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11 pages, 5479 KiB

Open AccessCommunication

The Nicotinic Receptor Polymorphism rs16969968 Is Associated with Airway Remodeling and Inflammatory Dysregulation in COPD Patients

by Lynda Saber Cherif, Zania Diabasana, Jeanne-Marie Perotin, Julien Ancel, Laure M. G. Petit, Maëva A. Devilliers, Arnaud Bonnomet, Nathalie Lalun, Gonzague Delepine, Uwe Maskos, Philippe Gosset, Myriam Polette, Anaëlle Muggeo, Thomas Guillard, Gaëtan Deslée and Valérian Dormoy

Cells 2022, 11(19), 2937; https://doi.org/10.3390/cells11192937 - 20 Sep 2022

Cited by 3 | Viewed by 1725

Abstract

Genome-wide association studies unveiled the associations between the single nucleotide polymorphism rs16969968 of CHRNA5, encoding the nicotinic acetylcholine receptor alpha5 subunit (α5SNP), and nicotine addiction, cancer, and COPD independently. Here, we investigated α5SNP-induced epithelial remodeling and inflammatory response in human COPD airways. We [...] Read more.

Genome-wide association studies unveiled the associations between the single nucleotide polymorphism rs16969968 of CHRNA5, encoding the nicotinic acetylcholine receptor alpha5 subunit (α5SNP), and nicotine addiction, cancer, and COPD independently. Here, we investigated α5SNP-induced epithelial remodeling and inflammatory response in human COPD airways. We included 26 α5SNP COPD patients and 18 wild-type α5 COPD patients in a multi-modal study. A comparative histologic analysis was performed on formalin-fixed paraffin-embedded lung tissues. Isolated airway epithelial cells from bronchial brushings were cultivated in the air-liquid interface. Broncho-alveolar fluids were collected to detect inflammatory mediators. Ciliogenesis was altered in α5SNP COPD bronchial and bronchiolar epithelia. Goblet cell hyperplasia was exacerbated in α5SNP small airways. The broncho-alveolar fluids of α5SNP COPD patients exhibited an increase in inflammatory mediators. The involvement of the rs16969968 polymorphism in airway epithelial remodeling and related inflammatory response in COPD prompts the development of innovative personalized diagnostic and therapeutic strategies. Full article

(This article belongs to the Special Issue Advances in COPD)

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20 pages, 2316 KiB

Open AccessFeature PaperArticle

Stem Cell-Based Regenerative Therapy and Derived Products in COPD: A Systematic Review and Meta-Analysis

by Luigino Calzetta, Marina Aiello, Annalisa Frizzelli, Francesca Camardelli, Mario Cazzola, Paola Rogliani and Alfredo Chetta

Cells 2022, 11(11), 1797; https://doi.org/10.3390/cells11111797 - 30 May 2022

Cited by 9 | Viewed by 2942

Abstract

COPD is an incurable disorder, characterized by a progressive alveolar tissue destruction and defective mechanisms of repair and defense leading to emphysema. Currently, treatment for COPD is exclusively symptomatic; therefore, stem cell-based therapies represent a promising therapeutic approach to regenerate damaged structures of [...] Read more.

COPD is an incurable disorder, characterized by a progressive alveolar tissue destruction and defective mechanisms of repair and defense leading to emphysema. Currently, treatment for COPD is exclusively symptomatic; therefore, stem cell-based therapies represent a promising therapeutic approach to regenerate damaged structures of the respiratory system and restore lung function. The aim of this study was to provide a quantitative synthesis of the efficacy profile of stem cell-based regenerative therapies and derived products in COPD patients. A systematic review and meta-analysis was performed according to PRISMA-P. Data from 371 COPD patients were extracted from 11 studies. Active treatments elicited a strong tendency towards significance in FEV₁ improvement (+71 mL 95% CI -2–145; p = 0.056) and significantly increased 6MWT (52 m 95% CI 18–87; p < 0.05) vs. baseline or control. Active treatments did not reduce the risk of hospitalization due to acute exacerbations (RR 0.77 95% CI 0.40–1.49; p > 0.05). This study suggests that stem cell-based regenerative therapies and derived products may be effective to treat COPD patients, but the current evidence comes from small clinical trials. Large and well-designed randomized controlled trials are needed to really quantify the beneficial impact of stem cell-based regenerative therapy and derived products in COPD. Full article

