Mucous hypersecretion and relationship to cough.
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Mucus hypersecretion in asthma: causes and effects
MUC5B is the principal gel-forming mucin at baseline in small airways of humans and mice, and therefore likely performs most homeostatic clearance functions. MUC5AC is the principal gel-forming mucin upregulated in airway inflammation and is under negative control by forkhead box a2 and positive control by hypoxia inducible factor Mucin secretion is regulated separately from production, principally by extracellular triphosphate nucleotides that bind P2Y2 receptors on the lumenal surface of airway secretory cells, generating intracellular second messengers that activate the exocytic proteins, Munc and synaptotagmin Summary Markedly upregulated production of MUC5AC together with stimulated secretion leads to airflow obstruction in asthma.
The precise roles of mucin hypersecretion in asthma symptoms such as dyspnea and cough and in physiologic phenomena such as airway hyperresponsiveness remain to be defined. However, exactly what constitutes mucus hypersecretion and how it connects with disease manifestations other than asphyxiation has been poorly understood.
This review will present recent data that clarify the relations among mucous metaplasia, mucin production, mucin secretion, and mucus hypersecretion. The connections between these molecular and cellular processes and the symptoms, signs, and pathophysiology of asthma are increasingly studied and will also be reviewed.
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Mucus hypersecretion To begin, a few definitions are warranted. There are approximately 20 mucin and mucin-like genes encoded in mammalian genomes, and these are designated by the letters MUC all capitals in humans, first letter only capitalized in mice followed by a number [ 34 ].
Mucins can be divided into those that are anchored in the plasma membrane and those that are secreted. The secreted mucins can be further divided into those that contain sulfhydryl groups near their termini, which allow cross-linking, and those that do not; the former are primarily responsible for the structure of the mucus gel layer and are often referred to as polymeric or gel-forming mucins.
Due to their structure, size and location distal airways are much more vulnerable to these factors than proximal airways. Since the diameter of distal airways is per definition comparatively small and its resistance consequently high, any further reduction of the diameter carries the risk of premature closure.
Furthermore, compared to proximal airways that contain cartilaginous elements the wall structure of small airways is much more fragile and is differentially subjected to other mechanical influences. Thus, their opening depends among others on airway liquid surface tension and elastic recoil of the attached alveolar structures. Loss of these factors due to mechanical disruption of the mentioned structures or the diluting effect of plasma extravasation have been shown to increase airway resistance and air trapping in severe asthmatics [ 16 ].
The combination of any of these non-contractile factors with smooth muscle contraction, which is also markedly increased in distal airways of asthmatic patients as assessed by histamine provocation [ 17 ] could amplify airway resistance and consequently premature airway closure [ 18 - 20 ].
This can ultimately lead to the dramatic situation depicted by fatal asthma. Altered and increased mucus production in distal airways seems to play a pivotal role in the formation of this life-threatening condition of asthma.Prevention and Homeopathic treatment from cough and cold in winter season?
While clinical studies demonstrated that patients dying from this disease displayed small airway plugging by mucoinflammatory exsudates, a conglomerate of mucus, fibrin, plasma exsudates, and inflammatory cells, a quite recent study mechanistically demonstrated the impact of mucus and its well-known component Muc5AC on lung function in mice.
In different mouse models of experimental allergic asthma animals lacking this mucin did not only reveal diminished mucus hyperproduction and goblet cell hyperplasia, but surprisingly did not display an exaggerated airway response towards the methacholine MCh inhalation [ 21 ].
Whether this observation could really be traced back to an involvement of Muc5Ac in the development of AHR as suggested by the authors has not been proven. However, the most striking finding of this study was that wildtype animals undergoing provocation with the highest concentration of the secretagogue MCh displayed marked occlusion of distal airways by mucus plugs.
This resembled the pathology observed in fatal asthmatics. In contrast, mice deficient for Muc5AC revealed impressively less mucus occlusion of distal airways suggesting mucus hypersecretion as a major factor in the pathogenesis of fatal asthma. Since only a small proportion of asthmatic patients indeed get in danger to develop fatal asthma, one could raise the question whether fatal asthma could be the dramatic result of a fundamentally deregulated mucus secretion in distal airways.
Mucus in general is a gel-like, viscous secretion composed of various macromolecules, inorganic salts and water. It can be found throughout the body on mucous membranes for example in the gastrointestinal, urogenital, visual, auditory, and respiratory systems.
In humans the mucus of the respiratory tract is produced by goblet cells of the airway epithelium and submucosal glands. There, it functions as first line of defense against airway infection and plays a major role in mucociliar clearance of the airways. Pathogens, particles and other chemicals are caught up in a mucus layer covering beating cilia, which constantly sweep the mucus from distal to proximal airways to finally force it out of the lung [ 22 - 24 ].
