Physiology and Pathophysiology of Human Airway Mucus

The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both two-phase gas liquid pumping and cough-dependent mechanisms, and mucus transport rates are heavily dependent on mucus concentration. Importantly, mucus transport rates are accurately predicted by the gel-on-brush model of the mucociliary apparatus from the relative osmotic moduli of the mucus and periciliary-glycocalyceal (PCL-G) layers. The fluid available to hydrate mucus is generated by transepithelial fluid transport. Feedback interactions between mucus concentrations and cilia beating, via purinergic signaling, coordinate Na+ absorptive vs Cl- secretory rates to maintain mucus hydration in health. In disease, mucus becomes hyperconcentrated (dehydrated). Multiple mechanisms derange the ion transport pathways that normally hydrate mucus in muco-obstructive lung diseases, e.g., CF, COPD, NCFB, and PCD. A key step in muco-obstructive disease pathogenesis is the osmotic compression of the mucus layer onto the airway surface with the formation of adherent mucus plaques and plugs, particularly in distal airways. Mucus plaques create locally hypoxic conditions and produce airflow obstruction, inflammation, infection, and, ultimately, airway wall damage. Therapies to clear adherent mucus with hydrating and mucolytic agents are rational, and strategies to develop these agents are reviewed.

Bromhexine Use in the Outpatient Department in a Public Hospital in Al-Kharj

Aim: This study was conducted to demonstrate the prescribing pattern of bromhexine in a public hospital in Alkharj. Methodology: This is a retrospective study that included evaluating outpatient antibiotic prescriptions from 1st of January/2018 to 30th of June/2018 in a public hospital Al-kharj. The collected data were the personal data of the patients, the prescribing’ departments, the duration of bromhexine use, and the level of the prescribers. Results: Most of the patients were in the age group of 20-29 (32.35%) followed by 10-19 (20.59%). About 73.53% of the prescriptions were written by the emergency department, followed by the chest department (20.59%). All of the prescriptions were written by residents. Most of the patients used bromhexine for 5 days (76.47%) followed by 1 week (20.59%). Conclusion: The present study showed that bromhexine use in the outpatient setting was uncommon. More studies are needed to explore the frequency of prescribing other mucolytic agents.

Apparent Yield Stress of Sputum as a Relevant Biomarker in Cystic Fibrosis

The mucus obstructing the airways of Cystic Fibrosis (CF) patients is a yield stress fluid. Linear and non-linear rheological analyses of CF sputa can provide relevant biophysical markers, which could be used for the management of this disease. Sputa were collected from CF patients either without any induction or following an aerosol treatment with the recombinant human DNAse (rhDNAse, Pulmozyme®). Several sample preparations were considered and multiple measurements were performed in order to assess both the repeatability and the robustness of the rheological measurements. The linear and non-linear rheological properties of all CF sputa were characterized. While no correlation between oscillatory shear linear viscoelastic properties and clinical data was observed, the steady shear flow data showed that the apparent yield stress of sputum from CF patients previously treated with rhDNAse was approximately one decade lower than that of non-treated CF patients. Similar results were obtained with sputa from non-induced CF patients subjected ex vivo to a Pulmozyme® aerosol treatment. The results demonstrate that the apparent yield stress of patient sputa is a relevant predictive/prognostic biomarker in CF patients and could help in the development of new mucolytic agents.

Hypertonic saline in people with cystic fibrosis: review of comparative studies and clinical practice

Cystic fibrosis (CF) is a multisystem disorder, caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. These cause a reduced secretion of chloride, a marked absorption of sodium and, therefore, of water, through the epithelium, resulting in the formation of thickened secretions in organs such as lung or pancreas. These viscous secretions lead to airway obstruction, chronic infection and inflammation resulting in progressive lung damage, bronchiectasis and eventual respiratory failure. Although the average life expectancy has increased over the last 30 years, lung disease is the most common cause of death in people with CF. For these reasons, the improvement of sputum clearance is a major therapeutic aim in CF and early initiation of airway clearance is widely recommended and implemented. Symptomatic mucolytic therapy today is mainly based on inhalation of DNase, hypertonic saline or mannitol, in combination with physiotherapy. Mucolytic agents break down the gel structure of mucus and therefore decrease its elasticity and viscosity, reducing the pulmonary exacerbation frequency and to improve and stabilize lung function. Nevertheless, high quality studies comparing these mucolytic drugs are still few, and the individual experiences of patients and caregivers explain the high variability of their use globally. This review will summarize the current knowledge on hypertonic saline in the treatment of CF lung disease. Furthermore, we report the real-world prescription of inhaled mucolytic agents in CF.