(This article belongs to the Special Issue Advances in COPD)

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8 pages, 473 KiB

Open AccessCommunication

Loss of Neural Automaticity Contributes to Slower Walking in COPD Patients

by S. Ahmed Hassan, Leandro Viçosa Bonetti, Karina Tamy Kasawara, Matthew B. Stanbrook, Dmitry Rozenberg and W. Darlene Reid

Cells 2022, 11(10), 1606; https://doi.org/10.3390/cells11101606 - 11 May 2022

Cited by 6 | Viewed by 1691

Abstract

The physical impairments (e.g., slower walking speed) in patients with chronic obstructive pulmonary disease (COPD) have been attributed to peripheral characteristics (e.g., muscle atrophy). However, cognitive impairment may compromise motor control including walking automaticity. The objective of this study was to investigate PFC [...] Read more.

The physical impairments (e.g., slower walking speed) in patients with chronic obstructive pulmonary disease (COPD) have been attributed to peripheral characteristics (e.g., muscle atrophy). However, cognitive impairment may compromise motor control including walking automaticity. The objective of this study was to investigate PFC neural activity, evaluated using changes in oxygenated hemoglobin (ΔO₂Hb), during preferred paced walking (PPW) in COPD patients and age-matched controls. The ΔO₂Hb from the left and right dorsolateral PFC was measured using functional near-infrared spectroscopy. Fifteen COPD patients (age: 71 ± 8) and twenty age-matched controls (69 ± 7 years) participated. Two-way mixed ANOVA demonstrated that O₂Hb in both groups decreased during PPW from the start (quintile 1; Q1) to the end (quintile 5; Q5) in the left dorsolateral and medial PFC. Q1 was comprised of the data during the first 20% of the task, while Q5 included data collected in the last 20% of the task duration. PPW duration ranged between 30.0 and 61.4 s in the control group and between 28.6 and 73.0 s in COPD patients. COPD patients demonstrated a higher O₂Hb in Q5 compared to the negative O₂Hb in controls in the right medial and dorsolateral PFC during PPW. PPW velocity was lower in COPD patients compared to controls (1.02 ± 0.22 vs. 1.22 ± 0.14 m/s, p = 0.005). Healthy older controls exhibited automaticity during walking unlike patients with COPD. The lesser decrease in O₂Hb in COPD patients may be attributed to increased executive demands or affect-related cues (e.g., pain or dyspnea) during walking. Full article

(This article belongs to the Special Issue Advances in COPD)

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22 pages, 3596 KiB

Open AccessFeature PaperArticle

Role of Human Antigen R (HuR) in the Regulation of Pulmonary ACE2 Expression

by Noof Aloufi, Zahraa Haidar, Jun Ding, Parameswaran Nair, Andrea Benedetti, David H. Eidelman, Imed-Eddine Gallouzi, Sergio Di Marco, Sabah N. Hussain and Carolyn J. Baglole

Cells 2022, 11(1), 22; https://doi.org/10.3390/cells11010022 - 22 Dec 2021

Cited by 6 | Viewed by 3729

Abstract

Patients with COPD may be at an increased risk for severe illness from COVID-19 because of ACE2 upregulation, the entry receptor for SARS-CoV-2. Chronic exposure to cigarette smoke, the main risk factor for COPD, increases pulmonary ACE2. How ACE2 expression is controlled is [...] Read more.

