How Much Do We Know about Atopic Asthma： Where Are We Now？

Asthma is a common disease in the worldwide and it affects over 3.5 million adults and children in the UK. Asthma is a chronic disease characterized by airway hyperresponsiveness, airway inflammation, airway remodelling and reversible airway obstruction. Inflammatory cells, cytokines, chemokines, adhesion molecules, and mediators are involved in pathogenesis of asthma. Chronic airway inflammation and remodelling are the major characters in asthma, which result in decreased pulmonary function. The precise processes are far understood at moment. Although corticosteroid therapy plus other exiting drugs （bronchodilators and oral leukotriene receptor antagonists） influences many different inflammatory and structural cell types and continues to be as the ＂gold standard＂ of therapy in asthma, many thousands have chronic, severe diseases and suffer daily symptoms which make their lives a misery. There remains a clear need for novel approaches to therapy, which will be informed by a clearer understanding of disease pathogenesis, particularly in the target organ where airway inflammation and remodelling, the hallmarks of asthma occur. Cellular ＆ Molecular Immunology.     

Inhibition of NF-κB Expression and Allergen-induced Airway Inflammation in a Mouse Allergic Asthma Model by Andrographolide

Andrographolide from traditional Chinese herbal medicines previously showed it possesses a strong anti- inflammatory activity. In present study, we investigated whether Andrographolide could inhibit allergen-induced airway inflammation and airways hyper-responsiveness and explored the mechanism of Andrographolide on allergen-induced airway inflammation and airways hyper-responsiveness. After sensitized and challenged by ovalbumin, the BALB/c mice were administered intraperitoneally with Andrographolide. Hyper-responsiveness was recorded. The lung tissues were assessed by histological examinations. NF-κB in lung was determined by immunofluorescence staining and Western blotting. Treatment of mice with Androqrapholide displayed lower Penh in response to asthma group mice. After treatment with Andrographolide, the extent of inflammation and cellular infiltration in the airway were reduced. Andrographolide interrupted NF-κB to express in cell nucleus. The level of NF-κB expression was inhibited by Andrographolide. The data indicate that Andrographolide from traditional Chinese herbal medicines could inhibit extensive infiltration of inflammatory cells in lung and decrease airway hyperreactivity. Andrographolide could inhibit NF-κB expression in lung and suppress NF-κB expressed in the nucleus of airway epithelial cells.     

The role of chemokines in acute and chronic hepatitis C infection

Hepatitis C imposes a significant burden on global healthcare. Chronic infection is associated with progressive inflammation of the liver which typically manifests in cirrhosis, organ failure and cancer. By virtue of elaborate evasion strategies, hepatitis C virus （HCV） succeeds as a persistent human virus. It has an extraordinary capacity to subvert the immune response enabling it to establish chronic infections and associated liver disease. Chemokines are low molecular weight chemotactic peptides that mediate the recruitment of inflammatory cells into tissues and back into the lymphatics and peripheral blood. Thus, they are central to the temporal and spatial distribution of effector and regulatory immune cells. The interactions between chemokines and their cognate receptors help shape the immune response and therefore, have a major influence on the outcome of infection. However, chemokines represent a target for modulation by viruses including the HCV. HCV is known to modulate chemokine expression in vitro and may therefore enable its survival by subverting the immune response in vivo through altered leukocyte chemotaxis resulting in impaired viral clearance and the establishment of chronic low-grade inflammation. In this review, the roles of chemokines in acute and chronic HCV infection are described with a particular emphasis placed on chemokine modulation as a means of immune subversion. We provide an in depth discussion of the part played by chemokines in mediating hepatic fibrosis while addressing the potential applications for these chemoattractants in prognostic medicine.     

Therapeutic effects of DNA vaccine on allergen-induced allergic airway inflammation in mouse model

Vaccination with DNA encoding Dermatophagoides pteronyssinus group 2 （Der p 2） allergen previously showed its effects of immunologic protection on Der p 2 allergen-induced allergic airway inflammation in mice. In present study, we investigated whether DNA vaccine encoding Der p 2 could exert therapeutic role on allergen-induced allergic airway inflammation in mouse model and explored the mechanism of DNA vaccination in asthma specific-allergen immunotherapy. After sensitized and challenged by Der p 2, the BALB/c mice were immunized with DNA vaccine. The degrees of cellular infiltration were scored. IgE levels in serum and IL-4/IL-13 levels in BALF were determined by ELISA. The lung tissues were assessed by histological examinations. Expressions of STAT6 and NF-kB in lung were determined by immunohistochemistry staining. Vaccination of mice with DNA vaccine inhibited the development of airway inflammation and the production of mucin induced by allergen, and reduced the level of Der p 2-specific IgE level. Significant reductions of eosinophil infiltration and levels of IL-4 and IL-13 in BALF were observed after vaccination. Further more, DNA vaccination inhibited STAT6 and NF-kB expression in lung tissue in Der p 2-immunized mice. These results indicated that DNA vaccine encoding Der p 2 allergen could be used for therapy of allergen-induced allergic airway inflammation in our mouse model. Cellular ＆ Molecular Immunology.     

