Mucus in respiratory airways


Mucus in respiratory airways

Mucus in airways acts with ciliary beating to keep clear the airways, giving rise to the mucociliary ascendant.
Mucus is very complex in its composition, is mainly produced by goblet cells and serous glands in bronchi wall. The main protein in mucus is the mucoprotein. In pathological hypersecreting states as in asthma and COPD, occurs changes in phenotypic expression with hyperplasia of goblet cells and hypertrophy of serous glands. The excess of mucus causes plugging in the airways and impacts not only lung function, but causes morbidity even mortality.


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Introduction

The mucus is a complex mixture of proteins, lipids, water, and electrolytes that, under normal conditions, maintains the moisture of the airway epithelium. It allows the air to be conditioned adhering particles which bypasses upper airways. The main protein of the mucus is the mucin.
Mucin  
Imagen credit:
Taken from Lafitte, in
It is produced by goblet, mucous, and serous cells ( Flicker JH et al, 2008 ) and stored until a secretory signal is given. The mucus secretion may be stimulated by mediators produced by macrophages, lymphocytes, and epithelium.
  Goblet cell in H/E staining
Credit of image
Goblet secrets mucin, suspended in a solution of electrolytes.
 Goblet cells, serous glands in bronchi. Hematoxyllin and eosine staining
Image credit:
The proteic component is assembled from amino acids on ribosomes, then it move up trough endoplasmic reticulum to enter to the Golgi saccules. In this Golgi saccules simple sugars enter and combine with proteins by glycosylation and sulfate is added. The saccules of glycoprotein are transformed and hydrated into globules of mucus. Finally the mucin globules move toward the cell apex for subsequent release from the cell into the lumen.
Drawing of a Goblet cell, depicting the different structures giving place to mucoprotein.
From Neutra and Leblond, taken with modifications of

Secretory cells release not only mucin but a variety of antimicrobial molecules such as lisozyme, defensins, and IgA, immunomodulatory molecules such as the so called secretoglobins and cytokines, and recently described protective molecules such as trefoil proteins and heregulin in constitutive and inducible way; all of these molecules can become incorporated into mucus (Fahy JV & Dickey BF, 2010 )

Function of mucus

The mucus-lined nasal and sinus passages collect pollen, dust, dirt, fungal spores, and other particulates from the air. Mucus production is balanced with the sweeping action of ciliated epithelium, which facilitates drainage and particulate removal.

 

Different particles in air: molds, polen dust mites.
The consistency of mucus (a complex of water, sugar, lipids, and protein) can change from a planar structure to a globular structure that is not as effective at covering mucosal membranes and collecting particulates.

Mucins

Mucins are large glycoproteins and can be divided into membrane-bound and secreted mucins. There are nine membrane-bound (MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC13, MUC16, MUC17 and MUC20) and six secreted mucins (MUC2, MUC5B, MUC5AC, MUC6, MUC7 and MUC19) have been described.
The secreted mucins can be further subdivided into gel-forming (MUC2, MUC5B, MUC5AC, MUC6 and MUC19) and non-gel-forming mucins (MUC7). The gel-forming mucins constitute the main structural component of the mucus gel protecting the underlying epithelia. (Lidell ME and Hansson GC, 2006 )

Mucus hypersecretion and phenotypical changes

Airway mucus hypersecretion is a key feature in the pathophysiology of chronic respiratory diseases both reversible and non-reversible like asthma and chronic obstructive pulmonary disease (COPD). The mucus hypersecretion is associated with phenotypic changes in the airways, notably, with increasing in the number of surface epithelial goblet cells (hyperplasia) and in the size of the submucosal glands (hypertrophy).
The phenomena of hyperplasia and hypertrophy are associated with increased production of mucin, the gel-forming component of mucus. In this way, the excessive mucus production contributes to morbidity and mortality in many patients, particularly in those with more severe disease ( Lai H & Rogers DF, 2010 )
 

Biofilm in mucus

Biofilms play an important role in otitis media, sinusitis, chronic cholesteatomatous otitis media, tonsillitis and adenoiditis, thus demonstrating that adenoidectomy may be helpful to children suffering from such a morbid conditions. It is presently estimated that biofilm formation is involved in at least 60% of all chronic and/or recurrent infections. In addition, 30% of the exudates developing in the course of otitis media has shown to be positive for the presence of biofilms; likewise biofilms have been found in tonsillar crypts and in odontostomatologic infections as well. Studies have been carried out on both the use and the efficacy of N-acetylcysteine (NAC) in biofilm breakdown. It has been shown that NAC, used at different concentrations, is able to reduce bacterial adhesion in several anatomical districts (Legnani D, 2009).

