Mucins MUC5B and MUC5AC in Distal Airways and Honeycomb Spaces: Comparison among Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia, Fibrotic Nonspecific Interstitial Pneumonitis, and Control Lungs

Conti, Caterina; Montero-Fernandez, Ángeles; Borg, Elaine; Osadolor, Tina; Viola, Patrizia; Lauretis, Angelo De; Stock, Carmel; Bonifazi, Martina; Bonini, Matteo; Caramori, Gaetano; Lindahl, Gisela; Blasi, Francesco; Nicholson, Andrew G.; Wells, Athol U.; Sestini, Piersante; Renzoni, Elisabetta A.

doi:10.1164/rccm.201507-1322le

Cited by 43 publications

(27 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The minor allele causes increased MUC5B production by distal bronchiolar epithelial cells, and MUC5B protein accumulates in the honeycomb cysts of IPF lungs. 10 , 36 , 37 The prevailing theories are that over-production of MUC5B impairs mucociliary clearance, contributes to lung injury or epithelial cell stress and/or disrupts reparative mechanisms in the distal lung, leading to lung fibrosis. 38 …”

Section: Discussionmentioning

confidence: 99%

The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study

Ley

Newton

Arnould

et al. 2017

The Lancet Respiratory Medicine

233

168

View full text Add to dashboard Cite

SUMMARY Background Patients with hypersensitivity pneumonitis (HP) may develop lung fibrosis, which is associated with reduced survival. Families with pulmonary fibrosis can present with members diagnosed with idiopathic pulmonary fibrosis (IPF) or chronic HP (cHP), suggesting that fibrotic HP may share risk factors with IPF. Methods In an observational study of two independent cohorts of patients with cHP (UCSF n=145, UTSW n=72), we measured two common single nucleotide polymorphisms associated with IPF (MUC5B rs35705950 & TOLLIP rs5743890) and peripheral blood leukocyte telomere length and evaluated their associations with cHP disease, survival, and clinical-radiograph-pathologic features. Findings The frequency of the MUC5B minor allele, but not the TOLLIP minor allele, was significantly increased in cHP patients in both cohorts (UCSF MAF 24.4% & UTSW MAF 32.3%) compared to healthy controls (MAF 10.7%; p-values for comparison = <0.0001 for both cohorts) and similar to IPF (UCSF MAF 33.3% & UTSW MAF 32.0%, p-values for comparison=0.10 & 0.95, respectively). The MUC5B minor allele (adjusted OR 1.91, p=0.045) and shorter telomere length (adjusted OR 0.23, p=0.002) were associated with extent of radiographic fibrosis and other measures of lung remodeling and fibrosis in the combined cHP cohorts. Shorter telomere length had a significant association (adjusted HR 0.18, p=0.001) with reduced survival in the combined cHP cohorts. Interpretation The MUC5B promoter polymorphism rs35705950 and shorter telomere length are associated with extent of fibrosis in cHP. Shorter telomere length is associated with histopathology findings typical of usual interstitial pneumonia and reduced survival in cHP. Funding NIH grants KL2TR001870, T32HL098040, UL1TR001105, R01HL093096, and the Nina Ireland Program for Lung Health.

show abstract

Section: Discussionmentioning

confidence: 99%

The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study

Ley

Newton

Arnould

et al. 2017

The Lancet Respiratory Medicine

233

168

View full text Add to dashboard Cite

show abstract

“…Importantly, recent studies of normal and diseased tissues have established the presence of MUC5B expression in superficial epithelia, suggesting distal airway superficial epithelia may locally secrete the MUC5B associated with plugging (19)(20)(21). Of particular relevance to small airway MUC5B expression is the discovery of the link between MUC5B overexpression in peripheral airways and idiopathic pulmonary fibrosis (IPF) (22,23).…”

mentioning

confidence: 99%

Localization of Secretory Mucins MUC5AC and MUC5B in Normal/Healthy Human Airways

