Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium

Goldfarbmuren, K.C.; Jackson, Nathan D.; Sajuthi, Satria; Dyjack, Nathan; Li, Katie S.; Rios, Cydney; Plender, Elizabeth G.; Montgomery, Michael T.; Everman, Jamie L.; Bratcher, Preston E.; Vladar, Eszter K.; Seibold, Max A.

doi:10.1038/s41467-020-16239-z

Cited by 177 publications

(231 citation statements)

References 79 publications

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“…We previously found that Bpifb1 and Muc5b gene expression was strongly correlated in mouse lung tissue 10 , and here we have shown that BPIFB1 and MUC5B protein are colocalized in airway epithelial cells and present in secreted mucus. Cellular co-expression between BPIFB1 and MUC5B mRNA has also been demonstrated in human airways by single cell RNA sequencing studies 30,31 and between BPIFB1 and MUC5AC protein in COPD 32 . Lastly, our finding that BPIFB1 is present in mucin secretory granules, which are tightly packed and only contain the necessary proteins for mucus, implicates an additional regulatory mechanism coupling these two proteins.…”

Section: Resultsmentioning

confidence: 90%

BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance

Donoghue

Markovetz

Morrison

et al. 2020

Preprint

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15Airway mucociliary clearance (MCC) is required for host defense and often diminished in 16 chronic lung diseases. Effective clearance depends upon coordinated actions of the airway 17 epithelium and a mobile mucus layer. Dysregulation of the primary secreted airway mucin 18 proteins, MUC5B and MUC5AC, is associated with a reduction in the rate of MCC; however, 19 how other secreted proteins impact the integrity of the mucus layer and MCC remains unclear. 20 We previously identified the gene Bpifb1 as a regulator of the levels of MUC5B in the airways 21 using genetic approaches. Here, we show that BPIFB1 is required for normal mucociliary 22 clearance in vivo using Bpifb1 knockout (KO) mice. Reduced MCC in Bpifb1 KO mice occurred in 23 the absence of defects in sodium or chloride ion transport or changes in ciliary beat frequency. 24 We found that BPIFB1 loss resulted in airway mucus flakes with significantly increased complex 25 viscosity, a key biophysical property of mucus known to impact MCC. Finally, BPIFB1 protein 26 colocalized with MUC5B in secretory granules and was present in mucus on the airway surface. 27 Collectively, our findings demonstrate that BPIFB1 is an important component of the 28 mucociliary apparatus in mice and may be a key protein constituent of the mucus network. 29 30 31 42 particular, the concentration, organization, and post-translational modifications of MUC5AC 43 and MUC5B have been shown to alter biophysical properties of mucus that are required for 44

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Section: Resultsmentioning

confidence: 90%

BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance

Donoghue

Markovetz

Morrison

et al. 2020

Preprint

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“…Secretory club cells (expressing CCSP , SCGB1A1 , and SCGB3A2 ) serve a protective role by both metabolizing inhaled toxins using cytochrome P450 in their smooth endoplasmic reticulum and through secretion of glycosaminoglycans, uteroglobin, and a surfactant-like substance ( 90 , 93 ). Tuft cells, originally described in the intestine as chemosensory cells that facilitate Th2 inflammation through their production of IL-25 and thymic stromal lymphopoietin (TSLP), have recently been identified as a rare airway EC type (identified by expression of POU2F3 ) ( 94 ). The role of pulmonary neuroendocrine cells (PNECs), present in bronchial airway epithelium (identified by expression of SYP , CHGA , PGP9.5 , ROBO2 , and ENO2 ), and their secretion of bioactive amines and peptides, remains poorly understood ( 95 ).…”

Section: Alveolar and Airway Ec Smentioning

confidence: 99%

Cross-Talk Between Alveolar Macrophages and Lung Epithelial Cells is Essential to Maintain Lung Homeostasis

Bissonnette

Lauzon-Joset

Debley³

et al. 2020

Front. Immunol.

127

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The main function of the lung is to perform gas exchange while maintaining lung homeostasis despite environmental pathogenic and non-pathogenic elements contained in inhaled air. Resident cells must keep lung homeostasis and eliminate pathogens by inducing protective immune response and silently remove innocuous particles. Which lung cell type is crucial for this function is still subject to debate, with reports favoring either alveolar macrophages (AMs) or lung epithelial cells (ECs) including airway and alveolar ECs. AMs are the main immune cells in the lung in steady-state and their function is mainly to dampen inflammatory responses. In addition, they phagocytose inhaled particles and apoptotic cells and can initiate and resolve inflammatory responses to pathogens. Although AMs release a plethora of mediators that modulate immune responses, ECs also play an essential role as they are more than just a physical barrier. They produce anti-microbial peptides and can secrete a variety of mediators that can modulate immune responses and AM functions. Furthermore, ECs can maintain AMs in a quiescent state by expressing anti-inflammatory membrane proteins such as CD200. Thus, AMs and ECs are both very important to maintain lung homeostasis and have to coordinate their action to protect the organism against infection. Thus, AMs and lung ECs communicate with each other using different mechanisms including mediators, membrane glycoproteins and their receptors, gap junction channels, and extracellular vesicles. This review will revisit characteristics and functions of AMs and lung ECs as well as different communication mechanisms these cells utilize to maintain lung immune balance and response to pathogens. A better understanding of the cross-talk between AMs and lung ECs may help develop new therapeutic strategies for lung pathogenesis.

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“…Expression of these genes and their associated programs in the nasal airway epithelium is of particular interest given that the nasal epithelium is the primary site of infection for upper airway respiratory viruses, including coronaviruses, and acts as the gateway through which upper airway infections can spread into the lung. The airway epithelium is composed of multiple resident cell types (e.g., mucus secretory, ciliated, basal stem cells and rare epithelial cell types) interdigitated with immune cells (e.g., T cells, mast cells, macrophages), and the relative abundance of these cell types in the epithelium can greatly influence the expression of particular genes 9 – 11 , including ACE2 and TMPRSS2 . Furthermore, since the airway epithelium acts as a sentinel for the entire respiratory system, its cellular composition, along with its transcriptional and functional characteristics, are significantly shaped by interaction with environmental stimuli.…”

Section: Introductionmentioning

confidence: 99%

Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium

et al. 2020

Self Cite

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Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

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Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium

Cited by 177 publications

References 79 publications

BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance

BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance

Cross-Talk Between Alveolar Macrophages and Lung Epithelial Cells is Essential to Maintain Lung Homeostasis

Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium

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