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Article ; Online: Loss of Fas signaling in fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis

Elizabeth F. Redente / Sangeeta Chakraborty / Satria Sajuthi / Bart P. Black / Ben L. Edelman / Max A. Seibold / David W.H. Riches

JCI Insight, Vol 6, Iss

2021 Volume 1

Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the ... ...

Abstract	Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts, as well as continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, potentially novel flow cytometry strategies to quantify lung fibroblast subsets, and transcriptional profiling of lung fibroblasts by bulk and single cell RNA sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued profibrotic functions of lung fibroblasts. Our studies provide insights into the mechanisms that contribute to fibroblast survival, persistence, and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis impairs fibrosis resolution.
Keywords	Pulmonology ; Medicine ; R
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Loss of Fas signaling in fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis.

Redente, Elizabeth F / Chakraborty, Sangeeta / Sajuthi, Satria / Black, Bart P / Edelman, Ben L / Seibold, Max A / Riches, David Wh

JCI insight

2020 Volume 6, Issue 1

Abstract	Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts, as well as continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, potentially novel flow cytometry strategies to quantify lung fibroblast subsets, and transcriptional profiling of lung fibroblasts by bulk and single cell RNA sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued profibrotic functions of lung fibroblasts. Our studies provide insights into the mechanisms that contribute to fibroblast survival, persistence, and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis impairs fibrosis resolution.
MeSH term(s)	Animals ; Bleomycin/toxicity ; Disease Models, Animal ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Flow Cytometry ; Gene Expression Profiling ; Homeostasis ; Humans ; Idiopathic Pulmonary Fibrosis/chemically induced ; Idiopathic Pulmonary Fibrosis/metabolism ; Idiopathic Pulmonary Fibrosis/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; RNA-Seq ; Signal Transduction ; Single-Cell Analysis ; fas Receptor/deficiency ; fas Receptor/genetics
Chemical Substances	Fas protein, mouse ; fas Receptor ; Bleomycin (11056-06-7)
Language	English
Publishing date	2020-12-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.141618
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Author Correction: Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology.

Sajuthi, Satria P / Everman, Jamie L / Jackson, Nathan D / Saef, Benjamin / Rios, Cydney L / Moore, Camille M / Mak, Angel C Y / Eng, Celeste / Fairbanks-Mahnke, Ana / Salazar, Sandra / Elhawary, Jennifer / Huntsman, Scott / Medina, Vivian / Nickerson, Deborah A / Germer, Soren / Zody, Michael C / Abecasis, Gonçalo / Kang, Hyun Min / Rice, Kenneth M /

Kumar, Rajesh / Zaitlen, Noah A / Oh, Sam / Rodríguez-Santana, José / Burchard, Esteban G / Seibold, Max A

Nature communications

2022 Volume 13, Issue 1, Page(s) 5806

Language	English
Publishing date	2022-10-03
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-33097-z
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Article ; Online: Influenza virus infection increases ACE2 expression and shedding in human small airway epithelial cells.

Schweitzer, Kelly S / Crue, Taylor / Nall, Jordan M / Foster, Daniel / Sajuthi, Satria / Correll, Kelly A / Nakamura, Mari / Everman, Jamie L / Downey, Gregory P / Seibold, Max A / Bridges, James P / Serban, Karina A / Chu, Hong Wei / Petrache, Irina

The European respiratory journal

2021 Volume 58, Issue 1

Abstract: Background: Patients with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demonstrate high rates of co-infection with respiratory viruses, including influenza A (IAV), suggesting pathogenic ... ...

Abstract	Background: Patients with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demonstrate high rates of co-infection with respiratory viruses, including influenza A (IAV), suggesting pathogenic interactions. Methods: We investigated how IAV may increase the risk of COVID-19 lung disease, focusing on the receptor angiotensin-converting enzyme (ACE)2 and the protease TMPRSS2, which cooperate in the intracellular uptake of SARS-CoV-2. Results: We found, using single-cell RNA sequencing of distal human nondiseased lung homogenates, that at baseline, ACE2 is minimally expressed in basal, goblet, ciliated and secretory epithelial cells populating small airways. We focused on human small airway epithelial cells (SAECs), central to the pathogenesis of lung injury following viral infections. Primary SAECs from nondiseased donor lungs apically infected (at the air-liquid interface) with IAV (up to 3×10 Conclusion: These results indicate that IAV amplifies the expression of molecules necessary for SARS-CoV-2 infection of the distal lung. Furthermore, post-translational changes in ACE2 by IAV may increase vulnerability to lung injury such as acute respiratory distress syndrome during viral co-infections. These findings support efforts in the prevention and treatment of influenza infections during the COVID-19 pandemic.
MeSH term(s)	COVID-19 ; Epithelial Cells ; Humans ; Influenza, Human ; Pandemics ; Peptidyl-Dipeptidase A ; SARS-CoV-2
Chemical Substances	Peptidyl-Dipeptidase A (EC 3.4.15.1)
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639359-7
ISSN	1399-3003 ; 0903-1936
ISSN (online)	1399-3003
ISSN	0903-1936
DOI	10.1183/13993003.03988-2020
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Zs.A 2322: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 292: Show issues

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Article ; Online: Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium.