Patients with COPD may be at an increased risk for severe illness from COVID-19 because of ACE2 upregulation, the entry receptor for SARS-CoV-2. Chronic exposure to cigarette smoke, the main risk factor for COPD, increases pulmonary ACE2. How ACE2 expression is controlled is not known but may involve HuR, an RNA binding protein that increases protein expression by stabilizing mRNA. We hypothesized that HuR would increase ACE2 protein expression. We analyzed scRNA-seq data to profile ELAVL1 expression in distinct respiratory cell populations in COVID-19 and COPD patients. HuR expression and cellular localization was evaluated in COPD lung tissue by multiplex immunohistochemistry and in human lung cells by imaging flow cytometry. The regulation of ACE2 expression was evaluated using siRNA-mediated knockdown of HuR. There is a significant positive correlation between ELAVL1 and ACE2 in COPD cells. HuR cytoplasmic localization is higher in smoker and COPD lung tissue; there were also higher levels of cleaved HuR (CP-1). HuR binds to ACE2 mRNA but knockdown of HuR does not change ACE2 protein levels in primary human lung fibroblasts (HLFs). Our work is the first to investigate the association between ACE2 and HuR. Further investigation is needed to understand the mechanistic underpinning behind the regulation of ACE2 expression. Full article

(This article belongs to the Special Issue Advances in COPD)

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13 pages, 1116 KiB

Open AccessArticle

Dysregulation of the CD163-Haptoglobin Axis in the Airways of COPD Patients

by Andrew Higham, James M. Baker, Natalie Jackson, Rajesh Shah, Simon Lea and Dave Singh

Cells 2022, 11(1), 2; https://doi.org/10.3390/cells11010002 - 21 Dec 2021

Cited by 4 | Viewed by 2749

Abstract

Pulmonary iron levels are increased in chronic obstructive pulmonary disease (COPD) patients. Iron causes oxidative stress and is a nutrient for pathogenic bacteria. Iron may therefore play an important role in the pathophysiology of COPD. The CD163-haptglobin axis plays a central role in [...] Read more.

Pulmonary iron levels are increased in chronic obstructive pulmonary disease (COPD) patients. Iron causes oxidative stress and is a nutrient for pathogenic bacteria. Iron may therefore play an important role in the pathophysiology of COPD. The CD163-haptglobin axis plays a central role in the regulation of iron bioavailability. The aim of this study was to examine dysregulation of the CD163-haptglobin axis in COPD. We measured soluble CD163 (sCD163) and haptoglobin levels in sputum supernatants by enzyme-linked immunosorbent assay (ELISA) and sputum macrophage CD163 and haptoglobin expression by flow cytometry in COPD patients and controls. SCD163 levels were lower in COPD patients compared to controls (p = 0.02), with a significant correlation to forced expiratory volume in 1 s (FEV1)% predicted (rho = 0.5, p = 0.0007). Sputum macrophage CD163 expression was similar between COPD patients and controls. SCD163 levels and macrophage CD163 expression were lower in COPD current smokers compared to COPD ex-smokers. Haptoglobin levels were not altered in COPD patients but were regulated by genotype. Macrophage CD163 and haptolgobin expression were significantly correlated, supporting the role of CD163 in the cellular uptake of haptoglobin. Our data implicates a dysfunctional CD163-haptoglobin axis in COPD, which may contribute to disease pathophysiology, presumably due to reduced clearance of extracellular iron. Full article

(This article belongs to the Special Issue Advances in COPD)

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15 pages, 4202 KiB

Open AccessArticle

Response to Electrostimulation Is Impaired in Muscle Cells from Patients with Chronic Obstructive Pulmonary Disease

by Matthias Catteau, Emilie Passerieux, Léo Blervaque, Farés Gouzi, Bronia Ayoub, Maurice Hayot and Pascal Pomiès

Cells 2021, 10(11), 3002; https://doi.org/10.3390/cells10113002 - 03 Nov 2021

Cited by 5 | Viewed by 2149

Abstract

Among the comorbidities associated with chronic obstructive pulmonary disease (COPD), skeletal muscle weakness and atrophy are known to affect patient survival rate. In addition to muscle deconditioning, various systemic and intrinsic factors have been implicated in COPD muscle dysfunction but an impaired COPD [...] Read more.

