pathogen Scedosporium aurantiacum

2017

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Scedosporium aurantiacum is an opportunistic filamentous fungus increasingly isolated from the sputum of cystic fibrosis patients, and is especially prevalent in Australia. At the moment, very little is known about the infection mechanism of this fungus. Secreted proteases have been shown to contribute to fungal virulence in several studies with other fungi. Here we have compared the profiles of proteases secreted by a clinical isolate Scedosporium aurantiacum (WM 06.482) and an environmental strain (WM 10.136) grown on a synthetic cystic fibrosis sputum medium supplemented with casein or mucin. Protease activity was assessed using class-specific substrates and inhibitors. Subtilisin-like and trypsin-like serine protease activity was detected in all cultures. The greatest difference in the secretion of proteases between the two strains occurred in mucin-supplemented medium, where the activities of the elastase-like, trypsin-like and aspartic proteases were, overall, 2.5–75 fold higher in the clinical strain compared to the environmental strain. Proteases secreted by the two strains in the mucin-supplemented medium were further analyzed by mass spectrometry. Six homologs of fungal proteases were identified from the clinical strain and five from the environmental strain. Of these, three were common for both strains including a subtilisin peptidase, a putative leucine aminopeptidase and a PA-SaNapH-like protease. Trypsin-like protease was identified by mass spectrometry only in the clinical isolate even though trypsin-like activity was present in all cultures. In contrast, high elastase-like activity was measured in the culture supernatant of the clinical strain but could not be identified by mass spectrometry searching against other fungi in the NCBI database. Future availability of an annotated genome will help finalise identification of the S. aurantiacum proteases.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 52%

Secretion of Proteases by an Opportunistic Fungal Pathogen Scedosporium aurantiacum

2017

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“…One possibility is that other properties of cystic fibrosis mucus could override the feedback system. These include the presence of DNA (41), a different ratio of two mucin subtypes that make up the airway mucus (Muc5AC and Muc5B) as a result of goblet cell hyperplasia (42), and proteolytic cleavage of mucins by bacterial- and neutrophil-released proteases (43). Furthermore, the mucins themselves on the airway epithelia of cystic fibrosis patients may be abnormal, reflecting possible defects in mucin biosynthesis (3, 44) or defective unfolding during release from intracellular granules as a result of defective CFTR-mediated HCO 3 − transport (4, 5).…”

Section: Discussionmentioning

confidence: 99%

Mechanosensitive ATP Release Maintains Proper Mucus Hydration of Airways

et al. 2013

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The clearance of mucus from the airways protects the lungs from inhaled noxious and infectious materials. Proper hydration of the mucus layer enables efficient mucus clearance through beating of cilia on airway epithelial cells, and reduced clearance of excessively concentrated mucus occurs in patients with chronic obstructive pulmonary disease and cystic fibrosis. Key steps in the mucus transport process are airway epithelia sensing and responding to changes in mucus hydration. We reported that extracellular adenosine triphosphate (ATP) and adenosine were important luminal auto-crine and paracrine signals that regulated the hydration of the surface of human airway epithelial cultures through their action on apical membrane purinoceptors. Mucus hydration in human airway epithelial cultures was sensed by an interaction between cilia and the overlying mucus layer: Changes in mechanical strain, proportional to mucus hydration, regulated ATP release rates, adjusting fluid secretion to optimize mucus layer hydration. This system provided a feedback mechanism by which airways maintained mucus hydration in an optimum range for cilia propulsion. Understanding how airway epithelia can sense and respond to changes in mucus properties helps us to understand how the mucus clearance system protects the airways in health and how it fails in lung diseases such as cystic fibrosis.

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“…P. aeruginosa is the most prevalent infectious agent in this population and is associated with lung function decline. CF patients also suffer from sustained airway neutrophilia [156], resulting in an excess of purulent phlegm and pro-inflammatory factors [157]. The combination of infection and inflammation ultimately drives >80% of CF patients’ morbidity and mortality [155].…”

Section: Clinical and In Vivo Research On The Health Effects Of Scn−mentioning

confidence: 99%

Biochemical mechanisms and therapeutic potential of pseudohalide thiocyanate in human health

Chandler

Day

2015

Free Radical Research

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Thiocyanate (SCN−) is an ubiquitous molecule in mammalian biology, reaching up to mM concentrations in extracellular fluids. Two-electron oxidation of SCN− by H2O2 produces hypothiocyanous acid (HOSCN), a potent antimicrobial species. This reaction is catalyzed by chordate peroxidases (e.g., myeloperoxidase and lactoperoxidase), occurring in human secretory mucosa, including the oral cavity, airway and alimentary tract, and regulates resident and transient flora as part of innate immunity. Increasing SCN− levels limits the concentrations of a family of 2-electron oxidants (H2O2, hypohalous acids and haloamines) in favor of HOSCN formation, altering the oxidative impact on host tissue by substitution of repairable thiol and selenol oxidations instead of biomolecule degradation. This fine-tuning of inflammatory oxidation paradoxically associates with maintained host defense and decreased host injury during infections, due in part to phylogenetic differences in the thioredoxin reductase system between mammals and their pathogens. These differences could be exploited by pharmacologic use of SCN−. Recent preclinical studies have identified antimicrobial and anti-inflammatory effects of SCN− in pulmonary and cardiovascular animal models, with implications for treatment of infectious lung disease and atherogenesis. Further research is merited to expand on these findings and identify other diseases where SCN− may be of use. High oral bioavailability and an increased knowledge of the biochemical effects of SCN− on a subset of pro-inflammatory reactions suggest clinical utility.

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Serine Proteases Degrade Airway Mucins in Cystic Fibrosis

Cited by 54 publications

References 46 publications

Secretion of Proteases by an Opportunistic Fungal Pathogen Scedosporium aurantiacum

Secretion of Proteases by an Opportunistic Fungal Pathogen Scedosporium aurantiacum

Mechanosensitive ATP Release Maintains Proper Mucus Hydration of Airways

Biochemical mechanisms and therapeutic potential of pseudohalide thiocyanate in human health

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