Search Results (10)

Muco-obstructive lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and bronchiectasis, are characterized by the accumulation of highly viscoelastic mucus that compromises mucociliary clearance and fosters infection and inflammation. Mucoactive therapy, encompassing both true mucolytics and non-cleaving agents, seeks to restore airway patency by altering mucus structure, hydration, and transport properties, yet its clinical impact remains variable. This narrative review provides a critical reappraisal of the pharmacological actions and therapeutic outcomes of the main mucolytic agents: N-acetylcysteine (NAC), erdosteine, carbocisteine, bromhexine, ambroxol, and dornase alfa. Beyond their classical role in reducing mucus viscosity, these drugs exhibit pleiotropic effects, including antioxidant, anti-inflammatory, and immunomodulatory activities. Specifically, for thiol-based compounds, the action consists of breaking the disulfide bonds that stabilize the mucin network; for carbocisteine, it lies in modulating mucin glycosylation and chloride transport. Ambroxol and bromhexine act by stimulating surfactant secretion and enhancing mucociliary clearance. Finally, dornase alfa exerts an enzymatic effect on extracellular DNA, a key contributor to the tenacity of mucus in cystic fibrosis. Clinical evidence indicates that NAC and erdosteine can reduce exacerbation rates in COPD, carbocisteine shows benefit with prolonged administration, and dornase alfa remains a cornerstone in CF management. However, therapeutic efficacy is constrained by heterogeneous mucus composition, pharmacokinetic limitations, and disease-specific variability. A key interpretative message is that clinical benefit appears greatest when the dominant biophysical determinant of mucus pathology is specifically targeted, supporting a transition from broad disease-label prescribing to mechanism-informed, phenotype-aware mucolytic therapy. Emerging strategies, such as agents targeting mucin–DNA interactions and advanced inhalation delivery systems, promise improved specificity and durability. By integrating mechanistic insights with clinical data, this review underscores the need for personalized mucolytic therapy and innovative approaches to overcome current challenges in managing muco-obstructive lung diseases. Full article

Mucus plugging of the respiratory tract occurs in airway diseases, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. It can cause blockage of the airways, leading to breathlessness and lung failure. Here, we used a ventilatory setup to demonstrate the effect of BromAc^® in dissolving mucus plugs in a novel ex vivo ovine obstructive lung model. Mucus simulant was filled into the trachea of freshly slaughtered ovine lungs and ventilated via an endotracheal tube (ETT) using Continuous Mandatory Ventilation. Predetermined single or repeated doses of Bromelain, Acetylcysteine (Ac), BromAc^®, and saline control were administered via an Aerogen^® vibrating nebulizer and ventilated for 30 or 60 min. Ventilatory recording of resistance, compliance, and tidal volume was conducted, and rheology pre- and post-treatment were measured. A significant decline in airway resistance (p < 0.0001) compared to the saline control was observed when treated with Bromelain, Ac, and BromAc^®, with the latter showing a stronger mucolytic effect than single agents. The decline in resistance was also effective in shorter time points (p < 0.05) at lower doses of the drugs. Changes in compliance, peak pressure, and tidal volume were not observed after administration of the drugs. Rheology measurements revealed that BromAc^®TM significantly reduced the viscosity of the mucin at the end of 30 min and 60 min time points (p < 0.001) compared to the saline control. BromAc^® showed complete dissolution of the respiratory mucus simulant and improved ventilatory airflow parameters in the ex vivo ovine model. Full article

(1) Background: Stereological estimations significantly contributed to our understanding of lung anatomy and physiology. Taking stereology fully 3-dimensional facilitates the estimation of novel parameters. (2) Methods: We developed a protocol for the analysis of all airspaces of an entire lung. It includes (i) high-resolution synchrotron radiation-based X-ray tomographic microscopy, (ii) image segmentation using the free machine-learning tool Ilastik and ImageJ, and (iii) calculation of the airspace diameter distribution using a diameter map function. To evaluate the new pipeline, lungs from adult mice with cystic fibrosis (CF)-like lung disease (βENaC-transgenic mice) or mice with elastase-induced emphysema were compared to healthy controls. (3) Results: We were able to show the distribution of airspace diameters throughout the entire lung, as well as separately for the conducting airways and the gas exchange area. In the pathobiological context, we observed an irregular widening of parenchymal airspaces in mice with CF-like lung disease and elastase-induced emphysema. Comparable results were obtained when analyzing lungs imaged with μCT, sugges-ting that our pipeline is applicable to different kinds of imaging modalities. (4) Conclusions: We conclude that the airspace diameter map is well suited for a detailed analysis of unevenly distri-buted structural alterations in chronic muco-obstructive lung diseases such as cystic fibrosis and COPD. Full article

Epithelial-to-mesenchymal transition (EMT) is a reversible process, in which epithelial cells lose their epithelial traits and acquire a mesenchymal phenotype. This transformation has been described in different lung diseases, such as lung cancer, interstitial lung diseases, asthma, chronic obstructive pulmonary disease and other muco-obstructive lung diseases, such as cystic fibrosis and non-cystic fibrosis bronchiectasis. The exaggerated chronic inflammation typical of these pulmonary diseases can induce molecular reprogramming with subsequent self-sustaining aberrant and excessive profibrotic tissue repair. Over time this process leads to structural changes with progressive organ dysfunction and lung function impairment. Although having common signalling pathways, specific triggers and regulation mechanisms might be present in each disease. This review aims to describe the various mechanisms associated with fibrotic changes and airway remodelling involved in chronic airway diseases. Having better knowledge of the mechanisms underlying the EMT process may help us to identify specific targets and thus lead to the development of novel therapeutic strategies to prevent or limit the onset of irreversible structural changes. Full article

