Mucins and Asthma: Are We Headed to the Revolutionary Road?

Mucus represents the first line of defense of our respiratory tract and mucociliary clearance is essential for maintaining the homeostasis of airway epithelium. The latter mechanisms are altered in asthma and mucus plugging of proximal and distal airways is the main cause of death in cases of fatal asthma. Starting from the influential review performed by Luke R. Bonser and David J. Erle in 2017, we discuss the latest evidence in terms of mucins regulation and potential treatment of mucus hypersecretion and tissue remodeling in severe asthma.

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Influenza A virus enhances ciliary activity and mucociliary clearance via TLR3 in airway epithelium

Respiratory Research ◽

10.1186/s12931-020-01555-1 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Yosuke Kamiya ◽

Tomoyuki Fujisawa ◽

Mineo Katsumata ◽

Hideki Yasui ◽

Yuzo Suzuki ◽

...

Keyword(s):

Respiratory Tract ◽

Influenza A Virus ◽

Host Defense ◽

Airway Epithelium ◽

Influenza A ◽

Mucociliary Clearance ◽

Atp Release ◽

Extracellular Atp ◽

Ciliary Activity ◽

Tlr3 Activation

Abstract Background Viral respiratory tract infections, such as influenza A virus (IAV), are common and life-threatening illnesses worldwide. The mechanisms by which viruses are removed from the respiratory tract are indispensable for airway host defense. Mucociliary clearance is an airway defense mechanism that removes pathogens from the respiratory tract. The coordination and modulation of the ciliary beating of airway epithelial cells play key roles in maintaining effective mucociliary clearance. However, the impact of respiratory virus infection on ciliary activity and mucociliary clearance remains unclear. Methods Tracheal samples were taken from wild-type (WT) and Toll-like receptor 3 (TLR3)-knockout (KO) mice. Transient organ culture of murine trachea was performed in the presence or absence of IAV, polyI:C, a synthetic TLR3 ligand, and/or reagents. Subsequently, cilia-driven flow and ciliary motility were analyzed. To evaluate cilia-driven flow, red fluorescent beads were loaded into culture media and movements of the beads onto the tracheal surface were observed using a fluorescence microscope. To evaluate ciliary motility, cilia tips were labeled with Indian ink diluted with culture medium. The motility of ink-labeled cilia tips was recorded by high-speed cameras. Results Short-term IAV infection significantly increased cilia-driven flow and ciliary beat frequency (CBF) compared with the control level in WT culture. Whereas IAV infection did not elicit any increases of cilia-driven flow and CBF in TLR3-KO culture, indicating that TLR3 was essential to elicit an increase of cilia-driven flow and CBF in response to IAV infection. TLR3 activation by polyI:C readily induced adenosine triphosphate (ATP) release from the trachea and increases of cilia-driven flow and CBF in WT culture, but not in TLR3-KO culture. Moreover, blockade of purinergic P2 receptors (P2Rs) signaling using P2R antagonist, suramin, suppressed polyI:C-mediated increases of cilia-driven flow and CBF, indicating that TLR3-mediated ciliary activation depended on released extracellular ATP and the autocrine ATP-P2R loop. Conclusions IAV infection readily increases ciliary activity and cilia-driven flow via TLR3 activation in the airway epithelium, thereby hastening mucociliary clearance and “sweeping” viruses from the airway as an initial host defense response. Mechanically, extracellular ATP release in response to TLR3 activation promotes ciliary activity through autocrine ATP-P2R loop.

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The relevance of the application mukoactive preparations in patients with inflammatory pathology of ent organs

Medical Council ◽

10.21518/2079-701x-2018-20-65-69 ◽

2018 ◽

pp. 65-69

Author(s):

V. M. Svistushkin ◽

G. N. Nikiforova ◽

D. M. Pshonkina ◽

O. Yu. Karpovа

Keyword(s):

Respiratory Tract ◽

Mucociliary Clearance ◽

Inflammatory Diseases ◽

Respiratory Epithelium ◽

Formation Processes ◽

Mucous Secretion ◽

Pathogenetic Mechanism ◽

First Line ◽

Almost All ◽

Positive Effect

The mucous membrane of the respiratory tract is the first line of protection of the human body from various damaging agents. This function is provided by mucociliary clearance and its component by mucociliary transport. Optimum work of ciliated epithelium is possible only with normal rheology of mucous secretion - viscosity, elasticity, adhesiveness. The development of mucociliary dysfunction is the main pathogenetic mechanism of almost all inflammatory diseases of the respiratory tract and middle ear. The main areas of treatment for patients with infectious and inflammatory diseases of the respiratory tract and ear are evacuation of the pathological secretion, restoration of the synthesis of physiological mucus and a positive effect on the restructuring of the respiratory epithelium. The effectiveness of a mucoactive drug is determined by its ability to directly affect several components of mucociliary clearance - regulation of viscosity and secretion composition, its formation processes and evacuation rate. These characteristics correspond to carbocysteine.

