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Bicarbonate Effects on Antibacterial Immunity and mucus Glycobiology in the Cystic Fibrosis Lung:A Review With Selected Experimental Observations

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Infectious Microbes & Diseases 2022年第3期4卷 103-110页

作者： Ruth Siew Tzung-Lin Ou Samira Dahesh Kathryn Akong Victor Nizet Department of Pediatrics University of California San DiegoLa JollaCaliforniaUSA School of Medicine China Medical UniversityTaichungTaiwan Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San DiegoLa JollaCaliforniaUSA

The primary defect in cystic fibrosis(CF)is abnormal chloride and bicarbonate transport in the CF transmembrane conductance regulator epithelial ion channel.The apical surface of the respiratory tract is lined by an airway surface liquid(ASL)layer composed of mucin comprising mainly MUC5A and MUC5B glycoproteins.ASL homeostasis depends on sodium bicarbonate secretion into the airways and secretion deficits alter mucus properties leading to airway obstruction,inflammation and infections.Downstream effects of abnormal ion transport in the lungs include altered intrinsic immune defenses.We observed that neutrophils killed Pseudomonas aeruginosa more efficiently when it had been exposed to sodium bicarbonate,and formation of neutrophil extracellular traps by neutrophils was augmented in the presence of increasing bicarbonate concentrations.Physiological levels of bicarbonate sensitized P.aeruginosa to the antimicrobial peptide cathelicidin LL-37,which is present in both lung ASL and neutrophil extracellular traps.Sodium bicarbonate has various uses in clinical medicine and in the care of CF patients and could be further explored as a therapeutic adjunct against Pseudomonas infections.

关键词： cystic fibrosis bicarbonate mucus pneumonia bacterial infection neutrophil cathelicidin neutrophil extracellular traps

Rosuvastatin attenuates mucus secretion in a murine model of chronic asthma by inhibiting the gamma-aminobutyric acid type A receptor

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Chinese Medical Journal 2012年第8期125卷 1457-1464页

作者： ZHU Tao ZHANG Wei WANG Dao-xin HUANG Ni-wen BO Hong DENG Wang DENG Jia Department of Respiratory Medicine Second Affiliated Hospital ofChongqing Medical University Chongqing 400010 China Department of Respiratory Medicine West China Hospital Sichuan UniversityChengdu Sichuan 610041 China Departemnt ofNephrology West China Hospital Sichuan UniversityChengdu Sichuan 610041 China

Background Asthma is a chronic inflammatory disease characterized by reversible bronchial constriction, pulmonary inflammation and airway remodeling. Current standard therapies for asthma provide symptomatic control, but fail to target the underlying disease pathology. Furthermore, no therapeutic agent is effective in preventing airway remodeling. A substantial amount of evidence suggests that statins have anti-inflammatory properties and immunomodulatory activity. In this study, we investigated the effect of rosuvastatin on airway inflammation and its inhibitory mechanism in mucus hypersecretion in a murine model of chronic asthma. Methods BALB/c mice were sensitized and challenged by ovalbumin to induce asthma. The recruitment of inflammatory cells into bronchoalveolar lavage fluid （BALF） and the lung tissues were measured by Diff-Quik staining and hematoxylin and eosin （H＆E） staining. ELISA was used for measuring the levels of IL-4, IL-5, IL-13 and TNF-a in BALE Periodic acid-Schiff （PAS） staining was used for mucus secretion. Gamma-aminobutyric acid type A receptor （GABAAR） β2 expression was measured by means of immunohistochemistry, reverse transcription-polymerase chain reaction （RT-PCR） and Western blotting. Results Rosuvastatin reduced the number of total inflammatory cells, lymphocytes, macrophages, neutrophils, and eosinophils recruited into BALF, the levels of IL-4, IL-5, IL-13 and TNF-a in BALF, along with the histological mucus index （HMI） and GABAAR 132 expression. Changes occurred in a dose-dependent manner. Conclusions Based on its ability to reduce the inflammatory response and mucus hypersecretion by regulating GABAAR activity in a murine model of chronic asthma, rosuvastatin may be a useful therapeutic agent for treatment of asthma.

