Dynamic expression of mucins and the genes controlling mucin-type O-glycosylation within the mouse respiratory system.

The COVID-19 global pandemic has underscored the need to understand how viruses and other pathogens are able to infect and replicate within the respiratory system. Recent studies have highlighted the role of highly O-glycosylated mucins in the protection of the respiratory system as well as how mucin-type O-glycosylation may be able to modify viral infectivity. Therefore, we set out to identify the specific genes controlling mucin-type O-glycosylation throughout the mouse respiratory system as well as determine how their expression and the expression of respiratory mucins is influenced by infection or injury. Here, we show that certain mucins and members of the Galnt family are abundantly expressed in specific respiratory tissues/cells and demonstrate unique patterns of O-glycosylation across diverse respiratory tissues. Moreover, we find that the expression of certain Galnts and mucins is altered during lung infection and injury in experimental mice challenged with infectious agents, toxins, and allergens. Finally, we examine gene expression changes of Galnts and mucins in a mouse model of SARS-CoV-2 infection. Our work provides foundational knowledge regarding the specific expression of Galnt enzyme family members and mucins throughout the respiratory system, and how their expression is altered upon lung infection and injury.

Airway mucus, infection, and therapeutic strategies

The respiratory tract epithelium is hydrated by a mucous layer, which forms a protective barrier for the defense against sometimes life-threatening foreign particles, including bacteria and viruses. The mucous layer is fluid in nature and facilitates ciliary beating, enabling mucociliary clearance. The mucus consists of a complex array of macromolecules called mucins, which are linked to complex long carbohydrate chains called O-glycans. Certain debilitating disorders such as cystic fibrosis, and even the recent COVID-19 can lead to the impairment of this layer by affecting its transport properties. In turn or individually, pathogens of the respiratory tract can evade this barrier by directly interacting with the intact mucus and bypassing it or by surviving in the already damaged layer. Therefore, understanding the specificities of mucin dysfunction and the mucin-pathogen relationship in immunocompromised infections is important for the development of therapeutics targeting mucin-associated mechanisms. © 2023 Elsevier Inc. All rights reserved.

Models using native tracheobronchial mucus in the context of pulmonary drug delivery research: Composition, structure and barrier properties.

Mucus covers all wet epithelia and acts as a protective barrier. In the airways of the lungs, the viscoelastic mucus meshwork entraps and clears inhaled materials and efficiently removes them by mucociliary escalation. In addition to physical and chemical interaction mechanisms, the role of macromolecular glycoproteins (mucins) and antimicrobial constituents in innate immune defense are receiving increasing attention. Collectively, mucus displays a major barrier for inhaled aerosols, also including therapeutics. This review discusses the origin and composition of tracheobronchial mucus in relation to its (barrier) function, as well as some pathophysiological changes in the context of pulmonary diseases. Mucus models that contemplate key features such as elastic-dominant rheology, composition, filtering mechanisms and microbial interactions are critically reviewed in the context of health and disease considering different collection methods of native human pulmonary mucus. Finally, the prerequisites towards a standardization of mucus models in a regulatory context and their role in drug delivery research are addressed.

Mucus targeting as a plausible approach to improve lung function in COVID-19 patients.

COVID-19 (SARS-CoV-2) has emerged as one of the worst pandemics that have tormented the globe due to its highly contagious nature. Even if the disease manifests fever-like symptoms mostly, the disease may progress to the pulmonary-hyper inflammatory phase, with severe pneumonia, hypoxia and subsequent multiple organ infection. This subsequently creates a huge burden to the health care systems across the globe for an immediate arrangement of ventilator facilities, oxygen supply and advanced health care. We evaluated the pathological similarity of COVID-19 with other airway obstructive disorders such as COPD and asthma and found typical mucus hypersecretion and mucus plugging in COVID-19 subjects. From several bronchoscopy and clinical autopsy carried out in COVID-19 patients, the overexpression of mucin gene was evident which play a significant role in mucus hypersecretion and accumulation, leading to airway obstruction and further to respiratory distress. In the present work, we highlight the need for intense research inputs to elucidate the exact role the mucus plays in worsening COVID-19 symptoms. This will further help to find a proper approach to quantify the airway mucus plugging in each patient and to develop an appropriate therapy either to inhibit mucus secretion or to improve mucus clearance through well-designed clinical trials.