聚偏氟乙烯中空纤维血液透析器的研究

Objective Currently applied membrane materials for hemodialysis are mainly polysulfone and polyethers. However, defects still remain in the removal of β2-MG and biocompatibility. Polyvinylidene fluoride (PVDF) has not been put in use in hemodialysis. This study focused on the evaluation of mechanics performance and the dialysis performance of PVDF membrane material. Methods PVDF hollow fiber membranes were spun by changing the membrane forming conditions. The membranes were sealed to dialyzers by centrifugal moulding method. The simulation solution, instead of patient blood, was used to evaluate the dialysis performance of PVDF hollow fiber membrane dialyzers. Results The tensile failure strength of PVDF membrane was about 20 cN. The tensile elongation of PVDF membrane was about 200%. The clearance rates of the dialyzers prepared with the fiber whose wall thickness was 30μ m to urea and lysozyme were 90% and 75%, separately,while the rejection to BAS reached 90% above. With the mass content of (polyethylene glycol, PEG) was 19%,the rejection rate of bovine serum was 91%, which was higher than that with the PEG mass content of 22%. When the flow velocity of dialysis fluid was increased, the clearance rate of urea and lysozyme was improved, but the rejection of BAS was not much affected. Conclusion The results show that the mechanics performance can satisfy the demand of dialysis. The clearance rate of urea and lysozyme has greatly improved. The retention of bovine serum albumin by using PVDF dialyzers is ideal. The PVDF can be exploited as a new membrane material.     

The immune response induced by hepatitis B virus principal antigens

Hepatitis B virus （HBV） infection occurs primarily in hepatocytes in the liver with release of infectious virions and non-infectious empty surface antigen particles into the bloodstream. HBV replication is non-cytopathic. Transient infections run a course of several months, and chronic infections are often life-long. Chronic infections can lead to liver failure with cirrhosis and hepatocellniar carcinoma. It is generally accepted that neutralizing anti-HBs antibodies plays a key role in recovery from HBV infection by containing the spread of infection in the infected host and facilitating the removal and destruction of viral particles. However, the immune response initiated by the T-cell response to viral antigens is also important for viral clearance and disease pathogenesis in HBV infection. The three structural forms of the viral proteins, the HBsAg, the particulate HBcAg, and the nonparticulate HBeAg, may preferentially elicit different Th cell subsets. The different IgG subclass profiles of anti-HBs, anti-HBc, and anti-HBe in different HBV infection status were revealed. Moreover, the different IgG subclass profiles in chronic carriers did not change with different ALT and AST levels and may reflect the difference between stimulating antigens, immune response, and the stages of viral disease and provide the basis for the use of vaccines and prophylactic treatments for individuals at high risk of human HBV infection. This review elucidates the detailed understanding of the immune responses induced during transient and persistent infection, and the development of immunotherapy and immunodiagnosis in patients with HBV infection, and possible means of reducing the liver damage.     