关键词： airway remodeling asthma gamma-aminobutyric acid type A receptor β2 mucus rosuvastatin

Comparative study of mucoadhesive and mucus-penetrative nanoparticles based on phospholipid complex to overcome the mucus barrier for inhaled delivery of baicalein

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Acta Pharmaceutica Sinica B 2020年第8期10卷 1576-1585页

作者： Wujun Dong Jun Ye Junzhuo Zhou Weijue Wang Hongliang Wang Xu Zheng Yanfang Yang Xuejun Xia Yuling Liu State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China State Key Laboratory of Nonlinear Mechanics Institute of MechanicsChinese Academy of SciencesBeijing 100190China

Efficient mucosal delivery remains a major challenge for the reason of the respiratory tract mucus act as a formidable barrier to nanocarriers by trapping and clearing foreign particulates. The surface property of nanoparticles determines their retention and penetration ability within the respiratory tract mucus. However, the interaction between nanoparticles and mucus, and how these interactions impact distribution has not been extensively investigated. In this study, polymeric nanoparticles loaded with a baicalein-phospholipid complex were modified with two kinds of polymers, mucoadhesive and mucus-penetrative polymer. Systematic investigations on the physicochemical property, mucus penetration, transepithelial transport, and tissue distribution were performed to evaluate the interaction of nanoparticles with the respiratory tract. Both nanoparticles had a similar particle size and good biocompatibility, exhibited a sustained-release profile, but showed a considerable difference in zeta potential. Interestingly, mucus-penetrative nanoparticles exhibited a higher diffusion rate in mucus, deeper penetration across the mucus layer, enhanced in vitro cellular uptake, increased drug distribution in airways, and superior local distribution and bioavailability as compared to mucoadhesive nanoparticles.These results indicate the potential of mucus-penetrative nanoparticles in design of a rational delivery system to improve the efficiency of inhaled therapy by promoting mucus penetration and increasing local distribution and bioavailability.

关键词： sustained mucus barrier

Development of a physiologically relevant dripping analytical method using simulated nasal mucus for nasal spray formulation analysis

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Journal of Pharmaceutical Analysis 2016年第5期6卷 283-291页

作者： Tina Masiuk Parul Kadakia Zhenyu Wang Respiratory Product Development Merck Research Laboratories Merck & Co.Inc.

Current methods for nasal spray formulations have been elementary evaluating the dripping characteristics of a formulation and have not assessed the behavior of the nasal formulation in the presence of varying types of mucus depending on the indication or diseased state. This research investigated the effects of nasal mucus on the dripping behavior of nasal formulations and focused on developing an improved in vitro analytical test method that is more physiologically relevant in characterizing nasal formulation dripping behavior. Method development was performed using simulated nasal mucus preparations for both healthy and diseased states as coatings for the dripping experiment representing a wide range of viscosity. Factors evaluated during development of this in vitro test method included amount of mucus, application of mucus, drying times, and compatibility of the mucus on a C18 Thin Layer Chromatography(TLC) substrate. The dripping behavior of nasal formulations containing a range of 1%Avicel to 3.5% Avicel was assessed by actuating the nasal spray on a perpendicular TLC plate coated with either healthy or diseased simulated nasal mucus. After actuation of the nasal spray, the dripping of the formulation on the coated TLC plate was measured after the plate was repositioned vertically. The method that was developed generated reproducible results on the dripping behavior of nasal formulations and provided critical information about the compatibility of the formulation with the nasal mucus for different diseased states, aiding in nasal spray formulation development and physical characterization of the nasal spray.

关键词： Nasal spray Nasal spray dripping method Nasal mucus Nasal formulation dripping

Modulating intestinal mucus barrier for nanoparticles penetration by surfactants

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Asian Journal of Pharmaceutical Sciences 2019年第5期14卷 543-551页

作者： Xin Zhang Wei Dong Hongbo Cheng Meixia Zhang Yongqiang Kou Jian Guan Qiaoyu Liu Mingyue Gao Xiuhua Wang ShiruiMao School of Pharmacy Shenyang Pharmaceutical UniversityShenyang110016China Laboratory of Metabolic Disease Research and Drug Development China Medical UniversityShenyang110122China