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New Ultrastructural Observations on Injury and Regeneration of Cilia in Mammalian Conducting Airway Epithelium

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100099544 ◽

1981 ◽

Vol 39 ◽

pp. 624-625

Author(s):

J.L. Carson ◽

A.M. Collier

Keyword(s):

Respiratory Tract ◽

Airway Epithelium ◽

Defense Mechanisms ◽

Normal Growth ◽

Fetal Lung ◽

Secretory Cells ◽

Airway Epithelial ◽

Ciliated Cells ◽

Conducting Airway ◽

Conducting Airways

The ciliated cells lining the conducting airways of mammals are integral to the defense mechanisms of the respiratory tract, functioning in coordination with secretory cells in the removal of inhaled and cellular debris. The effects of various infectious and toxic agents on the structure and function of airway epithelial cell cilia have been studied in our laboratory, both of which have been shown to affect ciliary ultrastructure.These observations have led to questions about ciliary regeneration as well as the possible induction of ciliogenesis in response to cellular injury. Classical models of ciliogenesis in the conducting airway epithelium of the mammalian respiratory tract have been based primarily on observations of the developing fetal lung. These observations provide a plausible explanation for the embryological generation of ciliary beds lining the conducting airways but do little to account for subsequent differentiation of ciliated cells and ciliogenesis during normal growth and development.

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Potentially (near) fatal asthma

Allergy and Asthma Proceedings ◽

10.2500/aap.2019.40.4257 ◽

2019 ◽

Vol 40 (6) ◽

pp. 403-405 ◽

Cited By ~ 1

Author(s):

Paul A. Greenberger

Keyword(s):

Severe Asthma ◽

Health Care Professionals ◽

Rescue Therapy ◽

Respiratory Acidosis ◽

Acute Severe Asthma ◽

Increased Risk ◽

High Risk Type ◽

Fatal Asthma ◽

Long Acting ◽

Near Fatal Asthma

Potentially (near) fatal asthma (PFA) defines a subset of patients with asthma who are at increased risk for death from their disease. The diagnosis of PFA should motivate treating physicians, health professionals, and patients to be more aggressive in the monitoring, treatment, and control of this high-risk type of asthma. A diagnosis of PFA is made when any one of the following are present: (1) a history of endotracheal intubation from asthma, (2) acute respiratory acidosis (pH < 7.35) or respiratory failure from acute severe asthma, (3) two or more episodes of acute pneumothorax or pneumomediastinum from asthma, (4) two or more episodes of acute severe asthma, despite the use of long-term oral corticosteroids and other antiasthma medications. There are two predominant phenotypes of near-fatal exacerbations: “subacute” exacerbation and “hyperacute” exacerbation. The best way to “treat” acute severe asthma is 3‐7 days before it occurs (i.e., at the onset of symptoms or change in respiratory function) and to optimize control of asthma by decreasing the number of symptomatic days and the days and/or nights that require rescue therapy and increasing baseline respiratory status in “poor perceivers.” PFA is treated with a multifaceted approach; physicians and health-care professionals should appreciate limitations of pharmacotherapy, including combination inhaled corticosteroid‐long-acting β-agonist products as well as addressing nonadherence, psychiatric, and socioeconomic issues that complicate care.

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SUDDEN AND UNEXPECTED DEATH IN INFANCY AND CHILDHOOD

PEDIATRICS ◽

10.1542/peds.17.5.663 ◽

1956 ◽

Vol 17 (5) ◽

pp. 663-699 ◽

Cited By ~ 2

Author(s):

Lester Adelson ◽

Eleanor Roberts Kinney

Keyword(s):