The Antiviral Properties of Human Milk: A Multitude of Defence Tools from Mother Nature.

The anti-infective properties of breast milk have been known for decades. In recent years, an increasing number of papers have described the variety of bioactive compounds that are present in breast milk with varying degrees of antiviral activity. However, to date, the totality of the properties of these compounds is not fully understood and, above all, their synergistic interaction is not yet known. The purpose of this review is to describe the current knowledge about the antiviral compounds in breast milk, both with specific and non-specific action against pathogens. Due to the current pandemic situation from SARS-CoV-2 (Severe acute respiratory syndrome Coronavirus-2), research has focused on a multitude of potential antiviral substances, taking breast milk as a biological model of reference. Future research is needed to expand the knowledge of these compounds, which will hopefully assist in the development of therapies applicable even at later ages.

Effects of Environmental Factors on Severity and Mortality of COVID-19.

Background: Most respiratory viruses show pronounced seasonality, but for SARS-CoV-2, this still needs to be documented. Methods: We examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application. Findings: Meta-analysis of the mortality risk in seven European hospitals estimated odds ratios per 1-day increase in the admission date to be 0.981 (0.973-0.988, p < 0.001) and per increase in ambient temperature of 1°C to be 0.854 (0.773-0.944, p = 0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to the intensive care unit, and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. Interpretation: Severity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation.

Potential Mechanisms for Traditional Chinese Medicine in Treating Airway Mucus Hypersecretion Associated With Coronavirus Disease 2019.

BACKGROUND: The rapid development of coronavirus disease 2019 (COVID-19) pandemic has become a great threat to global health. Its mortality is associated with inflammation-related airway mucus hypersecretion and dysfunction of expectoration, and the subsequent mucus blockage of the bronchioles at critical stage is attributed to hypoxemia, complications, and even death. Traditional Chinese medicine (TCM) has rich experience in expectorant, including treatment of COVID-19 patients with airway mucus dysfunction, yet little is known about the mechanisms. This study is aiming to explore the potential biological basis of TCM herbal expectorant for treating COVID-19. OBJECTIVE: To get core herbs with high used frequency applications in the actions of expectoration by using association rule algorithm and to investigate the multitarget mechanisms of core herbs in expectorant formulae for COVID-19 therapies. METHODS: Forty prescriptions for expectorant were retrieved from TCM Formulae. The ingredient compounds and targets of core herbs were collected from the TCMSP database, Gene-Cards, and NCBI. The protein interaction network (PPI) was constructed by SRING, and the network analysis was done by Cytoscape software. Bioconductor was applied for functional enrichment analysis of targets. RESULTS: The core herbs of expectorant could regulate core pathways (MAP kinase activity, cytokine receptor binding, G-protein-coupled receptor binding, etc.) via interactions of ingredients (glycyrol, citromitin, etc.) on mucin family to eliminate phlegm. CONCLUSION: TCM herbal expectorant could regulate MAPK and cytokine-related pathways, thereby modulating Mucin-family to affect mucus generation and clearance and eventually retarding the deterioration of COVID-19 disease.

A bird eye view on cystic fibrosis: An underestimated multifaceted chronic disorder.

Cystic fibrosis (CF) is an autosomal recessive disease which involves the mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF involves in the inflammatory processes and is considered as a multisystem disorder that is not confined to lungs, but it also affects other vital organs that leads to numerous co-morbidities. The respiratory disorder in the CF results in mortality and morbidity which is characterized by series of serious events involving mucus hypersecretion, microbial infections, airways obstruction, inflammation, destruction of epithelium, tissue remodeling and terminal lung diseases. Mucins are the high molecular weight glycoproteins important for the viscoelastic properties of the mucus, play a significant role in the disease mechanisms. Determining the functional association between the CFTR and mucins might help to identify the putative target for specific therapeutic approach. In fact, furin enzyme which helps in the entry of novel COVID-19 virus into the cell, is upregulated in CF and this can also serve as a potential target for CF treatment. Moreover, the use of nano-formulations for CF treatment is an area of research being widely studied as they have also demonstrated promising outcomes. The in-depth knowledge of non-coding RNAs like miRNAs and lncRNAs and their functional association with CFTR gene expression and mutation can provide a different range of opportunity to identify the promising therapeutic approaches for CF.