Extracellular vesicles in chronic periodontitis北大核心

BACKGROUND: Extracellular vesicles can control the inflammatory response by participating in immunomodulation of intercellular signaling, while also repairing periodontal tissue and promoting periodontal tissue regeneration. The application of this technology to the preventive diagnosis and tissue regeneration of chronic periodontitis is expected to become a method of cell-free tissue regeneration. OBJECTIVE: To review the synthesis and secretion of extracellular vesicles, biological function, relationship with chronic periodontitis, and recent advances in the diagnosis, prevention and treatment of chronic periodontitis. METHODS: The first author applied the computer to search for relevant studies involving extracellular vesicles in the prevention and treatment of chronic periodontitis in databases such as PubMed, Web of Science and CNKI. The search keywords were “extracellular vesicle, exosome, periodontal disease, immunomodulatory, outermembrane vesicles, bone regeneration” in Chinese and English. The retrieval time was from April 2014 to October 2021. RESULTS AND CONCLUSION: Extracellular vesicles are balloon-like bodies that can be produced by almost all cells, which are widely present in various body fluids, and are rich in proteins, lipids and genetic material on the surface, which affect the biological behavior of target cells by mediating information transfer between cells. On the one hand, the inflammatory response of chronic periodontitis is inseparable from the mediation of extracellular vesicles secreted by bacteria, which can be used as a biomarker to diagnose and evaluate chronic periodontitis; on the other hand, the new chronic periodontitis vaccine made by extracellular vesicles has initially been effective, and the extracellular vesicles containing information molecules can also participate in regulating the immune response and promoting the repair and regeneration of periodontal tissue. Therefore, in the field of tissue damage repair and regeneration of chronic periodontitis, extracellular vesicles are a new and potential cell-free therapy, but their extraction, purification and safety are still challenges to be overcome before clinical translation. © 2023, Publishing House of Chinese Journal of Tissue Engineering Research. All rights reserved.     

The Clinical Randomized Controlled Trial on the Safety and Efficacy of Polyethersulfone Membrane Dialyzer in the Maintenance of Hemodialysis Patients

Objective:To observe the safety and efficacy of polyethersulfone membrane dialyzer used by chronic renal failure patients in clinical maintenance hemodialysis(MHD).Methods:From January to February 2009,36 patients were recruited from Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.The experiment was approved by the ethnical committee of Xinhua Hospital and under permissions from patients.All the patients were randomized into polyethersulfone group(PES,n=18) and polysulfone group(PS,n=18).Hemodialysis was given by using Fresenius 4008S capacity-controlled dialyser and ultra-purified bicarbonate dialysate,more than 3.5 h each time,three times per-week,followed by heparin anticoagulation for a week,three times totally.Changes in blood urea nitrogen(BUN),serum creatinine(Scr),phosphate(P2+),hemoglobin and albumin levels were determined for the efficacy and safety evaluation.Results:The serum BUN,Scr and P2+ concentrations significantly reduced after hemodialysis with different dialyzers,and the decrease amplitude of two groups was equivalent(P0.05).The clearance rate of the serum BUN and Scr had no significant difference among two groups(P0.05).The clearance rate(ml/min) of the serum P2+ was 144.57±27.83 v.s.117.15±22.77 in two groups.The clearance rate of the serum P2+ in PES group was more than that in PS group,and the difference was significant between two groups(P=0.0001).It was indicated that PES and PS membrane could efficiently eliminate serum micromolecule solute in MHD patients,so PES membrane excelled PS membrane in eliminating serum P2+.The hemodialysis safety index,for example serum hemoglobin,albumin and blood pressure,had no significant difference between the two groups before and after hemodialysis(P0.05).Conclusion:The efficacy and safety of the PES hollow fiber membrane dialyzer is equivalent to that of the imported PS membrane dialyzer in hemodialysis for MHD patients.The PES membrane excels PS membrane in eliminating serum P2+.     

Association of KIR Genotypes and Haplotypes with Susceptibility to Chronic Hepatitis B Virus Infection in Chinese Han Population

Killer immunoglobulin-like receptor （KIR） genes can regulate the activation of NK and T cells upon interaction with HLA class I molecules. Hepatitis B virus （HBV） infection has been regarded as a multi-factorial disorder disease. Previous studies revealed that KIRs were involved in HCV and HIV infection or clearance. The aim of this study was to explore the possibility of the inheritance of KIR genotypes and haplotypes as a candidate for susceptibility to persistent HBV infection or HBV clearance. The sequence specific primer polymerase chain reaction （SSP-PCR） was employed to identify the KIR genes and pseudogenes in 150 chronic hepatitis B （CHB） patients, 251 spontaneously recovered （SR） controls, and 412 healthy controls. The frequencies of genotype G7 M, FZ1 increased in CHB patients compared with healthy control subjects. The frequency of genotype AH was higher in SR controls than that in both CHB patients and healthy controls. The carriage frequencies of genotype G and AH were higher; while, the frequencies of AF and AJ were lower in SR controls than those in healthy control subjects. The frequency of A haplotype was lower, whereas, the frequency of B haplotype was higher in CHB patients and SR controls than those in healthy controls. In healthy controls, haplotype 4 was found lower compared with that in CHB patients and SR controls and the frequency of haplotype 5 was higher in SR controls than that in other two groups. Based on these findings, it seems that the genotypes M and FZ1 are HBV susceptive genotypes; AH, on the other hand, may be protective genotypes that facilitate the clearance of HBV. It appears that the haplotype 4 is HBV susceptive haplotype, whereas, haplotype 5 may be the protective haplotype that facilitates the clearance of HBV. Cellular ＆ Molecular Immunology. 2008;5（6）：457-463.     

