From Mucins to Mucus
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Mucus is essential for protection of the airways; however, in chronic airway disease mucus hypersecretion is an important factor in morbidity and mortality. The properties of the mucus gel are dictated in large part by the oligomeric mucins and, over the past decade, we have gained a better understanding of the molecular nature of these complex O-linked glycoproteins. We know now that MUC5AC mucins, as well as different glycoforms of the MUC5B mucin, are the predominant gel-forming glycoproteins in airways mucus. Furthermore, the amount, molecular size, and morphology of these glycoproteins can be altered in disease. From more recent data, it has become clear that oligomeric mucins alone do not constitute mucus, and other mucin and nonmucin components must be important contributors to mucus organization and hence airways defense. Therefore, the challenge over the coming decade will be to investigate how the oligomeric mucins are organized to yield “functional” mucus. Such studies will provide a clearer pe...Cite
MUC1
Metaplasia
Submucosal glands
Goblet cell
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Lactoferrin
Goblet cell
Submucosal glands
Mucociliary clearance
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Mucus secreted mainly by epithelial goblet cells and submucosal glands covering the respiratory tract plays an important role in the protection from external aggressions, such as solid particles, pathogens and chemical agents by mucociliary clearance. The viscoelastic properties of mucus are mainly determined by the presence of extensively-glycosylated high molecular weight mucins. A lot of factors influence the expression and secretion of mucins in airway, lead to mucus overproduction, which is a distinguishing feature of chronic obstructive pulmonary disease (COPD) and causes disruption of the mucociliary clearance function, resulting in airway block, chronic infection and death.
Mucociliary clearance
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Goblet cell
Submucosal glands
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Abstract Background Airway surface liquid, often referred to as mucus, is a thin layer of fluid covering the luminal surface that plays an important defensive role against foreign particles and chemicals entering the lungs. Airway mucus contains various macromolecules, the most abundant being mucin glycoproteins, which contribute to its defensive function. Airway epithelial cells cultured in vitro secrete mucins and nonmucin proteins from their apical surface that mimics mucus production in vivo . The current study was undertaken to identify the polypeptide constituents of human airway epithelial cell secretions to gain a better understanding of the protein composition of respiratory mucus. Results Fifty-five proteins were identified in the high molecular weight fraction of apical secretions collected from in vitro cultures of well-differentiated primary human airway epithelial cells and isolated under physiological conditions. Among these were MUC1, MUC4, MUC5B, and MUC16 mucins. By proteomic analysis, the nonmucin proteins could be classified as inflammatory, anti-inflammatory, anti-oxidative, and/or anti-microbial. Conclusions Because the majority of the nonmucin proteins possess molecular weights less than that selected for analysis, it is theoretically possible that they may associate with the high molecular weight and negatively charged mucins to form a highly ordered structural organization that is likely to be important for maintaining the proper defensive function of airway mucus.
Proteome
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The airways mucus gel performs a critical function in defending the respiratory tract against pathogenic and environmental challenges. In normal physiology, the secreted mucins, in particular the polymeric mucins MUC5AC and MUC5B, provide the organizing framework of the airways mucus gel and are major contributors to its rheological properties. However, overproduction of mucins is an important factor in the morbidity and mortality of chronic airways disease (e.g., asthma, cystic fibrosis, and chronic obstructive pulmonary disease). The roles of these enormous, multifunctional, O-linked glycoproteins in health and disease are discussed.
Respiratory tract
Mucociliary clearance
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Mucociliary clearance
Respiratory tract
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Mucus is a highly hydrated uniquely structured gel that in conjunction with the ciliated cells in the surface epithelium forms the mucociliary clearance system essential for the protection of the respiratory tract [1]. The polymer matrix of the mucus biofilm is provided by very large complex glycoproteins that were formerly known as mucus glycoproteins but which are now commonly referred to as mucins [2-7]. Mucins are high-M" extensively 0-linked glycoproteins of exceptional mass size and daunting complexity that are synthesised by cells in both the surface epithelium and in the underlying submucosal glands. In normal airways mucus production asthma, cystic fibrosis and chronic bronchitis, mucus hypersecretion may cause major problems in airway clearance, resulting in impaired gas exchange and bacterial colonisation leading to infection and lung damage. In this chapter we will focus on the large polymeric mucins that are responsible for the formation of the gel-like protective barrier in human airways.
Respiratory tract
Submucosal glands
Chronic bronchitis
Mucociliary clearance
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Mucociliary clearance
Goblet cell
MUC1
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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.
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