A morphometric study of mucins and small airway plugging in cystic fibrosis

Burgel, Pierre‐Régis; Montani, David; Danel, Claire; Dusser, Daniel; Nadel, Jay A.

doi:10.1136/thx.2006.062190

Cited by 132 publications

(145 citation statements)

References 32 publications

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“…TNF-a released by LPS-activated macrophages could be considered as a therapeutic target to prevent mucus formation in chronic pulmonary disorders. This hypothesis is supported by the fact that increased lung macrophages, 24,27 as well as enhanced MUC5B phenotype, 4,6 have been shown in COPD and CF patients, and that high levels of TNF-a were also reported in tissues from individuals with COPD. 50 Among COPD patients, a group present chronic bronchitis, and COPD groups with or without chronic bronchitis have similar high amounts of macrophages in bronchial biopsies.…”

Section: Discussionsupporting

confidence: 63%

“…3 In baseline conditions of chronic inflammatory respiratory disorders, MUC5B and/or MUC5AC are increased in different compartments of the respiratory tract. [3][4][5][6] For example, MUC5B and MUC5AC are augmented in small airway lumen and epithelium from patients with advanced CF; 4 GCH related only with increased MUC5AC phenotype has been reported in bronchus from mild and moderate asthmatic patients; 5 and abnormally high amounts of MUC5B and MUC5AC are present in the sputum from individuals with COPD, MUC5B being the predominant mucin. 6 MUC5B and MUC5AC can be upregulated when human bronchus epithelial cells (HBEC) are cultured with retinoic acid, interleukin (IL)-6, IL-17, and neuroregulin1b1.…”

Section: Abstract: Airways; Cytokines; Lps; Lung Inflammation; Tnf-alphamentioning

confidence: 99%

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Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Silva

Berčík

2012

Laboratory Investigation

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Airway goblet cell hyperplasia (GCH)-detectable by mucin staining-and abnormal macrophage infiltrate are pathological features present in many chronic respiratory disorders. However, it is unknown if both factors are associated. Using in-vivo and in-vitro models, we investigated whether macrophages are related with GCH and changes in mucin immunophenotypes. Lung sections from Sprague-Dawley rats treated for 48 h with one intra-tracheal dose of PBS or LPS (n ¼ 4-6 per group) were immunophenotyped for rat-goblet cells, immune, and proliferation markers. Human monocytederived macrophages (MDM) were pre-treated with or without LPS, immunophenotyped, and their supernatant, as well as cytokines at levels equivalent to supernatant were used to challenge primary culture of normal human bronchus epithelial cells (HBEC) in air-liquid interface, followed by MUC5B and MUC5AC mucin immunostaining. An association between increased bronchiolar goblet cells and terminal-bronchiolar proliferative epithelial cells confirmed the presence of GCH in our LPS rat model, which was related with augmented bronchiolar CD68 macrophage infiltration. The in-vitro experiments have shown that MUC5AC phenotype was inhibited when HBEC were challenged with supernatant from MDM pre-treated with or without LPS. In contrast, TNF-a and interleukin-1b at levels equivalent to supernatant from LPS-treated MDM increased MUC5AC. MUC5B was induced by LPS, supernatant from LPS-treated MDM, a mix of cytokines including TNF-a and TNF-a alone at levels present in supernatant from LPS-treated MDM. We demonstrated that macrophages are related with bronchiolar GCH, and that they induced MUC5B and inhibited MUC5AC in HBEC, suggesting a role for them in the pathogenesis of airway MUC5B-related GCH. KEYWORDS: airways; cytokines; LPS; lung inflammation; TNF-alphaMucus is a gel that covers the airway epithelium and is constituted by different glycoproteins called mucins, which are secreted by goblet cells from submucosal glands and the airway epithelium. 1 Mucus dissolves noxious gases and entraps foreign particles and pathogens, facilitating their clearance by mucociliary transport as a mechanism of innate defense. 2 However, in chronic inflammatory respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), there is a pathological goblet cell hyperplasia (GCH) and mucus hypersecretion that can generate airway occlusion, associated with morbidity and death. 1 The main gel-forming mucins found in human airways are MUC5B and MUC5AC. 1 In healthy individuals, low levels of MUC5B and MUC5AC can be detected in mucus; although MUC5B is mainly present in the submucosal glands and MUC5AC is predominantly distributed in the airway epithelium. 3 In baseline conditions of chronic inflammatory respiratory disorders, MUC5B and/or MUC5AC are increased in different compartments of the respiratory tract. [3][4][5][6] For example, MUC5B and MUC5AC are augmented in small airway lumen and epithelium from patients with advanced CF; 4 GC...