Atomization inhalation of terbutaline and budesonide efficiently improved immunity and lung function of AECOPD patients

Chronic obstructive pulmonary disease （COPD） is a syndrome of chronic progressive airflow limitation as a result of chronic inflammation of the airways and lung parenchyma. COPD patients always have airway hyperreactivity （AHR）, so how to reduce AHR becomes the key purpose of clinical treatment. It is hypothesized that combined inhalation of corticosteroids and β2-agonists can reduce the AHR in COPD. In this study, atomization inhalation of budesonide and terbutaline plus conventional therapies was applied to treat AECOPD （acute exacerbation of chronic obstructive pulmonary disease） patients for two weeks. The results showed that additional inhalation of budesonide and terbutaline could upregulate serum IL-2 levels, the percentages of CD3^＋ T and CD4^＋ T cells, and CD4/CD8 ratio, and decrease eosinophils and serum CRP level more efficiently than conventional treatment in patients with AECOPD. And the lung function of the atomization inhalation group was improved more obviously after the treatment compared with the conventional treatment group. Thus, atomization inhalation of terbutaline and budesonide can control AECOPD effectively, and has wide clinical perspective in controlling and preventing the exacerbation of COPD. Cellular ＆ Molecular Immunology. 2008;5（4）：287-291.     

Pathophysiology of chronic, bronchial hypersecretion (author's transl)]

The biochemical and rheological analysis of sputum allows one to detect abnormalities of the bronchial secretion and to describe the development of the bronchial disease. The main biochemical components of sputum and their biological activities are first described. The fibrillar structure of the mucus is related to heavy weight glycoproteins and these macromolecules contribute to the viscoelastic properties of the bronchial secretion, by their capacity to combine with other proteins such as secretory immunoglobulin A (S-IgA). As the chronic bronchial hypersecretory state progresses, the glandular synthesis of mucins and/or secretory proteins decreases while the passive filtration of blood-derived proteins, such as serumalbumin, increases. Such biochemical changes are frequently associated with a rise in viscosity and a loss in elasticity of sputum. These rheological modifications result in an impairment of the mucociliary clearance and therefore contribute to airway obstruction. The assessment of different indices such as the equilibrium in mucin secretion, S-IgA/serum-albumin ratio, viscosity and elasticity of sputum and its mucociliary transport rate, should lead to a better knowledge of the defense properties of the bronchial mucosa.     

Respiratory tract mucin genes and mucin glycoproteins in health and disease

This review focuses on the role and regulation of mucin glycoproteins (mucins) in airway health and disease. Mucins are highly glycosylated macromolecules (> or =50% carbohydrate, wt/wt). MUC protein backbones are characterized by numerous tandem repeats that contain proline and are high in serine and/or threonine residues, the sites of O-glycosylation. Secretory and membrane-tethered mucins contribute to mucociliary defense, an innate immune defense system that protects the airways against pathogens and environmental toxins. Inflammatory/immune response mediators and the overproduction of mucus characterize chronic airway diseases: asthma, chronic obstructive pulmonary diseases (COPD), or cystic fibrosis (CF). Specific inflammatory/immune response mediators can activate mucin gene regulation and airway remodeling, including goblet cell hyperplasia (GCH). These processes sustain airway mucin overproduction and contribute to airway obstruction by mucus and therefore to the high morbidity and mortality associated with these diseases. Importantly, mucin overproduction and GCH, although linked, are not synonymous and may follow from different signaling and gene regulatory pathways. In section i, structure, expression, and localization of the 18 human MUC genes and MUC gene products having tandem repeat domains and the specificity and application of MUC-specific antibodies that identify mucin gene products in airway tissues, cells, and secretions are overviewed. Mucin overproduction in chronic airway diseases and secretory cell metaplasia in animal model systems are reviewed in section ii and addressed in disease-specific subsections on asthma, COPD, and CF. Information on regulation of mucin genes by inflammatory/immune response mediators is summarized in section iii. In section iv, deficiencies in understanding the functional roles of mucins at the molecular level are identified as areas for further investigations that will impact on airway health and disease. The underlying premise is that understanding the pathways and processes that lead to mucus overproduction in specific airway diseases will allow circumvention or amelioration of these processes.     