Improving peroral delivery efficiency is always a persistent goal for both small-molecule and macromolecular drug development. However,intestinal mucus barrier which greatly impedes drug-loaded nanoparticles penetration is commonly overlooked. Therefore,in this study,taking fluorescent labeled PLGA(poly(lactic-co-glycolic acid)) nanoparticles as a tool,the influence of anionic and nonionic surfactants on mucus penetration ability of nanoparticles and their mucus barrier regulating ability were studied. The movement of PLGA nanoparticles in mucus was tracked by multiple particles tracking method(MPT).Alteration of mucus properties by addition of surfactants was evaluated by rheology and morphology study. Rat intestinal villus penetration study was used to further evaluate penetration enhancement of nanoparticles. The effective diffusivities of the nanoparticles in surfactants pretreated mucus were increased by 2–3 times and the mucus barrier regulating capacity was also surfactant type dependent. Sodium dodecyl sulfate(SDS) increased the complex viscosity and viscoelastic properties of mucus,but poloxamer presented a decreased trend. Tween 80 maintained the rheological property of the mucus. With the mucus barrier regulated by surfactants,the penetration of nanoparticles in intestinal villus was obviously increased. In summary,the mucus penetration ability of nanoparticles could be enhanced by altering mucus microenvironment with surfactants. Tween 80 which largely retains the original mucus rheology and morphology properties may be a promising candidate for facilitating nanoparticle penetration through the mucus barrier with good safety profile.

关键词： mucus barrier mucus modulating agents Rheology PLGA nanoparticles Surfactants

Antimicrobial and hemolytic activity of fish epidermal mucus Cynoglossus arel and Arius caelatus

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Asian Pacific Journal of Tropical Medicine 2011年第4期4卷 305-309页

作者： Subramanian Bragadeeswaran Selvam Priyadharshini Kolandhasamy Prabhu Solomon Raj Sophia Rani Centre of Advanced Study in Marine Biology Faculty of Marine SciencesAnnamalai University

Objective:To study the antimicrobial,hemolytic activity and immunomodulatory activity of fish epidermal mucus and their chemical constituents from Cynoglossus arel(C.arel) and Alius caelatus(A.caelatus).mucus plays an important role in the prevention of colonization by parasites,bacteria and fungi.Methods:Epidermal mucus was obtained from two marine fishes,lyophilized and the chemical composition of epidermal mucus was analysed by FT-IR analysis.The in vitro antimicrobial activity against human pathogens(fungi,gram positive and gram-negative bacteria) and also the hemolytic activity and immunomodulatory activity were determined.Results:Totally ten human pathogens were tested against the fish mucus.Out of the ten pathogens,five pathogens have proved to be sensitive to the mucus.Maximum zone of inhibition was observed against Vibrio cholera(V.cholera)(9 mm and 2 mm in diameter),followed by Staphylococcus aureus(S.aureus) with a inhibition zone of(6 mm and 3 mm),Streptococcus areus(S.areus)(5 mm and 4 mm),Vibrio parahemolyticus(V.parahemolyticus)(4 mm and 5 mm) respectively.Conclusions:The present investigation has revealed that positive progresses in the fish mucus extracts against human pathogens and hemolytic activity.But further efforts are required for the purification and isolation of the active antimicrobial compounds in order to establish their possible applications.

关键词： Antibacterial activity Antifungal activity Fish mucus Cynoglossus arel Arius caelatus

The co-effect of microstructures and mucus on the adhesion of abalone from a mechanical perspective

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Biosurface and Biotribology 2021年第4期7卷 180-186页

作者： Jing Li Chuandong Ma Jun Liu Xiangwei Dong Jianlin Liu College of Mechanical and Electrical Engineering China University of Petroleum(East China)QingdaoChina College of Pipeline and Civil Engineering China University of Petroleum(East China)QingdaoChina

Reliable and reversible adhesion underwater is challenging due to the water molecules and weak layers of contaminants at the contact interface,which requires to deepen the un-derstanding of wet adhesion of biological surfaces.Herein,the co-effect of microstruc-tures and mucus of abalone foot on wet adhesion is investigated from both experimental and theoretical perspectives.The morphologies,adhesion force and coefficient of friction indicate that the mucus in adhesion zone is crucial for successful attachment of abalone based on capillary forces and viscous forces,and the mucus in non-adhesion zone with lower adhesion force and friction coefficient may behave as a lubricant for the loco-motion.The theoretical calculation manifests that the microstructures may help abalone to form multiple liquid bridges with the secreted mucus,and significantly increase the wet adhesion force of abalone.These findings will bring profound views into the underlying mechanisms of biological surface adhesion.