Sudden Death ◽

Respiratory Tract ◽

Pulmonary Edema ◽

Cause Of Death ◽

Respiratory Infections ◽

Past History ◽

Prognostic Significance ◽

Control Group ◽

Unexpected Death ◽

History Of

One hundred twenty-six consecutive cases of sudden and unexpected death in children between the ages of 10 days and 2 years were studied. Anatomic and microbiologic studies were carried out and an investigation was made at the home in each case. Both sexes were equally vulnerable. Eighty-five per cent of the children were less than 6 months old. The peak incidence was at 2 months. Ninety-nine children were found dead and 27 were observed to die. The same variety and severity of anatomic lesions were found in both categories. Sixteen children in the same age range who died rapidly following known lethal voilence were studied as a control group. Of the nontraumatic sudden death ("unexplained") series 106 (84 per cent) revealed microscopic inflammatory changes in 1 or more sites of the respiratory tract, and histologic evidence of inflammatory disease in other organs was seen in many cases. Acute hemorrhagic pulmonary edema was a common anatomic finding (82 per cent). It was usually accompanied by visceral and cerebral congestion and hemorrhages. Special investigative procedures including staining of the liver for glycogen, determination of the glucose level of the cerebrospinal fluid and study of the adrenals for sudanophilia and birefringence indicated that these factors are without significance in sudden death in early life. A variety of congenital and acquired abnormalities, the presence of which had been unsuspected, was demonstrated at necropsy. Eleven per cent of the 126 cases showed no anatomic abnormalities other than the circulatory phenomena. No single bacterial organism or group of organisms was isolated with any degree of consistency from any site. All attempts to isolate viruses were negative. Ante-mortem symptomatology, circumstances of death, history of contact with infectious disease, and past history of repeated respiratory infection were without prognostic significance and were not pathognomic as to the cause of death. Eighty children had histories of mild illness for 48 hours or less prior to death. Fifty-three children had received some form of treatment during this interval. Sixty-nine children had histories of contact with infectious diseases. Forty-one children had past histories of repeated respiratory infections. The cases came from every social level. Sixty-five per cent had received good care while 35 per cent had received poor care. Many of the control cases showed inflamatory disease in the respiratory tract similar to that seen in the natural death group as well as anatomic evidence of lethal trauma. The inflammatory lesions are thus not incompatible with life. Several hypotheses are offered in an effort to link microscopic inflammatory respiratory tract changes with hemorrhagic pulmonary edema and sudden death. Anatomic and anamnestic evidence exclude mechanical suffocation by bedding. No statement as to the cause of death of an infant who has died suddenly and unexpectedly should be made without complete gross and microscopic studies and thorough investigation of the scene and circumstances of death.

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Severe Asthma (Fatal Asthma, Refractory Asthma)

Bronchial Asthma ◽

10.5005/jp/books/10107_20 ◽

2005 ◽

pp. 306-306

Author(s):

D Behera

Keyword(s):

Severe Asthma ◽

Fatal Asthma ◽

Refractory Asthma

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Interaction between ion transporters and the mucociliary transport system in dog and baboon

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.4.1348 ◽

1997 ◽

Vol 83 (4) ◽

pp. 1348-1359 ◽

Cited By ~ 21

Author(s):

Scot L. Winters ◽

Donovan B. Yeates

Keyword(s):

Respiratory Tract ◽

Transport System ◽

Mucociliary Clearance ◽

Beat Frequency ◽

Nuclear Imaging ◽

Ciliary Beat Frequency ◽

Lung Deposition ◽

Mucociliary Transport ◽

Ion Transporters ◽

Dry Air

Winters, Scot L., and Donovan B. Yeates. Interaction between ion transporters and the mucociliary transport system in dog and baboon. J. Appl. Physiol. 83(4): 1348–1359, 1997.—To gain insight into the role of epithelial ion channels, pumps, and cotransporters in regulating airway water and mucociliary transport, we administered inhibitors of the Na+ channel (amiloride), 3Na-2K-adenosinetriphosphatase (acetylstrophanthidin), and Na-K-2Cl cotransporter (furosemide) to anesthetized dogs and/or baboons. Tracheal ciliary beat frequency was measured by using heterodyne laser light scattering. Tracheal mucus velocity (TMV) and bronchial mucociliary clearance (BMC) or lung mucociliary clearance were measured by using radioaerosols and nuclear imaging. Respiratory tract fluid output was collected by using a secretion-collecting endotracheal tube. In six dogs, amiloride aerosol [lung deposition, 96 ± 11 μg (means ± SE)] had minimal effect, whereas acetylstrophanthidin aerosol (lung deposition, 71 ± 9 μg) increased BMC, and furosemide (40 mg iv) markedly increased TMV. In five baboons, TMV increased after iv furosemide administration (2 mg/kg) as well as by aerosol (lung deposition, 20 ± 3 mg), coincident with increases in ciliary-mucus coupling from 11.5 ± 0.1 to 29.5 ± 0.4 and 46.5 ± 0.7 μm/beat, respectively. Furosemide also increased lung mucociliary clearance in baboons. In dogs, respiratory tract fluid output increased after intravenous furosemide from 2.2 ± 0.5 to 6.8 ± 1.7 mg/min. When combined with dry-air inhalation, furosemide failed to stimulate TMV and reversed the inhibition of BMC by dry air. Thus pharmacological manipulation of the Na-K-2Cl cotransporter and the 3Na-2K-adenosinetriphosphatase pump may provide increases of clinical relevance in airway hydration and mucociliary transport.

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