This mucus layer is composed of a low-viscosity and therefore low resistance liquid layer up to the height of the cilia supporting the cilia beating and an overlying high-viscosity gel layer [ 232526 ]. The physical, viscoelastic property of mucus is determined by the quality and quantity of the mucins. Mucins are high molecular weight glycoproteins with variable numbers of serine, threonine and proline rich repeats.
Serine and threonine are sites of O-linked glycosylation for the peptide backbone [ 2829 ]. From the 22 known human mucin genes 16 mucins genes are expressed in the lung, of which Muc1, Muc4, Muc5AC, Muc5B, and Muc16 reveal the highest expression profiles [ 30 - 34 ]. There are two different types of mucins, the membrane-tethered mucins like Muc1, Muc4, and MucC16, which contribute to the periciliary layer, and the secreted gel-forming mucins like Muc5AC and Muc5B, which form the upper gel-layer and determine the mucus viscosity [ 2835 - 37 ].
Whereas Muc5B is produced by both, goblet cells and the submucosal glands, Muc5AC is mainly produced by goblet cells and is widely used as marker for goblet cell metaplasia [ 38 - 41 ]. Furthermore, increased Muc5AC expression is induced during airway inflammationwhereas Muc5B expression is constitutive and remains unaltered [ 4243 ].
Both the synthesis of mucins and mucus secretion into the airway lumen are highly regulated on several levels with low basal rates and high stimulated rates for example during inflammation [ 27 ].
The basal rate of secretion fits the basal rate of mucin synthesis in distal human airways. Therefore, under healthy conditions only small amounts of mucin accumulate intracellularly in these cells [ 2344 ].
After translation at the endoplasmic reticulum ER both, Muc5AC and Muc5B, polymerize as homodimers consequently forming one of the largest macromolecules encoded in mammals. After successful protein translation Muc5AC and Muc5B are transported to the Golgi, where both mucins undergo further monomeric polymerization and previously mentioned O-glycosylation resulting in the negatively charged, hydrophobic properties of the mature glycoproteins.
This allows the dense dehydrated packaging of mucins in secretory granules [ 45 - 47 ]. Exocytosis of these granules is again highly regulated by several different extracellular ligands. Especially G-protein coupled receptors for example for ATP belong to the best studied receptors for mucin secretion [ 44 ].
By interaction with different intracellular factors receptor binding of these extracellular ligands triggers movement of the granules along the cytoskeleton to the plasma membrane for exocytosis resulting in the secretion of mucin to the airway lumen [ 27 ].
To acquire the ideal viscoelastic property for ciliary clearance mucins absorb more than fold their mass of water after secretion due to the high water binding capacity of their polysaccharides [ 4849 ]. The IL dependent regulation of mucus production and subsequent mucus processing is depicted in Figure 1.
This cytokine mainly produced by TH2 cells is capable of inducing all hallmarks of experimental asthma in mice also including AHR and allergic airway inflammation. In our previous work we were therefore interested in the ILdependent regulation of mucus production in different sections of the airway tree.
Overview of IL dependent mucus production and induction of ER stress by mucus processing. Muc5AC protein is translated, folded and further processed in the ER. Activation of Agr2 can reduce ER stress by promoting mucus transition and the rearrangement of disulfide bounds in incorrectly folded proteins. In a mouse model of OVA-induced experimental asthma, we made the apparently contradictive observation that goblet cells and mucus production were nearly absent in distal airways although Club cells were present and inflammatory cell infiltration and the expression of the TH2 cytokine IL in distal airways was as high as in proximal airways [ 50 ].
Based on these data we suggested that epithelial cells of distal airways could be less sensitive towards IL signaling and consequently for the induction of GCM and mucus production, so that these cells are less capable to produce excessive amounts of mucus. Such insensitivity towards IL could therefore represent a mechanism protecting distal airways from mucus occlusion and airway trapping.
We further wondered if this would be the only mechanism to prevent such a physiologically dangerous outcome in distal airways. It has previously been demonstrated that excessive production of mucins leads to stress responses in the ER, the so called unfolded protein response UPR [ 2851 ], and that this is necessary to maintain proper folding of mucins and therefore the secretory capacity of goblet cells Figure 1 [ 52 - 54 ].
Small Airways in Asthma: Distal is Different
In order to prevent cell death, UPR pathways are activated. In eukaryotic cells three UPR pathways exist: Upon accumulation of unfolded proteins or induction of ER stress, GRP78, glucose regulated protein 78 BiP acts as a chaperone and UPR becomes activated by the release of sensor proteins [ 57 ]. Therefore, the induction of UPR is essential for the maintenance of cellular health and mucus production.
A comprehensive study by Martino et al.