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

Nature communications

2020 Volume 11, Issue 1, Page(s) 2485

Abstract: Cigarette smoke first interacts with the lung through the cellularly diverse airway epithelium and goes on to drive development of most chronic lung diseases. Here, through single cell RNA-sequencing analysis of the tracheal epithelium from smokers and ... ...

Abstract	Cigarette smoke first interacts with the lung through the cellularly diverse airway epithelium and goes on to drive development of most chronic lung diseases. Here, through single cell RNA-sequencing analysis of the tracheal epithelium from smokers and non-smokers, we generate a comprehensive atlas of epithelial cell types and states, connect these into lineages, and define cell-specific responses to smoking. Our analysis infers multi-state lineages that develop into surface mucus secretory and ciliated cells and then contrasts these to the unique specification of submucosal gland (SMG) cells. Accompanying knockout studies reveal that tuft-like cells are the likely progenitor of both pulmonary neuroendocrine cells and CFTR-rich ionocytes. Our smoking analysis finds that all cell types, including protected stem and SMG populations, are affected by smoking through both pan-epithelial smoking response networks and hundreds of cell-specific response genes, redefining the penetrance and cellular specificity of smoking effects on the human airway epithelium.
MeSH term(s)	Animals ; Cells, Cultured ; Epithelial Cells/metabolism ; Gene Expression Profiling/methods ; Gene Knockout Techniques ; Gene Regulatory Networks ; Humans ; Lung/cytology ; Lung/metabolism ; Mice ; NIH 3T3 Cells ; Non-Smokers/statistics & numerical data ; Respiratory Mucosa/cytology ; Respiratory Mucosa/metabolism ; Sequence Analysis, RNA/methods ; Single-Cell Analysis/methods ; Smokers/statistics & numerical data ; Smoking/genetics ; Trachea/cytology ; Trachea/metabolism
Language	English
Publishing date	2020-05-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-16239-z
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Article ; Online: Genome-Wide Analysis Reveals Mucociliary Remodeling of the Nasal Airway Epithelium Induced by Urban PM

Montgomery, Michael T / Sajuthi, Satria P / Cho, Seung-Hyun / Everman, Jamie L / Rios, Cydney L / Goldfarbmuren, Katherine C / Jackson, Nathan D / Saef, Benjamin / Cromie, Meghan / Eng, Celeste / Medina, Vivian / Elhawary, Jennifer R / Oh, Sam S / Rodriguez-Santana, Jose / Vladar, Eszter K / Burchard, Esteban G / Seibold, Max A

American journal of respiratory cell and molecular biology

2020 Volume 63, Issue 2, Page(s) 172–184

Abstract: Air pollution particulate matter <2.5 μm ( ... ...

Abstract	Air pollution particulate matter <2.5 μm (PM
MeSH term(s)	Air Pollutants/adverse effects ; Air Pollution/adverse effects ; Asthma/chemically induced ; Asthma/genetics ; Genome-Wide Association Study/methods ; Humans ; Inflammation/chemically induced ; Inflammation/genetics ; Mucin 5AC/genetics ; Mucin-5B/genetics ; Nasal Mucosa/diagnostic imaging ; Particulate Matter/adverse effects ; Respiratory Mucosa/drug effects ; Transcription Factors/genetics
Chemical Substances	Air Pollutants ; Mucin 5AC ; Mucin-5B ; Particulate Matter ; Transcription Factors
Language	English
Publishing date	2020-04-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2019-0454OC
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Zs.A 2851: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Single-Cell and Population Transcriptomics Reveal Pan-epithelial Remodeling in Type 2-High Asthma.

Jackson, Nathan D / Everman, Jamie L / Chioccioli, Maurizio / Feriani, Luigi / Goldfarbmuren, Katherine C / Sajuthi, Satria P / Rios, Cydney L / Powell, Roger / Armstrong, Michael / Gomez, Joe / Michel, Cole / Eng, Celeste / Oh, Sam S / Rodriguez-Santana, Jose / Cicuta, Pietro / Reisdorph, Nichole / Burchard, Esteban G / Seibold, Max A

Cell reports

2020 Volume 32, Issue 1, Page(s) 107872

Abstract: The type 2 cytokine-high asthma endotype (T2H) is characterized by IL-13-driven mucus obstruction of the airways. To further investigate this incompletely understood pathobiology, we characterize IL-13 effects on human airway epithelial cell cultures ... ...