K⁺ channels are involved in many critical functions in lung physiology. Recently, the family of Ca²⁺-activated K⁺ channels (K_Ca) has received more attention, and a massive amount of effort has been devoted to developing selective medications targeting these channels. Within the family of K_Ca channels, three small-conductance Ca²⁺-activated K⁺ (K_Ca2) channel subtypes, together with the intermediate-conductance K_Ca3.1 channel, are voltage-independent K⁺ channels, and they mediate Ca²⁺-induced membrane hyperpolarization. Many K_Ca2 channel members are involved in crucial roles in physiological and pathological systems throughout the body. In this article, different subtypes of K_Ca2 and K_Ca3.1 channels and their functions in respiratory diseases are discussed. Additionally, the pharmacology of the K_Ca2 and K_Ca3.1 channels and the link between these channels and respiratory ciliary regulations will be explained in more detail. In the future, specific modulators for small or intermediate Ca²⁺-activated K⁺ channels may offer a unique therapeutic opportunity to treat muco-obstructive lung diseases. Full article

(1) Background: We have previously shown that sputum rheology can discriminate between patients with COPD and other muco-obstructive lung diseases, and that it is correlated with mucin content and sputum eosinophilia. We now hypothesize that it could be a more-accurate guide than clinical evaluation for the prescription of azithromycin to prevent exacerbations of COPD and to reduce exposure to antibiotics; (2) Methods: “COPD CaRhe” is a multicentric, randomized, controlled trial comparing outcomes in two parallel arms (36 vs. 36 patients). Patients will be recruited in the university hospitals of Montpellier, Bordeaux, and Toulouse, in France, and they should have a diagnosis of COPD with frequent exacerbations (≥3/year). Enrollment will occur during a routine visit to a respiratory department, and follow-up visits will occur every 3 months for a period of 1 year. At each visit, a 3-month prescription of azithromycin will be provided to those patients who obtain a score of <70 on the Cough and Sputum Assessment Questionnaire (CASA-Q) or a critical stress score of σc > 39 on a rheological assessment of sputum, depending upon their randomization group. The primary outcome will be the number of exacerbations of COPD; (3) Discussion: By using sputum rheology, the COPD CaRhe study may provide clinicians with an objective biomarker to guide the prescription of azithromycin while reducing the cumulative exposure to macrolides. Full article

Obstructive lung diseases, such as chronic obstructive pulmonary disease, asthma, or non-cystic fibrosis bronchiectasis, share some major pathophysiological features: small airway involvement, dysregulation of adaptive and innate pulmonary immune homeostasis, mucus hyperproduction, and/or hyperconcentration. Mucus regulation is particularly valuable from a therapeutic perspective given it contributes to airflow obstruction, symptom intensity, disease severity, and to some extent, disease prognosis in these diseases. It is therefore crucial to understand the mucus constitution of our patients, its behavior in a stable state and during exacerbation, and its regulatory mechanisms. These are all elements representing potential therapeutic targets, especially in the era of biologics. Here, we first briefly discuss the composition and characteristics of sputum. We focus on mucus and mucins, and then elaborate on the different sample collection procedures and how their quality is ensured. We then give an overview of the different direct analytical techniques available in both clinical routine and more experimental settings, giving their advantages and limitations. We also report on indirect mucus assessment procedures (questionnaires, high-resolution computed tomography scanning of the chest, lung function tests). Finally, we consider ways of integrating these techniques with current and future therapeutic options. Cystic fibrosis will not be discussed given its monogenic nature. Full article

Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored in the cell membrane have since been discovered. Muco-obstructive lung diseases (MucOLDs) are characterised by the accumulation of hyper-concentrated mucus in the small airways, leading to persistent inflammation, infection and dysregulated protease activity. Although neutrophilic serine proteases, particularly neutrophil elastase, have been implicated in the propagation of inflammation and local tissue destruction, it is likely that the serine TLPs also contribute to various disease-relevant processes given the roles that a number of these enzymes play in the activation of both the epithelial sodium channel (ENaC) and protease-activated receptor 2 (PAR2). More recently, significant attention has focused on the activation of viruses such as SARS-CoV-2 by host TLPs. The purpose of this review was to highlight key TLPs linked to the activation of ENaC and PAR2 and their association with airway dehydration and inflammatory signalling pathways, respectively. The role of TLPs in viral infectivity will also be discussed in the context of the inhibition of TLP activities and the potential of these proteases as therapeutic targets. Full article

Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases. Full article

Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality globally. Studies show that airway mucus hypersecretion strongly compromises lung function, leading to frequent hospitalization and mortality, highlighting an urgent need for effective COPD treatments. MUC5AC is known to contribute to severe muco-obstructive lung diseases, worsening COPD pathogenesis. Various pathways are implicated in the aberrant MUC5AC production and secretion MUC5AC. These include signaling pathways associated with mucus-secreting cell differentiation [nuclear factor-κB (NF-κB)and IL-13-STAT6- SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF), as well as epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR)], and signaling pathways related to mucus transport and excretion-ciliary beat frequency (CBF). Various inhibitors of mucus hypersecretion are in clinical use but have had limited benefits against COPD. Thus, novel therapies targeting airway mucus hypersecretion should be developed for effective management of muco-obstructive lung disease. Here, we systematically review the mechanisms and pathogenesis of airway mucus hypersecretion, with emphasis on multi-target and multi-link intervention strategies for the elucidation of novel inhibitors of airway mucus hypersecretion. Full article