Role of mechanical stress in regulating airway surface hydration and mucus clearance rates

Effective clearance of mucus is a critical innate airway defense mechanism, and under appropriate conditions, can be stimulated to enhance clearance of inhaled pathogens. It has become increasingly clear that extracellular nucleotides (ATP and UTP) and nucleosides (adenosine) are important regulators of mucus clearance in the airways as a result of their ability to stimulate fluid secretion, mucus hydration, and cilia beat frequency (CBF). One ubiquitous mechanism to stimulate ATP release is through external mechanical stress. This article addresses the role of physiologically relevant mechanical forces in the lung and their effects on regulating mucociliary clearance (MCC). The effects of mechanical forces on the stimulating ATP release, fluid secretion, CBF, and MCC are discussed. Also discussed is evidence suggesting that airway hydration and stimulation of MCC by stress-mediated ATP release may play a role in several therapeutic strategies directed at improving mucus clearance in patients with obstructive lung diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).     

Repeated stress reduces mucociliary clearance in animals with chronic allergic airway inflammation

We evaluated if repeated stress modulates mucociliary clearance and inflammatory responses in airways of guinea pigs (GP) with chronic inflammation. The GP received seven exposures of ovalbumin or saline 0.9%. After 4th inhalation, animals were submitted to repeated forced swim stressor protocol (5×/week/2 weeks). After 7th inhalation, GP were anesthetized. We measured transepithelial potential difference, ciliary beat frequency, mucociliary transport, contact angle, cough transportability and serum cortisol levels. Lungs and adrenals were removed, weighed and analyzed by morphometry. Ovalbumin-exposed animals submitted to repeated stress had a reduction in mucociliary transport, and an increase on serum cortisol, adrenals weight, mucus wettability and adhesivity, positive acid mucus area and IL-4 positive cells in airway compared to non-stressed ovalbumin-exposed animals (p < 0.05). There were no effects on eosinophilic recruitment and IL-13 positive cells. Repeated stress reduces mucociliary clearance due to mucus rheological-property alterations, increasing acid mucus and its wettability and adhesivity. These effects seem to be associated with IL-4 activation.     

The innate immune properties of airway mucosal surfaces are regulated by dynamic interactions between mucins and interacting proteins: the mucin interactome

Chronic lung diseases such as cystic fibrosis, chronic bronchitis, and asthma are characterized by hypersecretion and poor clearance of mucus, which are associated with poor prognosis and mortality. Little is known about the relationship between the biophysical properties of mucus and its molecular composition. The mucins MUC5B and MUC5AC are traditionally believed to generate the characteristic biophysical properties of airway mucus. However, the contribution of hundreds of globular proteins to the biophysical properties of mucus is not clear. Approximately one-third of the total mucus proteome comprises distinct, multi-protein complexes centered around airway mucins. These complexes constitute a discrete entity we call the “mucin interactome”. The data suggest that while the majority of these proteins interact with mucins via electrostatic and weak interactions, some interact through very strong hydrophobic and/or covalent interactions. Using reagents that interfere with protein–protein interactions, the complexes can be disassembled, and mucus rheology can be dramatically altered. Using MUC5B–glutathione S-transferase (GST) and MUC5B–galectin-3 as a representative of these interactions, we provide evidence that individual mucin protein interactions can alter the biophysical properties of mucus and modulate the biological function of the protein. We propose that the key mechano- and bio-active functions of mucus depend on the dynamic interactions between mucins and globular proteins. These observations challenge the paradigm that mucins are the only molecules that confer biophysical properties of mucus. These observations may ultimately lead to a greater understanding of the system and guide the development of strategies for more effective interventions using better therapeutic agents.     

Mucociliary clearance--a critical upper airway host defense mechanism and methods of assessment

PURPOSE OF REVIEW: Mucociliary clearance is a critical host defense mechanism of the airways. Effective mucociliary clearance requires appropriate mucus production and coordinated ciliary activity. The important role of these two components is best demonstrated in disorders such as primary ciliary dyskinesia and cystic fibrosis, both of which lead to lifelong recurrent respiratory tract infections. We review the methods used to analyze mucociliary clearance. RECENT FINDINGS: Utilization of microdialysis probes has improved temporal resolution of mucociliary clearance in murine airways, availing many genetic mouse models to critical mucociliary clearance analysis, while improved fixation technique for transmission electron microscopy has allowed for detailed resolution of the airway surface liquid. High-speed digital video analysis has improved quantification of ciliary beat frequency while advancements in air-liquid interface culturing techniques have generated in-vitro models to investigate mucociliary clearance. SUMMARY: Advancements in techniques for analysis of mucociliary clearance have improved our understanding of the interaction between the respiratory epithelium and the airway surface liquid, resulting in the ability to study pathologic processes involving mucociliary clearance in great detail.     