Mucus hypersecretion in COPD

    Neutrophils are the key cells in pathologies such as the called chronic obstructive pulmonary disease (COPD); there is emerging evidence that these neutrophils play a key role in Epidermal Growth Factor Receptor (EGFR)-mediated mucin production through releasing tumor necrosis factor-alpha (TNF-α) and hence inducing EGFR expression. Moreover, the differentiation of the mucus cells as well as secretion of the mucus from airway glands are induced by neutrophil elastase.
Nevertheless, by entrapping and removing foreign materials, the mucus forms a basic defense system of the respiratory system; is easier for the lung cleaning to eliminate particles by mucociliary clearance instead of phagocytic process by the alveolar macrophages.
In the large airways, mucus hypersecretion causes coughing and sputum production. In the peripheral airways, because of the smaller diameter, the formed mucus plugs are difficult to remove and may block the peripheral airway completely. This, in turn, may result in gas trapping with increased total lung capacity (TLC) and decreased forced vital capacity (FVC). In COPD, the mucus hypersecretion is so then associated with decline in functional class, disease exacerbation (Poole and Black, 2003), accelerated decline in FEV1 and inflammatory cell infiltration ( Wedzicha and Donaldson 2003).
Moreover, the remaining sputum hinders the accessibility of inhaled medication to the peripheral airways. Therefore the mucus clearance and sterility maintenance are of importance in COPD.
There is a large number of medications available that are meant to change the properties of airway secretion or block its production or release, or both. The so called mucolytics are responsible for the disruption of the mucous gel, generally by altering the degree of the cross-linking or the interactions between molecules in the gel. Mucolytics include compounds as N-acetylcysteine (NAC) and related compounds, dornase–α, F-actin, de-polymerizing agents and nondestructive mucolytics, like hypertonic saline and oligosaccharide agents and were previously reviewed (King and Rubin, 2002 ).

Mucus hypersecretion in asthma

The secretion of tenacious mucus forming plugs is a hallmark of asthma, and it may results in variable degrees of severity of the disease. It is the result of the inflammatory process in the small airways.
Asthmatic airways show both a hyperplasia and metaplasia of goblet cells, all of these cells  are mucin-producing in the epithelium. The hyperplasia refers to augmented numbers of goblet cells in larger airways, while metaplasia refers to the appearance of these cells in smaller airways where they normally are not seen. With the augmented number of mucin-producing and secreting cells, there is a simultaneous hypersecretion of mucin which characterizes asthma.
A major regulator of airway mucin secretion in both in vitro and in vivo studies has been shown to be MARCKS (myristoylated alanine-rich C kinase substrate) protein, a ubiquitous substrate of protein kinase C (PKC) at a cellular level (Green TD et al, 2011 )

References

Fahy JV, Dickey BF. Airway mucus function and dysfunction. N Engl J Med. 2010 Dec 2;363(23):2233-47. Review. PubMed PMID: 21121836.http://www.nejm.org/doi/pdf/10.1056/NEJMra0910061
Ficker JH. [Physiology and pathophysiology of bronchial secretion]. Pneumologie. 2008 Mar;62 Suppl 1:S11-S3 http://www.ncbi.nlm.nih.gov/pubmed/18317975
Green TD, Crews AL, Park J, Fang S, Adler KB. Regulation of mucin secretion and inflammation in asthma: A role for MARCKS protein? Biochim Biophys Acta. 2011 Jan 31. [Epub ahead of print] PubMed PMID: 1281703. http://www.ncbi.nlm.nih.gov/pubmed/21281703
Helms S, Miller A. Natural treatment of chronic rhinosinusitisAltern Med Rev. 2006 Sep;11(3):196-207. Review. PubMed PMID: 17217321. http://www.thorne.com/altmedrev/.fulltext/11/3/196.pdf
King M, Rubin BK. Pharmacological approaches to discovery and development of new mucolytic agentsAdv Drug Deliv Rev. 2002 Dec 5;54(11):1475-90 http://www.ncbi.nlm.nih.gov/pubmed/12458156
Lai H, Rogers DF. New pharmacotherapy for airway mucus hypersecretion in asthma and COPD: targeting intracellular signaling pathways. J Aerosol Med Pulm Drug Deliv. 2010 Aug;23(4):219-31. Review. PubMed PMID: 20695774. http://www.ncbi.nlm.nih.gov/pubmed/20695774
Legnani D. [Acute bacterial exacerbation of chronic obstructive pulmonary disease and biofilm].Infez Med. 2009 Jul;17 Suppl 2:10-9. Review. Italian. PubMed PMID: 19696555.http://www.ncbi.nlm.nih.gov/pubmed/19696555
Lidell ME, Hansson GC. Cleavage in the GDPH sequence of the C-terminal cysteine-rich part of the human MUC5AC mucinBiochem J. 2006 Oct 1;399(1):121-9. PubMed PMID: 16787389.http://www.ncbi.nlm.nih.gov/pubmed/16787389 Full text inhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570170/pdf/bj3990121.pdf
Neutra M, Leblond CP. The Golgi apparatusSci. Am. 1969; 220: 100–107http://www.ncbi.nlm.nih.gov/pubmed?term=237402
Pintucci JP, Corno S, Garotta M. Biofilms and infections of the upper respiratory tractEur Rev Med Pharmacol Sci. 2010 Aug;14(8):683-90. PubMed PMID: 20707288.http://www.ncbi.nlm.nih.gov/pubmed/20707288
Poole PJ, Black PN. Preventing exacerbations of chronic bronchitis and COPD: therapeutic potential of mucolytic agentsAm J Respir Med. 2003;2(5):367-370http://www.ncbi.nlm.nih.gov/pubmed/14719989
Sadowska AM, Verbraecken J, Darquennes K, De Backer WA. Role of N-acetylcysteine in the management of COPDInt J Chron Obstruct Pulmon Dis. 2006;1(4):425-34. Review. PubMed PMID: 18044098;
Wedzicha JA, Donaldson GC. Exacerbations of chronic obstructive pulmonary diseaseRespir Care. 2003 Dec;48(12):1204-13; discussion 1213-5. Review. PubMed  PMID: 14651761.

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Alejandro Melo-Florián

Writer, Internal Medicine specialist. Bogotá D.C -Colombia
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