Among the comorbidities associated with chronic obstructive pulmonary disease (COPD), skeletal muscle weakness and atrophy are known to affect patient survival rate. In addition to muscle deconditioning, various systemic and intrinsic factors have been implicated in COPD muscle dysfunction but an impaired COPD muscle adaptation to contraction has never been extensively studied. We submitted cultured myotubes from nine healthy subjects and nine patients with COPD to an endurance-type protocol of electrical pulse stimulation (EPS). EPS induced a decrease in the diameter, covered surface and expression of MHC1 in COPD myotubes. Although the expression of protein degradation markers was not affected, expression of the protein synthesis marker mTOR was not induced in COPD compared to healthy myotubes after EPS. The expression of the differentiation markers p16^INK4a and p21 was impaired, while expression of Myf5 and MyoD tended to be affected in COPD muscle cells in response to EPS. The expression of mitochondrial biogenesis markers PGC1α and MFN2 was affected and expression of TFAM and COX1 tended to be reduced in COPD compared to healthy myotubes upon EPS. Lipid peroxidation was increased and the expression of the antioxidant enzymes SOD2 and GPx4 was affected in COPD compared to healthy myotubes in response to EPS. Thus, we provide evidence of an impaired response of COPD muscle cells to contraction, which might be involved in the muscle weakness observed in patients with COPD. Full article

(This article belongs to the Special Issue Advances in COPD)

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16 pages, 5493 KiB

Open AccessArticle

Cortactin Modulates Lung Endothelial Apoptosis Induced by Cigarette Smoke

by Mounica Bandela, Eleftheria Letsiou, Viswanathan Natarajan, Lorraine B. Ware, Joe G. N. Garcia, Sunit Singla and Steven M. Dudek

Cells 2021, 10(11), 2869; https://doi.org/10.3390/cells10112869 - 24 Oct 2021

Cited by 5 | Viewed by 2863

Abstract

Cigarette smoke (CS) is the primary cause of Chronic Obstructive Pulmonary Disease (COPD), and an important pathophysiologic event in COPD is CS-induced apoptosis in lung endothelial cells (EC). Cortactin (CTTN) is a cytoskeletal actin-binding regulatory protein with modulation by Src-mediated tyrosine phosphorylation. Based [...] Read more.

Cigarette smoke (CS) is the primary cause of Chronic Obstructive Pulmonary Disease (COPD), and an important pathophysiologic event in COPD is CS-induced apoptosis in lung endothelial cells (EC). Cortactin (CTTN) is a cytoskeletal actin-binding regulatory protein with modulation by Src-mediated tyrosine phosphorylation. Based upon data demonstrating reduced CTTN mRNA levels in the lungs of smokers compared to non-smokers, we hypothesized a functional role for CTTN in CS-induced mitochondrial ROS generation and apoptosis in lung EC. Exposure of cultured human lung EC to CS condensate (CSC) led to the rearrangement of the actin cytoskeleton and increased CTTN tyrosine phosphorylation (within hours). Exposure to CS significantly increased EC mitochondrial ROS generation and EC apoptosis. The functional role of CTTN in these CSC-induced EC responses was explored using cortactin siRNA to reduce its expression, and by using a blocking peptide for the CTTN SH3 domain, which is critical to cytoskeletal interactions. CTTN siRNA or blockade of its SH3 domain resulted in significantly increased EC mitochondrial ROS and apoptosis and augmented CSC-induced effects. Exposure of lung EC to e-cigarette condensate demonstrated similar results, with CTTN siRNA or SH3 domain blocking peptide increasing lung EC apoptosis. These data demonstrate a novel role for CTTN in modulating lung EC apoptosis induced by CS or e-cigarettes potentially providing new insights into COPD pathogenesis. Full article

(This article belongs to the Special Issue Advances in COPD)

