Cystic Fibrosis Airway Mucus Hyperconcentration Produces a Vicious Cycle of Mucin, Pathogen, and Inflammatory Interactions that Promotes Disease Persistence

Batson, Bethany D.; Zorn, Bryan; Radicioni, Giorgia; Livengood, Stephanie; Kumagai, Tadashi; Dang, Hong; Ceppe, Agathe; Clapp, Phillip W.; Tunney, Michael; Elborn, Stuart; McElvaney, Gerry; Muhlebach, Marianne S.; Boucher, Richard C.; Tiemeyer, Michael; Wolfgang, Matthew C.; Kesımer, Mehmet

doi:10.1165/rcmb.2021-0359oc

Cited by 23 publications

(37 citation statements)

References 52 publications

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“…It is assumed that MUC5AC sticks more to the surface epithelium and also coats the MUCB mucin bundles [ 43 , 44 ]. The ratio of MUC5AC/MUC5B is about 0.1 in sputum [ 45 ] and 0.3 in BAL fluid, respectively [ 17 ]. As particularly MUC5AC expression is strongly up-regulated by immune reactions of both the Th1 and Th2 type, it is the major cause of problems in obstructive lung diseases [ 35 , 43 ].…”

Section: Introductionmentioning

confidence: 99%

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Different Molecular Forms of TFF3 in the Human Respiratory Tract: Heterodimerization with IgG Fc Binding Protein (FCGBP) and Proteolytic Cleavage in Bronchial Secretions

Weste

Houben

Harder

et al. 2022

IJMS

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The polypeptide TFF3 belongs to the trefoil factor family (TFF) of lectins. TFF3 is typically secreted from mucous epithelia together with mucins. Both intestinal and salivary TFF3 mainly exist as disulfide-linked heterodimers with IgG Fc binding protein (FCGBP). Here, we investigated bronchial tissue specimens, bronchial secretions, and bronchoalveolar lavage (BAL) fluid from patients with a chronic obstructive pulmonary disease (COPD) background by fast protein liquid chromatography and proteomics. For the first time, we identified different molecular forms of TFF3 in the lung. The high-molecular mass form represents TFF3-FCGBP oligomers, whereas the low-molecular mass forms are homodimeric and monomeric TFF3 with possibly anti-apoptotic activities. In addition, disulfide-linked TFF3 heterodimers with an Mr of about 60k and 30k were detected in both bronchial secretions and BAL fluid. In these liquids, TFF3 is partly N-terminally truncated probably by neutrophil elastase cleavage. TFF3-FCGBP is likely involved in the mucosal innate immune defense against microbial infections. We discuss a hypothetical model how TFF3 might control FCGBP oligomerization. Furthermore, we did not find indications for interactions of TFF3-FCGBP with DMBT1gp340 or the mucin MUC5AC, glycoproteins involved in mucosal innate immunity. Surprisingly, bronchial MUC5AC appeared to be degraded when compared with gastric MUC5AC.

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Section: Introductionmentioning

confidence: 99%

“…As particularly MUC5AC expression is strongly up-regulated by immune reactions of both the Th1 and Th2 type, it is the major cause of problems in obstructive lung diseases [ 35 , 43 ]. For example, the MUC5AC/MUC5B ratio is raised to 1.5 in the BAL fluid of asymptomatic smokers [ 17 ] and 0.4 in the sputum of CF patients [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

Different Molecular Forms of TFF3 in the Human Respiratory Tract: Heterodimerization with IgG Fc Binding Protein (FCGBP) and Proteolytic Cleavage in Bronchial Secretions

Weste

Houben

Harder

et al. 2022

IJMS

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“…MUC5AC/B secretion increased during CF as did mucus viscoelasticity [ 183 ]. Many studies demonstrated that more sialylated and less sulfated airway-mucus qualities modify microbial features [ 156 ]. To sum up, we have grounds to assume that CF immune surveillance and immunotherapy offer a rationale for the treatment approach.…”