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Section: Discussionsupporting

confidence: 63%

Section: Abstract: Airways; Cytokines; Lps; Lung Inflammation; Tnf-alphamentioning

confidence: 99%

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Silva

Berčík

2012

Laboratory Investigation

View full text Add to dashboard Cite

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“…Although CF pulmonary decline is attributed frequently to progressive mucus plugging and bronchiectasis (30)(31)(32)(33)(34)(35), peribronchiolar stenosis has been reported ORIGINAL RESEARCH frequently in "older" patients with CF (36)(37)(38). Lesions in our biopsied adolescent patients reflect similarities to findings in end-stage disease, suggesting the important contribution of distal airway limitation to respiratory decline.…”

Section: Discussionsupporting

confidence: 51%

Constrictive Bronchiolitis in Cystic Fibrosis Adolescents with Refractory Pulmonary Decline

et al. 2016

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Rationale: Refractory lung function decline in association with recurrent pulmonary exacerbations is a common, yet poorly explained finding in cystic fibrosis (CF). To investigate the histopathologic mechanisms of pulmonary deterioration during adolescence and early adulthood, we reviewed clinicallyindicated lung biopsy specimens obtained during a period of persistent decline.Objectives: To determine if peribronchiolar remodeling is prominent in lung biopsy specimens obtained in adolescents with CF refractory to conventional therapy.Methods: Six adolescents with CF (mean age, 16.2 y; mean FEV 1 , 52% predicted at biopsy) with significant pulmonary deterioration over 12-24 months (mean FEV 1 decline of 14% predicted/year) despite aggressive intervention underwent computed tomography imaging and ultimately lung biopsy to aid clinical management. In addition to routine clinical evaluation, histopathologic investigation included staining for transforming growth factor-b (TGF-b, a genetic modifier of CF lung disease), collagen deposition (a marker of fibrosis), elastin (to evaluate for bronchiectasis), and a-smooth muscle actin (to identify myofibroblasts).

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“…The luminal contents of tracheal sections were observed in situ under a confocal microscope to visualize the native GFP organization. Transgenic animals displayed strong signals depicting complex networks of interpenetrating GFP-positive material, which resembles the entangled mesh of endogenous mucus (14,17).…”

Section: Resultsmentioning

confidence: 99%

Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

Ehré

Worthington

Liesman

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

172

178

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MUC5AC, a major gel-forming mucin expressed in the lungs, is secreted at increased rates in response to infectious agents, implying that mucins exert a protective role against inhaled pathogens. However, epidemiological and pathological studies suggest that excessive mucin secretion causes airways obstruction and inflammation. To determine whether increased MUC5AC secretion alone produces airway obstruction and/or inflammation, we generated a mouse model overexpressing Muc5ac mRNA ∼20-fold in the lungs, using the rCCSP promoter. The Muc5ac cDNA was cloned from mouse lungs and tagged internally with GFP. Bronchoalveolar lavage fluid (BALF) analysis demonstrated an approximate 18-fold increase in Muc5ac protein, which formed high-molecular-weight polymers. Histopathological studies and cell counts revealed no airway mucus obstruction or inflammation in the lungs of Muc5ac-transgenic (Muc5ac-Tg) mice. Mucus clearance was preserved, implying that the excess Muc5ac secretion produced an “expanded” rather than more concentrated mucus layer, a prediction confirmed by electron microscopy. To test whether the larger mucus barrier conferred increased protection against pathogens, Muc5ac-Tg animals were challenged with PR8/H1N1 influenza viruses and showed significant decreases in infection and neutrophilic responses. Plaque assay experiments demonstrated that Muc5ac-Tg BALF and purified Muc5ac reduced infection, likely via binding to α2,3-linked sialic acids, consistent with influenza protection in vivo. In conclusion, the normal mucus transport and absence of a pulmonary phenotype in Muc5ac-Tg mice suggests that mucin hypersecretion alone is not sufficient to trigger luminal mucus plugging or airways inflammation/goblet cell hyperplasia. In contrast, increased Muc5ac secretion appears to exhibit a protective role against influenza infection.

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A morphometric study of mucins and small airway plugging in cystic fibrosis

Cited by 132 publications

References 32 publications

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Constrictive Bronchiolitis in Cystic Fibrosis Adolescents with Refractory Pulmonary Decline

Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

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