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Review

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19 pages, 1362 KiB

Open AccessReview

Impaired Alveolar Re-Epithelialization in Pulmonary Emphysema

by Chih-Ru Lin, Karim Bahmed and Beata Kosmider

Cells 2022, 11(13), 2055; https://doi.org/10.3390/cells11132055 - 28 Jun 2022

Cited by 12 | Viewed by 5705

Abstract

Alveolar type II (ATII) cells are progenitors in alveoli and can repair the alveolar epithelium after injury. They are intertwined with the microenvironment for alveolar epithelial cell homeostasis and re-epithelialization. A variety of ATII cell niches, transcription factors, mediators, and signaling pathways constitute [...] Read more.

Alveolar type II (ATII) cells are progenitors in alveoli and can repair the alveolar epithelium after injury. They are intertwined with the microenvironment for alveolar epithelial cell homeostasis and re-epithelialization. A variety of ATII cell niches, transcription factors, mediators, and signaling pathways constitute a specific environment to regulate ATII cell function. Particularly, WNT/β-catenin, YAP/TAZ, NOTCH, TGF-β, and P53 signaling pathways are dynamically involved in ATII cell proliferation and differentiation, although there are still plenty of unknowns regarding the mechanism. However, an imbalance of alveolar cell death and proliferation was observed in patients with pulmonary emphysema, contributing to alveolar wall destruction and impaired gas exchange. Cigarette smoking causes oxidative stress and is the primary cause of this disease development. Aberrant inflammatory and oxidative stress responses result in loss of cell homeostasis and ATII cell dysfunction in emphysema. Here, we discuss the current understanding of alveolar re-epithelialization and altered reparative responses in the pathophysiology of this disease. Current therapeutics and emerging treatments, including cell therapies in clinical trials, are addressed as well. Full article

(This article belongs to the Special Issue Advances in COPD)

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15 pages, 1782 KiB

Open AccessReview

Unraveling the Pathogenesis of Asthma and Chronic Obstructive Pulmonary Disease Overlap: Focusing on Epigenetic Mechanisms

by Yung-Che Chen, Yu-Ping Chang, Kuo-Tung Huang, Po-Yuan Hsu, Chang-Chun Hsiao and Meng-Chih Lin

Cells 2022, 11(11), 1728; https://doi.org/10.3390/cells11111728 - 24 May 2022

Cited by 4 | Viewed by 3133

Abstract

Asthma and COPD overlap (ACO) is characterized by patients presenting with persistent airflow limitation and features of both asthma and COPD. It is associated with a higher frequency and severity of exacerbations, a faster lung function decline, and a higher healthcare cost. Systemic [...] Read more.

Asthma and COPD overlap (ACO) is characterized by patients presenting with persistent airflow limitation and features of both asthma and COPD. It is associated with a higher frequency and severity of exacerbations, a faster lung function decline, and a higher healthcare cost. Systemic inflammation in COPD and asthma is driven by type 1 T helper (Th1) and Th2 immune responses, respectively, both of which may contribute to airway remodeling in ACO. ACO-related biomarkers can be classified into four categories: neutrophil-mediated inflammation, Th2 cell responses, arachidonic acid-eicosanoids pathway, and metabolites. Gene–environment interactions are key contributors to the complexity of ACO and are regulated by epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs. Thus, this review focuses on the link between epigenetics and ACO, and outlines the following: (I) inheriting epigenotypes without change with environmental stimuli, or epigenetic changes in response to long-term exposure to inhaled particles plus intermittent exposure to specific allergens; (II) epigenetic markers distinguishing ACO from COPD and asthma; (III) potential epigenetic drugs that can reverse oxidative stress, glucocorticoid insensitivity, and cell injury. Improved understanding of the epigenetic regulations holds great value to give deeper insight into the mechanisms, and clarify their implications for biomedical research in ACO. Full article

(This article belongs to the Special Issue Advances in COPD)