Exogenous surfactant therapy and mucus rheology in chronic obstructive airway diseases

Exogenous surfactant is a specialized biomaterial used for substitution of the lipoprotein mixture normally present in the lungs-pulmonary surfactant. Respiratory Distress Syndrome is a disease of preterm infants mainly caused by pulmonary immaturity as evidenced by a deficiency of mature lung surfactant. Pulmonary surfactant is known to stabilize small alveoli and prevent them from collapsing during expiration. However, apart from alveoli, surfactant also lines the narrow conducting airways of the tracheobronchial tree. This paper reviews the role of this surfactant in the airways and its effect on mucus rheology and mucociliary clearance. Its potential role as a therapeutic biomaterial in chronic obstructive airway diseases, namely asthma, chronic bronchitis, and respiratory manifestations of cystic fibrosis, are discussed. This paper also attempts to elucidate the exact steps in the pathogenic pathway of these diseases which could be reversed by supplementation of exogenous surfactant formulations. It is shown that there is great potential for the use of present day surfactants (which are actually formulated for use in Respiratory Disease Syndrome) as therapy in the aforementioned diseases of altered mucus viscoelasticity and mucociliary clearance. However, for improved effectiveness, specific surfactant formulations satisfying certain specific criteria should be tailor-made for the clinical condition for which they are intended. The properties required to be fulfilled by the optimal exogenous surfactant in each of the above clinical conditions are enumerated in this paper.     

Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease

Airway diseases, including cigarette smoke-induced chronic bronchitis, cystic fibrosis, and primary ciliary dyskinesia are associated with decreased mucociliary clearance (MCC). However, it is not known whether a simple reduction in MCC or concentration-dependent mucus adhesion to airway surfaces dominates disease pathogenesis or whether decreasing the concentration of secreted mucins may be therapeutic. To address these questions, Scnn1b-Tg mice, which exhibit airway mucus dehydration/adhesion, were compared and crossed with Muc5b- and Muc5ac-deficient mice. Absence of Muc5b caused a 90% reduction in MCC, whereas Scnn1b-Tg mice exhibited an ∼50% reduction. However, the degree of MCC reduction did not correlate with bronchitic airway pathology, which was observed only in Scnn1b-Tg mice. Ablation of Muc5b significantly reduced the extent of mucus plugging in Scnn1b-Tg mice. However, complete absence of Muc5b in Scnn1b-Tg mice was associated with increased airway inflammation, suggesting that Muc5b is required to maintain immune homeostasis. Loss of Muc5ac had few phenotypic consequences in Scnn1b-Tg mice. These data suggest that: (i) mucus hyperconcentration dominates over MCC reduction alone to produce bronchitic airway pathology; (ii) Muc5b is the dominant contributor to the Scnn1b-Tg phenotype; and (iii) therapies that limit mucin secretion may reduce plugging, but complete Muc5b removal from airway surfaces may be detrimental.     

Serine proteases degrade airway mucins in cystic fibrosis

Airway mucins are the major molecular constituents of mucus. Mucus forms the first barrier to invading organisms in the airways and is an important defense mechanism of the lung. We confirm that mucin concentrations are significantly decreased in airway secretions of subjects with cystic fibrosis (CF) who have chronic Pseudomonas aeruginosa infection. In sputum from CF subjects without a history of P. aeruginosa, we found no significant difference in the mucin concentration compared to mucus from normal controls. We demonstrate that mucins can be degraded by synthetic human neutrophil elastase (HNE) and P. aeruginosa elastase B (pseudolysin) and that degradation was inhibited by serine proteases inhibitors (diisopropyl fluorophosphates [DFP], phenylmethylsulfonyl fluoride [PMSF], and 1-chloro-3-tosylamido-7-amino-2-heptanone HCl [TLCK]). The mucin concentration in airway secretions from CF subjects is similar to that for normal subjects until there is infection by P. aeruginosa, and after that, the mucin concentration decreases dramatically. This is most likely due to degradation by serine proteases. The loss of this mucin barrier may contribute to chronic airway infection in the CF airway.