Okuda

Chen

Subramani

et al. 2019

Am J Respir Crit Care Med

219

166

View full text Add to dashboard Cite

Rationale: MUC5AC and MUC5B are the predominant gel-forming mucins in the mucus layer of human airways. Each mucin has distinct functions and site-specific expression. However, the regional distribution of expression and cell types that secrete each mucin in normal/healthy human airways are not fully understood. Objectives: To characterize the regional distribution of MUC5B and MUC5AC in normal/healthy human airways and assess which cell types produce these mucins, referenced to the club cell secretory protein (CCSP). Methods: Multiple airway regions from 16 nonsmoker lungs without a history of lung disease were studied. MUC5AC, MUC5B, and CCSP expression/colocalization were assessed by RNA in situ hybridization and immunohistochemistry in five lungs with histologically healthy airways. Droplet digital PCR and cell cultures were performed for absolute quantification of MUC5AC/5B ratios and protein secretion, respectively. Measurements and Main Results: Submucosal glands expressed MUC5B, but not MUC5AC. However, MUC5B was also extensively expressed in superficial epithelia throughout the airways except for the terminal bronchioles. Morphometric calculations revealed that the distal airway superficial epithelium was the predominant site for MUC5B expression, whereas MUC5AC expression was concentrated in proximal, cartilaginous airways. RNA in situ hybridization revealed MUC5AC and MUC5B were colocalized with CCSP-positive secretory cells in proximal superficial epithelia, whereas MUC5B and CCSP-copositive cells dominated distal regions. Conclusions: In normal/healthy human airways, MUC5B is the dominant secretory mucin in the superficial epithelium and glands, with distal airways being a major site of expression. MUC5B and MUC5AC expression is a property of CCSP-positive secretory cells in superficial airway epithelia.

show abstract

“…The current consensus is that IPF is a consequence of multiple interacting genetic and environmental risk factors, with repeated damage and premature aging of alveolar epithelial cells (AECs) in genetically susceptible individuals ( Wells and Maher, 2017 ). One robust genetic linkages to IPF is MUC5B polymorphism; however, the role of this gene in IPF pathogenesis remains undefined ( Conti et al, 2016 ; Nakano et al, 2016 ). Unsurprisingly, the prototypic pro-fibrotic transforming growth factor-β (TGFβ) plays a central role in IPF, and while its function is well described, the source of excess TGFβ and activation of its latent form are poorly understood.…”

Section: Lung Fibrosismentioning

confidence: 99%

Cell-Based Therapies for Tissue Fibrosis

2017

View full text Add to dashboard Cite

The development of tissue fibrosis in the context of a wound-healing response to injury is common to many chronic diseases. Unregulated or persistent fibrogenesis may lead to structural and functional changes in organs that increase the risk of significant morbidity and mortality. We will explore the natural history, epidemiology, and pathogenesis of fibrotic disease affecting the lungs, kidneys, and liver as dysfunction of these organs is responsible for a substantial proportion of global mortality. For many patients with end-stage disease, organ transplantation is the only effective therapy to prolong life. However, not all patients are candidates for the major surgical interventions and life-long immunosuppression required for a successful outcome and donor organs may not be available to meet the clinical need. We will provide an overview of the latest treatment strategies for these conditions and will focus on stem or progenitor cell-based therapies for which there is substantial pre-clinical evidence based on animal models as well as early phase clinical trials of cell-based therapy in man.

show abstract

Mucins MUC5B and MUC5AC in Distal Airways and Honeycomb Spaces: Comparison among Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia, Fibrotic Nonspecific Interstitial Pneumonitis, and Control Lungs

Abstract: ------

Cited by 43 publications

References 15 publications

The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study

The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study

Localization of Secretory Mucins MUC5AC and MUC5B in Normal/Healthy Human Airways

Cell-Based Therapies for Tissue Fibrosis

Contact Info

Product

Resources

About