Airway succinate chemosensing induces CFTR-dependent anion secretion and mucus clearance which is impaired in cystic fibrosis.
Tábata ApablazaMarisol Barros-PobleteLivia DelpianoSandra VillanuevaAnita GuequénBárbara Tapia-BalladaresIram HaqFelipe TribiñosSebastián Hernández-RivasBernard VerdonMatthew G.S. BiggartY. SanchezChris WardB. Dnate’ BaxterDiego RestrepoIsabel CornejoRobert TarranMarcelo A. CatalánMichael A. GrayCarlos A. Flores
0
Citation
56
Reference
10
Related Paper
Abstract:
ABSTRACT The respiratory tract possesses a highly regulated innate defense system which includes efficient cilia-mediated mucus transport or mucociliary clearance (MCC). This essential process relies on appropriate hydration of airway surfaces which is controlled by a blend of transepithelial sodium and liquid absorption via the epithelial sodium channel (ENaC), and anion and liquid secretion, primarily regulated by the cystic fibrosis transmembrane conductance regulator (CFTR) channel. MCC is tightly regulated by second messenger signalling pathways. Succinate is derived from parasites, microorganisms and inflammatory cells, and its concentration increases in the airway surface liquid (ASL) during infections. Increases in ASL succinate activates the G-protein coupled succinate receptor (SUCNR1), which acts as a succinate sensor. Here, we tested the hypothesis that succinate signalling was linked to CFTR activity, ASL hydration and increased MCC. We observed that SUCNR1 activation stimulated anion secretion, increased mucus transport and induced bronchoconstriction in mouse airways. In parallel, stimulation of human bronchial epithelial cells (HBEC) with succinate activated anion secretion and increased ASL height. All functions activated by succinate/SUCNR1 were impeded when working with tissues and cells isolated from animal models or individuals affected cystic fibrosis (CF) or when CFTR was inhibited. Moreover, when HBECs derived from ΔF508 individuals were incubated with the triple drug combination of elexacaftor/tezacaftor/ivacaftor (ETI), succinate-induced anion secretion was restored, confirming the tight relationship between SUCNR1 signalling and CFTR function. Our results identify a novel activation pathway for CFTR that participates in the defence response of the airways, which is defective in CF. We propose that succinate acts as a danger molecule that alerts the airways to the presence of pathogens leading to a flushing out of the airways.Keywords:
Mucociliary clearance
Submucosal glands
Mannitol is a hyperosmolar agent and creates an osmolar gradient in the airway after being inhaled, which induces water flux into bronchial lumen. Thereafter, not only periciliary fluid depth is optimized but also mucus is hydrated. This event changes the surface properties of mucus and facilitates mucociliary clearance. When applied to disorders of mucus hypersecretion with impaired mucociliary clearance, it maintains airway hygiene by reducing mucus retention and subsequent mucus plug formation. Then patients' symptoms are eliminated,lung function is improved,bacterial colonization and exacerbation of chronic infection are reduced, and eventually life quality is improved. Therefore, it is considered to be a potential therapy for the disorders. Short-term studies have shown significant clinical outcomes, while long-term efficacy still needs to be approved.
Key words:
Mannitol; Inhalational therapy; Mucus hypersecretion; Mucociliary clearance
Mucociliary clearance
Expectorant
Cite
Citations (0)
Mucociliary clearance
Cite
Citations (0)
Insufficient hydration at the airway surface can make mucus adherent and poorly cleared. Cough, the major mechanism of mucus clearance in disease, is ineffective when mucus is adhesive. Inhaled mannitol creates an osmotic drive for water to move into the airway lumen. The consequent increased hydration of the airway surface decreases the adherence of mucus to the epithelium, facilitates the coupling of mucus and cilia thereby increasing mucus clearance. Inhaled mannitol also promotes effective coughing and stimulates mucociliary clearance. The beneficial effect of mannitol on mucus and its clearance has been demonstrated in patients with asthma, bronchiectasis and cystic fibrosis. Inhaled dry powder mannitol (Bronchitol™) is promising to be an effective treatment for the clearance of retained airway secretions.
Mucociliary clearance
Expectorant
Clearance
Cite
Citations (43)
Part 1 Basic science: dynein regulation ciliary regulation modelling of ciliary function basic aspect of mucus. Part 2 Clinical practice: mucociliary clearance in various septal deformities clinical studies in human tubal structures mucociliaryfunction of respiratory epithelium - human and animal studies bridging the gap between airway ion transport and mucociliary clearance laboratory and clinical studies of mucus airway bacteria and mucus production medical modulation of mucus definitionand diagnosis of primary and secondary mucociliary dysfunction biochemical and pharmacological regulation of mucociliary activity mucociliary clearance in paranasal sinuses miscellaneous ciliary function diagnosis, treatment and prevention ofmucociliary dysfunction. (Part contents).