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27 pages, 1785 KiB

Open AccessReview

Angiogenesis, Lymphangiogenesis, and Inflammation in Chronic Obstructive Pulmonary Disease (COPD): Few Certainties and Many Outstanding Questions

by Remo Poto, Stefania Loffredo, Francesco Palestra, Gianni Marone, Vincenzo Patella and Gilda Varricchi

Cells 2022, 11(10), 1720; https://doi.org/10.3390/cells11101720 - 23 May 2022

Cited by 14 | Viewed by 4474

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, predominantly affecting the lung parenchyma and peripheral airways, that results in progressive and irreversible airflow obstruction. COPD development is promoted by persistent pulmonary inflammation in response to several stimuli (e.g., cigarette smoke, bacterial [...] Read more.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, predominantly affecting the lung parenchyma and peripheral airways, that results in progressive and irreversible airflow obstruction. COPD development is promoted by persistent pulmonary inflammation in response to several stimuli (e.g., cigarette smoke, bacterial and viral infections, air pollution, etc.). Angiogenesis, the formation of new blood vessels, and lymphangiogenesis, the formation of new lymphatic vessels, are features of airway inflammation in COPD. There is compelling evidence that effector cells of inflammation (lung-resident macrophages and mast cells and infiltrating neutrophils, eosinophils, basophils, lymphocytes, etc.) are major sources of a vast array of angiogenic (e.g., vascular endothelial growth factor-A (VEGF-A), angiopoietins) and/or lymphangiogenic factors (VEGF-C, -D). Further, structural cells, including bronchial and alveolar epithelial cells, endothelial cells, fibroblasts/myofibroblasts, and airway smooth muscle cells, can contribute to inflammation and angiogenesis in COPD. Although there is evidence that alterations of angiogenesis and, to a lesser extent, lymphangiogenesis, are associated with COPD, there are still many unanswered questions. Full article

(This article belongs to the Special Issue Advances in COPD)

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17 pages, 1329 KiB

Open AccessReview

Respiratory Viral and Bacterial Exacerbations of COPD—The Role of the Airway Epithelium

by Michelle E. Love and David Proud

Cells 2022, 11(9), 1416; https://doi.org/10.3390/cells11091416 - 22 Apr 2022

Cited by 11 | Viewed by 6077

Abstract

COPD is a leading cause of death worldwide, with acute exacerbations being a major contributor to disease morbidity and mortality. Indeed, exacerbations are associated with loss of lung function, and exacerbation frequency predicts poor prognosis. Respiratory infections are important triggers of acute exacerbations [...] Read more.

COPD is a leading cause of death worldwide, with acute exacerbations being a major contributor to disease morbidity and mortality. Indeed, exacerbations are associated with loss of lung function, and exacerbation frequency predicts poor prognosis. Respiratory infections are important triggers of acute exacerbations of COPD. This review examines the role of bacterial and viral infections, along with co-infections, in the pathogenesis of COPD exacerbations. Because the airway epithelium is the initial site of exposure both to cigarette smoke (or other pollutants) and to inhaled pathogens, we will focus on the role of airway epithelial cell responses in regulating the pathophysiology of exacerbations of COPD. This will include an examination of the interactions of cigarette smoke alone, and in combination with viral and bacterial exposures in modulating epithelial function and inflammatory and host defense pathways in the airways during COPD. Finally, we will briefly examine current and potential medication approaches to treat acute exacerbations of COPD triggered by respiratory infections. Full article

(This article belongs to the Special Issue Advances in COPD)

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19 pages, 1424 KiB

Open AccessReview

Methods of Sputum and Mucus Assessment for Muco-Obstructive Lung Diseases in 2022: Time to “Unplug” from Our Daily Routine!

by Jeremy Charriot, Mathilde Volpato, Aurélie Petit, Isabelle Vachier and Arnaud Bourdin

Cells 2022, 11(5), 812; https://doi.org/10.3390/cells11050812 - 25 Feb 2022

Cited by 5 | Viewed by 4984

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Advances in COPD)

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