Section: Mucus Abnormalities and Diseasementioning

confidence: 99%

View from the Biological Property: Insight into the Functional Diversity and Complexity of the Gut Mucus

Gao

Xin

et al. 2023

IJMS

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Due to mucin’s important protective effect on epithelial tissue, it has garnered extensive attention. The role played by mucus in the digestive tract is undeniable. On the one hand, mucus forms “biofilm” structures that insulate harmful substances from direct contact with epithelial cells. On the other hand, a variety of immune molecules in mucus play a crucial role in the immune regulation of the digestive tract. Due to the enormous number of microorganisms in the gut, the biological properties of mucus and its protective actions are more complicated. Numerous pieces of research have hinted that the aberrant expression of intestinal mucus is closely related to impaired intestinal function. Therefore, this purposeful review aims to provide the highlights of the biological characteristics and functional categorization of mucus synthesis and secretion. In addition, we highlight a variety of the regulatory factors for mucus. Most importantly, we also summarize some of the changes and possible molecular mechanisms of mucus during certain disease processes. All these are beneficial to clinical practice, diagnosis, and treatment and can provide some potential theoretical bases. Admittedly, there are still some deficiencies or contradictory results in the current research on mucus, but none of this diminishes the importance of mucus in protective impacts.

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“…Furthermore, investigations of lung inflammation in CF have demonstrated an overwhelming burden of neutrophilic mediators in both bronchoalveolar lavage (BAL) and sputum [ 5 ]. The coexistence of both CF and AAT deficiency lung diseases can sustain a vicious vortex of airway inflammation, infection, and structural damage, leading to negative outcomes [ 6 ]. AAT deficiency is one of the commonest hereditary disorders among Caucasians, and its prevalence has been reported to vary greatly across regions.…”

Section: Introductionmentioning

confidence: 99%

Genetic and Serum Screening for Alpha-1-Antitrypsin Deficiency in Adult Patients with Cystic Fibrosis: A Single-Center Experience

et al. 2022

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Cystic fibrosis (CF) and alpha-1 antitrypsin (AAT) deficiency are two of the commonest genetic diseases affecting the Caucasian population. Neutrophil-mediated inflammation due to protease–antiprotease imbalance leads to progressive pulmonary involvement in both diseases. The aim of this study was to investigate the prevalence of AAT deficiency in CF adults. A prospective study enrolling CF adults was conducted at the Adult CF Center based in Milan from January 2018 to March 2019. Patients were tested for AAT serum protein quantification and expanded genotyping characterization of SERPINA1 during clinical stability. Genotyping characterization of SERPIN1 was compared to a control population of 2848 Caucasian individuals with the same geographical origin and similar demographic characteristics. Among 173 patients included in the study, the prevalence of AAT deficiency was 0. Genotype analysis was piMM in 166 (94.9%) patients and piMS in 9 patients (5.1%), respectively. No differences in terms of genotype characterization were found between the CF population and the control population. These data show that AAT deficiency is not common among adults with CF.

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Cystic Fibrosis Airway Mucus Hyperconcentration Produces a Vicious Cycle of Mucin, Pathogen, and Inflammatory Interactions that Promotes Disease Persistence

Cited by 23 publications

References 52 publications

Different Molecular Forms of TFF3 in the Human Respiratory Tract: Heterodimerization with IgG Fc Binding Protein (FCGBP) and Proteolytic Cleavage in Bronchial Secretions

Different Molecular Forms of TFF3 in the Human Respiratory Tract: Heterodimerization with IgG Fc Binding Protein (FCGBP) and Proteolytic Cleavage in Bronchial Secretions

View from the Biological Property: Insight into the Functional Diversity and Complexity of the Gut Mucus

Genetic and Serum Screening for Alpha-1-Antitrypsin Deficiency in Adult Patients with Cystic Fibrosis: A Single-Center Experience

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