Mucociliary clearance
Motile cilium
Cite
Citations (1)
Mucociliary clearance (MCC) plays an essential role in maintaining airway sterility and health. Conversely, mucociliary dysfunction is implicated across many airway obstructive diseases. Understanding the necessary requirements for successful MCC is imperative to establish the pathology of disease, as well as to develop therapeutic strategies. Although postural, that is, gravitational, drainage is used clinically to aid mucus clearance, it is ignored in both animal and cell culture models of MCC. In this study, we develop a novel mucus clearance assay that enables the first particle image velocimetry of human bronchial epithelial cell cultures tilted relative to the gravitational field. This tilting system makes it possible to observe drainage of the airway surface liquid and, thus, reveals the effect gravity has on mucociliary clearance. First, we use this assay to demonstrate that beating cilia alone cannot transport buffer upward against gravity. Next, we show the same cilia successfully transporting mucus upward. These results indicate that the biophysical and biochemical properties of mucus enable vertical clearance and that current assay systems are not equipped to determine which properties are required for physiologically relevant vertical mucociliary clearance.
Mucociliary clearance
Cite
Citations (9)
ABSTRACT Airway mucociliary clearance (MCC) is required for host defense and often diminished in chronic lung diseases. Effective clearance depends upon coordinated actions of the airway epithelium and a mobile mucus layer. Dysregulation of the primary secreted airway mucin proteins, MUC5B and MUC5AC, is associated with a reduction in the rate of MCC; however, how other secreted proteins impact the integrity of the mucus layer and MCC remains unclear. We previously identified the gene Bpifb1/Lplunc1 as a regulator of airway MUC5B levels using genetic approaches. Here, we show that BPIFB1 is required for normal mucociliary clearance in vivo using Bpifb1 knockout (KO) mice. Reduced MCC in Bpifb1 KO mice occurred in the absence of defects in sodium or chloride ion transport or reduced ciliary beat frequency. BPIFB1 loss resulted in airway mucus flakes with significantly increased complex viscosity, a key biophysical property of mucus known to impact MCC. Finally, we detected colocalization of BPIFB1 and MUC5B in secretory granules in mice and in the protein mesh of secreted mucus in human airway cultures. Collectively, our findings demonstrate that BPIFB1 is an important component of the mucociliary apparatus in mice and a key component of the mucus protein network.
Mucociliary clearance
Cite
Citations (2)
Cystic fibrosis (CF) is associated with the production of viscous and adherent mucus in the airway. Indeed, in some countries, CF is still called "mucoviscidosis". Mucus is a weak hydrogel exhibiting viscoelastic properties and these properties are important for normal function as they enable mucus to flow after secretion, to be effectively propelled by beating cilia (mucociliary clearance), and to provide a protective coating of the mucosal surfaces of our body that prevents dehydration and an exposure to external foreign substances and infectious agents. Mucus that is too thick or too thin can be difficult to transport by mucociliary clearance, and the production and accumulation of thick mucus in the airways eventually leads to mucostasis. The failure in function of mucus in airway clearance can lead to longer resident times of inhaled particulates including infectious agents, which results in chronic infection in the airway, lung damage and risk of death. Mucostasis and its associated problems are pathognomic features of the CF airway, and thus understanding the causes of abnormal mucus properties in CF is key to helping ameliorate the relentless progression of pulmonary disease. In cystic fibrosis, abnormal mucus viscosity and mucociliary clearance are due to decreased water and more solids, and not to changes in mucus pH
Mucociliary clearance
Cite
Citations (8)
This chapter contains section titled: Introduction Sources of airway mucus Control of mucus secretion and transport Control of mucociliary clearance Control of mucociliary clearance in patients with chronic obstructive pulmonary disease Control of mucociliary clearance in asthma Conclusions
Mucociliary clearance
Cite
Citations (8)
Mucociliary clearance
Cite
Citations (0)
Significance In many lung diseases, increased amounts of and/or abnormal mucus impair mucociliary clearance, a key defense against inhaled and aspirated material. Submucosal glands lining cartilaginous airways secrete mucus strands that are pulled by cilia until they break free from the duct and sweep upward toward the larynx, carrying particulates. In cystic fibrosis (CF) pigs, progressive clearance of insufflated microdisks was repeatedly interrupted as microdisks abruptly recoiled. Aerosolizing a reducing agent to break disulfide bonds linking mucins ruptured mucus strands, freeing them from submucosal gland ducts and allowing cilia to propel them up the airways. These findings highlight the abnormally increased elasticity of CF mucus and suggest that agents that break disulfide bonds might have value in lung diseases with increased mucus.
Mucociliary clearance
Submucosal glands
Cite
Citations (13)