关键词： abalone capillary force microstructure mucus wet adhesion

Comparison of virus-capsid mimicking biologic-shell based versus polymeric-shell nanoparticles for enhanced oral insulin delivery

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Asian Journal of Pharmaceutical Sciences 2023年第5期18卷 125-135页

作者： Zhixiang Cui Shuman Cui Lu Qin Yalin An Xin Zhang Jian Guan Tin Wui Wong Shirui Mao School of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China Particle Design Research Group Faculty of PharmacyUniversiti Teknologi MARA SelangorPuncak Alam 42300Malaysia Non-Destructive Biomedical and Pharmaceutical Research Centre Smart Manufacturing Research InstituteUniversiti Teknologi MARA SelangorPuncak Alam 42300Malaysia

Virus-capsid mimicking mucus-permeable nanoparticles are promising oral insulin carriers which surmount intestinal mucus barrier.However,the impact of different viruscapsid mimicking structure remains unexplored.In this study,utilizing biotin grafted chitosan as the main skeleton,virus-mimicking nanoparticles endowed with biologicshell(streptavidin coverage)and polymeric-shell(hyaluronic acid/alginate coating)were designed with insulin as a model drug by self-assembly processes.It was demonstrated that biologic-shell mimicking nanoparticles exhibited a higher intestinal trans-mucus(>80%,10 min)and transmucosal penetration efficiency(1.6–2.2-fold improvement)than polymeric-shell counterparts.Uptake mechanism studies revealed caveolae-mediated endocytosis was responsible for the absorption of biologic-shell mimicking nanoparticles whereas polymeric-shell mimicking nanoparticles were characterized by clathrin-mediated pathway with anticipated lysosomal insulin digestion.Further,in vivo hypoglycemic study indicated that the improved effect of regulating blood sugar levels was virus-capsid structure dependent out of which biologic-shell mimicking nanoparticles presented the best performance(5.1%).Although the findings of this study are encouraging,much more work is required to meet the standards of clinical translation.Taken together,we highlight the external structural dependence of virus-capsid mimicking nanoparticles on the mucopenetrating and uptake mechanism of enterocytes that in turn affecting their in vivo absorption,which should be pondered when engineering virus-mimicking nanoparticles for oral insulin delivery.

关键词： Oral insulin Streptavidin Virus-mimicking Nanoparticles Muco-penetrating mucus

Effects of intrapulmonary percussive ventilation on airway mucus clearance: A bench model

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World Journal of Critical Care Medicine 2017年第3期6卷 164-171页

作者： Lorena Fernandez-Restrepo Lauren Shaffer Bravein Amalakuhan Marcos I Restrepo Jay Peters Ruben Restrepo Division of Pediatric Critical Care Division of Pulmonary and Critical Care and Department of Respiratory Care University of Texas Health Science Center and the South Texas Veterans Health Care System

AIM To determine the ability of intrapulmonary percussive ventilation(IPV) to promote airway clearance in spontaneously breathing patients and those on mechanical ventilation.METHODS An artificial lung was used to simulate a spontaneously breathing patient(Group 1), and was then connected to a mechanical ventilator to simulate a patient on mechanical ventilation(Group 2). An 8.5 mm endotracheal tube(ETT) connected to the test lung, simulated the patient airway. Artificial mucus was instilled into the mid-portion of the ETT. A filter was attached at both ends of the ETT to collect the mucus displaced proximally(mouth-piece filter) and distally(lung filter). The IPV machine was attached to the proximal end of the ETT and was applied for 10-min each to Group 1 and 2. After each experiment, the weight of the various circuit components were determined and compared to their dry weights to calculate the weight of the displaced mucus.RESULTS In Group 1(spontaneously breathing model), 26.8% ± 3.1% of the simulated mucus was displaced proximally, compared to 0% in Group 2(the mechanically ventilated model) with a P-value of mucus in Group 2 remained in the mid-portion of the ETT where it was initially instilled and 80% ± 4.2% was displaced distally back towards the lung(P mucusmovement proximally towards the mouth-piece in the spontaneously breathing(SB) patient. There was also an overall statistically significant amount of mucus movement distally back towards the lung in the mechanically ventilated(MV) model. In the mechanically ventilated model, no mucus was observed to move towards the proximal/mouth piece section of the ETT. CONCLUSION This bench model suggests that IPV is associated with displacement of mucus towards the proximal mouthpiece in the SB patient, and distally in the MV model.

关键词： mucus Sputum Mechanical ventilators Percussion Respiratory drainage Breathing exercises