MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities

Hunninghake, Gary M.; Hatabu, Hiroto; Okajima, Yuka; Gao, Wei; Dupuis, Josée; Latourelle, Jeanne C.; Nishino, Mizuki; Araki, Toshimitsu; Zazueta, Oscar E.; Kurugol, Sila; Ross, James C.; Estépar, Raúl San Jośe; Murphy, Elissa; Steele, Mark P.; Loyd, James E.; Schwarz, Marvin I.; Fingerlin, Tasha E.; Rosas, Iván O.; Washko, George R.; O’Connor, George T.; Schwartz, David A.

doi:10.1097/01.sa.0000435633.11233.8a

Cited by 76 publications

(157 citation statements)

References 10 publications

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“…46,47 More recently, Schwartz and colleagues have, through several publications, linked a common single-nucleotide polymorphism in the promoter region of the mucin gene MUC5B to idiopathic interstitial pneumonias, including IPF. [48][49][50] The mutations in the surfactant family proteins, SFTPC and SFTPA2, both expressed exclusively by type II alveolar epithelial cells (AECs) in the lungs, suggest that AEC dysfunction is a prominent feature of IPF. Furthermore, accumulating evidence supports endoplasmic reticulum (ER) stress with consequent apoptosis as a prominent feature in IPF.…”

Section: Discussionmentioning

confidence: 99%

Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture

Jónsdóttir

Arason

Pálsson

et al. 2015

Laboratory Investigation

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Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high morbidity and mortality. The cellular source of the fibrotic process is currently under debate with one suggested mechanism being epithelial-to-mesenchymal transition (EMT) in the alveolar region. In this study, we show that airway epithelium overlying fibroblastic foci in IPF contains a layer of p63-positive basal cells while lacking ciliated and goblet cells. This basal epithelium shows increased expression of CK14, Vimentin and N-cadherin while retaining E-cadherin. The underlying fibroblastic foci shows both E-and N-cadherin-positive cells. To determine if p63-positive basal cells were able to undergo EMT in culture, we treated VA10, a p63-positive basal cell line, with the serum replacement UltroserG. A sub-population of treated cells acquired a mesenchymal phenotype, including an E-to N-cadherin switch. After isolation, these cells portrayed a phenotype presenting major hallmarks of EMT (loss of epithelial markers, gain of mesenchymal markers, increased migration and anchorage-independent growth). This phenotypic switch was prevented in p63 knockdown (KD) cells. In conclusion, we show that airway epithelium overlying fibroblastic foci in IPF lacks its characteristic functional identity, shows increased reactivity of basal cells and acquisition of a partial EMT phenotype. This study suggests that some p63-positive basal cells are prone to phenotypic changes and could act as EMT progenitors in IPF.

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Section: Discussionmentioning

confidence: 99%

Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture

Jónsdóttir

Arason

Pálsson

et al. 2015

Laboratory Investigation

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“…We previously published data on the epidemiologic and genetic associations of 2,633 adults recruited from the Third Generation and Offspring Cohorts who participated in the FHS-MDCT2 (Multidetector Computed Tomography 2) study from November 2008 to April 2011 (2). In addition to questionnaires, physical examinations, and measurements of respiratory physiology, participants in the FHS-MDCT2 study completed a volumetric, inspiratory, chest CT (Discovery VCT 64 PET/CT; GE Healthcare, Waukesha, WI) covering the whole lung.…”

Section: Methodsmentioning

confidence: 99%

“…Mortality was ascertained as of December 2013 resulting in a median follow-up time of 4.0 years from the completion of the FHS-MDCT2 study. MUC5B promoter polymorphism genotyping (rs35705950) in the FHS was performed using Taqman Genotyping Assays (Applied Biosystems, Foster City, CA), as described previously (2).…”

Section: Methodsmentioning

confidence: 99%

“…To date, primarily cross-sectional analyses, have demonstrated that research participants with ILA are more likely to have respiratory symptoms (1,2) and physiologic decrements including reduced lung volumes (1-3), exercise capacity (4), diffusion capacity of carbon monoxide (2,5), and an increased risk of death (6). However, there has been no study that has attempted to determine if the progression or development of ILA, defined by serial chest CT examinations, is associated with adverse clinical outcomes.…”

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confidence: 99%

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Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study

Araki¹,

Putman

Hatabu³

et al. 2016

Am J Respir Crit Care Med

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268

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Rationale: The relationship between the development and/or progression of interstitial lung abnormalities (ILA) and clinical outcomes has not been previously investigated.Objectives: To determine the risk factors for, and the clinical consequences of, having ILA progression in participants from the Framingham Heart Study.Methods: ILA were assessed in 1,867 participants who had serial chest computed tomography (CT) scans approximately 6 years apart. Mixed effect regression (and Cox) models were used to assess the association between ILA progression and pulmonary function decline (and mortality).Measurements and Main Results: During the follow-up period 660 (35%) participants did not have ILA on either CT scan, 37 (2%) had stable to improving ILA, and 118 (6%) had ILA with progression (the remaining participants without ILA were noted to be indeterminate on at least one CT scan). Increasing age and increasing copies of the MUC5B promoter polymorphism were associated with ILA progression. After adjustment for covariates, ILA progression was associated with a greater FVC decline when compared with participants without ILA (20 ml; SE, 66 ml; P = 0.0005) and with those with ILA without progression (25 ml; SE, 611 ml; P = 0.03). Over a median follow-up time of approximately 4 years, after adjustment, ILA progression was associated with an increase in the risk of death (hazard ratio, 3.9; 95% confidence interval, 1.3-10.9; P = 0.01) when compared with those without ILA.Conclusions: These findings demonstrate that ILA progression in the Framingham Heart Study is associated with an increased rate of pulmonary function decline and increased risk of death.

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“…fibrotische Veränderun-gen im hochauflösenden (HR) CT-Thorax sind jedoch ausgesprochen häufig in der Normalbevöl-kerung der über 50-Jährigen. [3] Eine Studie, die jüngst diese Altersgruppe in Framingham (USA) untersucht hat, kommt zu dem Schluss, dass fibrotische Veränderungen der Lunge bei 7 % im HRCT festzustellen sind und dass 2 % eine relevante Lungenfibrose aufweisen.…”

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Die idiopathische Lungenfibrose

Prasse

2015

Pneumologie

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Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and a disease of the elderly. Cigarette smoking and longterm exposure to substances harming alveolar epithelial cells are risk factors for the development of IPF. There is also evidence for a genetic susceptibility. IPF is defined as the idiopathic variant of Usual Interstitial Pneumonitis (UIP). Diagnosis of IPF is complex and based on the exclusion of other diseases associated with an UIP pattern. The only cure is lung transplantation. In the last years there was a breakthrough in the treatment of IPF. With pirfenidone and nintedanib there are now two compounds approved for the treatment of IPF

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MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities

Abstract: BACKGROUND-A common promoter polymorphism (rs35705950) in MUC5B, the gene

Cited by 76 publications

References 10 publications

Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture

Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture

Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study

Die idiopathische Lungenfibrose

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