Thiol-based mucolytics exhibit antiviral activity against SARS-CoV-2 through allosteric disulfide disruption in the spike glycoprotein

Small molecule therapeutics targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have lagged far behind the development of vaccines in the fight to control the COVID-19 pandemic. Here, we show that thiol-based mucolytic agents, P2119 and P2165, potently inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine profiling link the antiviral activity of repurposed mucolytic agents to the reduction of key disulfides, specifically, by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif (RBM) in the receptor binding domain (RBD) of the spike glycoprotein. Computational analyses provide insight into conformation changes that occur when these disulfides break or form, consistent with an allosteric role, and indicate that P2119/P2165 target a conserved hydrophobic binding pocket in the RBD with the benzyl thiol warhead pointed directly towards Cys432. These collective findings establish the vulnerability of human coronaviruses to repurposed thiol-based mucolytics and lay the groundwork for developing these compounds as a potential treatment, preventative and/or adjuvant against infection.

Premedication with simethicone and N-acetylcysteine for improving mucosal visibility during upper gastrointestinal endoscopy in a Western population

Background and study aim Pre-endoscopic use of a preparation with tensioactive and mucolytic agents improved gastric mucosa visualization in Eastern studies. Data on Western population are scanty. Patients and methods This prospective, endoscopist-blinded, randomized study enrolled patients who underwent esophagogastroduodenoscopy in a single center. Before endoscopy patients, were randomized to receive or not receive an oral preparation with simethicone and N-acetylcysteine in water. A pretested score (Crema Stomach Cleaning Score [CSCS]) for gastric mucosa cleaning evaluation was used. In detail, the stomach was divided into the antrum, body, and fundus and a score of 1 to 3 was assigned to each part (the higher the score, the better the preparation), and a total value ≤ 5 was considered as insufficient. Time between endoscope insertion and clean achievement (mouth to clean time) or the end of examination (mouth to mouth time) was recorded. Results A total of 197 patients were enrolled. The mean overall CSCS value and mucosal cleaning in all parts was better in treated patients than in controls. Prevalence total score ≤ 5 was significantly lower in patients treated before endoscopy. Need for water flush occurred less frequently in treated patients (P < 0.0001). The mouth to clean time was lower in the treated than in the control group (2.3 ± 1.6 vs 3.8 ± 1.6 min; P < 0.001), whereas no significant difference in mouth to mouth time emerged. Conclusions Data from this study show that premedication with simethicone and N-acetylcysteine results in significantly better endoscopic visualization of gastric mucosa, and the proposed CSCS could be useful for standardizing this evaluation.

Does Premedication with Mucolytic Agents Improve Mucosal Visualization during Oesophagogastroduodenoscopy: A Systematic Review and Meta-Analysis

Introduction. Gastric Cancer (GC) is the fourth most common malignancy worldwide and the second leading cause of cancer-related mortality for both sexes. The gold standard for diagnosing GC is oesophagogastroduodenoscopy (OGD). Excess mucus on the gastric mucosa impairs the detection of early GC. Aim. To synthesize available evidence of the effect of premedication with a mucolytic agent among adults undergoing elective nontherapeutic OGD, compared to placebo or other mucolytic agents, on mucosal visibility during OGD. Methods. A systematic review was conducted. PubMed, EMBASE, CINAHL, Cochrane central register of controlled trials (CENTRAL), and Web of Science were searched for relevant studies. A random-effects meta-analysis was performed to determine the mean difference in total mucosal visibility score (TMVS) between the pooled mucolytic agents and control. Subgroup analyses were performed to determine the mean TMVS difference for simethicone versus control and the impact of different timings and doses of mucolytic premedication. Results. 13 studies, involving 11,086 patients, including 6178 females (55.7%), with a mean age of 53.4 were identified and 6 of these were brought forward to meta-analysis. This revealed a mean difference of −2.69 (95% CI −3.5, −1.88) in total mucosal visibility scores (TMVS) between the pooled mucolytic agents and control. For simethicone, the mean difference was −2.68 (95% CI −4.94, −0.43). A simethicone dose of 133 mg was most effective with a mean difference of −4.22 (95% CI −5.11, −3.33). Assessing timing of administration across all mucolytic agents revealed a mean difference for the >20 minutes group of −3.68 (95% CI −4.77, −2.59). No adverse events were reported in any included trials. Conclusions. Regular use of premedication with mucolytic agents prior to routine OGD is associated with improved TMVS with no reported adverse events.