Abstract	The type 2 cytokine-high asthma endotype (T2H) is characterized by IL-13-driven mucus obstruction of the airways. To further investigate this incompletely understood pathobiology, we characterize IL-13 effects on human airway epithelial cell cultures using single-cell RNA sequencing, finding that IL-13 generates a distinctive transcriptional state for each cell type. Specifically, we discover a mucus secretory program induced by IL-13 in all cell types which converts both mucus and defense secretory cells into a metaplastic state with emergent mucin production and secretion, while leading to ER stress and cell death in ciliated cells. The IL-13-remodeled epithelium secretes a pathologic, mucin-imbalanced, and innate immunity-depleted proteome that arrests mucociliary motion. Signatures of IL-13-induced cellular remodeling are mirrored by transcriptional signatures characteristic of the nasal airway epithelium within T2H versus T2-low asthmatic children. Our results reveal the epithelium-wide scope of T2H asthma and present candidate therapeutic targets for restoring normal epithelial function.
MeSH term(s)	Asthma/genetics ; Biological Transport/drug effects ; Cellular Reprogramming/drug effects ; Child ; Cilia/drug effects ; Cilia/metabolism ; Down-Regulation/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Epithelium/drug effects ; Epithelium/metabolism ; Humans ; Immunity, Innate/drug effects ; Interferons/metabolism ; Interleukin-13/pharmacology ; Metaplasia ; Mucus/metabolism ; Single-Cell Analysis ; Transcriptome/drug effects ; Transcriptome/genetics
Chemical Substances	Interleukin-13 ; Interferons (9008-11-1)
Language	English
Publishing date	2020-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.107872
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Article ; Online: Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium

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

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 21

Abstract: Chronic lung diseases are characterized by molecular and cellular composition changes. Here the authors use single-cell RNA sequencing to map cell type-specific changes in human tracheal epithelium related to smoking, and to provide evidence for a tuft- ... ...

Abstract	Chronic lung diseases are characterized by molecular and cellular composition changes. Here the authors use single-cell RNA sequencing to map cell type-specific changes in human tracheal epithelium related to smoking, and to provide evidence for a tuft-like progenitor for pulmonary neuroendocrine cells and ionocytes.
Keywords	Science ; Q
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology.

Kumar, Rajesh / Zaitlen, Noah A / Oh, Sam / Rodríguez-Santana, José / Burchard, Esteban G / Seibold, Max A

Nature communications

2022 Volume 13, Issue 1, Page(s) 1632

Abstract: To identify genetic determinants of airway dysfunction, we performed a transcriptome-wide association study for asthma by combining RNA-seq data from the nasal airway epithelium of 681 children, with UK Biobank genetic association data. Our airway ... ...

Abstract	To identify genetic determinants of airway dysfunction, we performed a transcriptome-wide association study for asthma by combining RNA-seq data from the nasal airway epithelium of 681 children, with UK Biobank genetic association data. Our airway analysis identified 95 asthma genes, 58 of which were not identified by transcriptome-wide association analyses using other asthma-relevant tissues. Among these genes were MUC5AC, an airway mucin, and FOXA3, a transcriptional driver of mucus metaplasia. Muco-ciliary epithelial cultures from genotyped donors revealed that the MUC5AC risk variant increases MUC5AC protein secretion and mucus secretory cell frequency. Airway transcriptome-wide association analyses for mucus production and chronic cough also identified MUC5AC. These cis-expression variants were associated with trans effects on expression; the MUC5AC variant was associated with upregulation of non-inflammatory mucus secretory network genes, while the FOXA3 variant was associated with upregulation of type-2 inflammation-induced mucus-metaplasia pathway genes. Our results reveal genetic mechanisms of airway mucus pathobiology.
MeSH term(s)	Asthma/genetics ; Asthma/metabolism ; Child ; Epithelium/metabolism ; Humans ; Metaplasia/metabolism ; Mucin 5AC/genetics ; Mucin 5AC/metabolism ; Mucus/metabolism ; Transcriptome
Chemical Substances	Mucin 5AC
Language	English
Publishing date	2022-03-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-28973-7
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Article ; Online: Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

Satria P. Sajuthi / Jamie L. Everman / Nathan D. Jackson / Benjamin Saef / Cydney L. Rios / Camille M. Moore / Angel C. Y. Mak / Celeste Eng / Ana Fairbanks-Mahnke / Sandra Salazar / Jennifer Elhawary / Scott Huntsman / Vivian Medina / Deborah A. Nickerson / Soren Germer / Michael C. Zody / Gonçalo Abecasis / Hyun Min Kang / Kenneth M. Rice /

Rajesh Kumar / Noah A. Zaitlen / Sam Oh / NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium / José Rodríguez-Santana / Esteban G. Burchard / Max A. Seibold

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 17

Abstract: Understanding regulation of genes associated to disease can reveal insights into disease mechanisms. Here, the authors perform an airway epithelial transcriptome-wide association analysis to elucidate genetic determinants of airway dysfunction in asthma, ...

Abstract	Understanding regulation of genes associated to disease can reveal insights into disease mechanisms. Here, the authors perform an airway epithelial transcriptome-wide association analysis to elucidate genetic determinants of airway dysfunction in asthma, identifying genetic mechanisms of mucus pathobiology.
Keywords	Science ; Q
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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