Ontogeny and Biology of Human Small Airway Epithelial Club Cells

Zuo, Wu-Lin; Shenoy, Sushila; Li, Sheng; O’Beirne, Sarah L.; Strulovici-Barel, Yael; Leopold, Philip L.; Wang, Guoqing; Staudt, Michelle R.; Walters, Matthew S.; Mason, Christopher; Kaner, Robert J.; Mezey, Jason G.; Crystal, Ronald G.

doi:10.1164/rccm.201710-2107oc

Cited by 83 publications

(86 citation statements)

References 49 publications

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“…Recently Choudhary et al (2005) reported that among human organs CYP4B1 transcripts were found predominantly in the lung (70% of organ distribution, the remainder in heart, skeletal muscle and kidney; none in the liver). Zuo et al (2018) demonstrated in samples-gained by bronchoscopy and by scraping from the human small airways epithelial Clara (Club) cells-transcripts of the following CYPs: 2F1 (very abundant), 4B1 (abundant), 2J2, 51A1, as well as CYB5R3 (cytochrome b5 reductase 3).…”

Section: Xenobiotica-metabolizing Enzymes In the Human Lungmentioning

confidence: 99%

“…Leclerc et al (2011) observed in the human bronchial mucosa high levels of FMO2 and moderate levels of FMO5 transcripts, and in pulmonary parenchyma high levels of both of them. Zuo et al (2018) demonstrated in samples-gained by bronchoscopy and by scraping from the human small airways epithelial Clara (Club) cells-transcripts of FMO2.…”

Section: Non-cyp Oxidoreductases (Tables 2 9)mentioning

confidence: 99%

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Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

2019

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The xenobiotic metabolism in the lung, an organ of first entry of xenobiotics into the organism, is crucial for inhaled compounds entering this organ intentionally (e.g. drugs) and unintentionally (e.g. work place and environmental compounds). Additionally, local metabolism by enzymes preferentially or exclusively occurring in the lung is important for favorable or toxic effects of xenobiotics entering the organism also by routes other than by inhalation. The data collected in this review show that generally activities of cytochromes P450 are low in the lung of all investigated species and in vitro models. Other oxidoreductases may turn out to be more important, but are largely not investigated. Phase II enzymes are generally much higher with the exception of UGT glucuronosyltransferases which are generally very low. Insofar as data are available the xenobiotic metabolism in the lung of monkeys comes closed to that in the human lung; however, very few data are available for this comparison. Second best rate the mouse and rat lung, followed by the rabbit. Of the human in vitro model primary cells in culture, such as alveolar macrophages and alveolar type II cells as well as the A549 cell line appear quite acceptable. However, (1) this generalization represents a temporary oversimplification born from the lack of more comparable data; (2) the relative suitability of individual species/models is different for different enzymes; (3) when more data become available, the conclusions derived from these comparisons quite possibly may change.

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Section: Xenobiotica-metabolizing Enzymes In the Human Lungmentioning

confidence: 99%

Section: Non-cyp Oxidoreductases (Tables 2 9)mentioning

confidence: 99%

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

2019

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“…Two genes were significantly upregulated in transplantable lungs, MTRNR2L1, (encoding humanin-like 1), and SCGB1A1, a secretoglobin expressed by club cells (39). The humanin gene family encodes for highly similar small secretory 21-24 amino acid peptides (57) that have been shown to be protect cells from oxidative stress, starvation and hypoxia (41) and MTRNR2L1 transcription is increased by oxidative stress and toll-like receptor 4 agonists (58), therefore, its upregulation may enhance cellular integrity in lungs in the face of cell stressors associated with the organ procurement process.…”

Section: Discussionmentioning

confidence: 99%

“…A recent single cell RNA sequencing analysis of small airways cells identified SCGB1A1 (also known as uteroglobin or CC10) as a canonical marker of club cells, and cell trajectory analysis indicate that they may have the capacity to both de-differentiate into basal cells (with stem capacity) and trans-differentiate into ciliated epithelial cells. Analysis of cell-specific gene expression suggests that club cells may also play novel roles in host defence and have anti-protease activity via the expression of α1-antitrypsin (an important neutrophil elastase inhibitor) and SLPI (secretory leucoprotease inhibitor, a potent serine protease inhibitor) (39). SCGB1A1 has been shown to have direct anti-inflammatory actions inhibiting NFkB activation and CXCL8 secretion in airway epithelial cells(42) (43).…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional analysis identifies novel biomarkers associated with successful ex-vivo perfusion of human donor lungs

Ferdinand

Andreasson

et al. 2019

Preprint

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Transplantation is an effective treatment for end-stage lung disease but donor organ shortage is a major problem. Ex-vivo lung perfusion (EVLP) of marginal organs enables functional assessment under normothermic conditions to facilitate clinical decision-making around utilisation, but the molecular processes occurring during EVLP, and how they differ between more or less viable lungs, remains to be determined. Here we used RNA sequencing to delineate changes in gene expression occurring in n=10 donor lungs undergoing EVLP, comparing lungs that were deemed transplantable (n=6) to those deemed unusable (n=4). We found that lungs deemed suitable for transplantation following EVLP had reduced induction of a number of innate immune pathways during EVLP, but a greater increase in genes involved in oxidative phosphorylation, a critical ATP-degenerating pathway. Furthermore, SCGB1A1, a gene encoding an anti-inflammatory secretoglobin CC10, and other club cell genes were significantly increased in transplantable lungs following perfusion, whilst CHIT-1 was decreased.Using a larger validation cohort (n=18), we confirmed that the ratio of CHIT1 and SCGB1A1 protein levels in lung perfusate have potential utility to distinguish transplantable and nontransplantable lungs (AUC 0.81). Together, our data identify novel biomarkers that may assist with pre-transplant lung assessment, as well as pathways that may amenable to therapeutic intervention during EVLP. Single sentence summaryTranscriptional changes in lungs undergoing ex vivo normothermic perfusion identify chitinase1 and club cell genes as potential biomarkers to guide utilisation

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A High‐Throughput Distal Lung Air–Blood Barrier Model Enabled By Density‐Driven Underside Epithelium Seeding

Viola

Washington

Selva

et al. 2021

Adv Healthcare Materials

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High‐throughput tissue barrier models can yield critical insights on how barrier function responds to therapeutics, pathogens, and toxins. However, such models often emphasize multiplexing capability at the expense of physiologic relevance. Particularly, the distal lung's air–blood barrier is typically modeled with epithelial cell monoculture, neglecting the substantial contribution of endothelial cell feedback in the coordination of barrier function. An obstacle to establishing high‐throughput coculture models relevant to the epithelium/endothelium interface is the requirement for underside cell seeding, which is difficult to miniaturize and automate. Therefore, this paper describes a scalable, low‐cost seeding method that eliminates inversion by optimizing medium density to float cells so they attach under the membrane. This method generates a 96‐well model of the distal lung epithelium–endothelium barrier with serum‐free, glucocorticoid‐free air–liquid differentiation. The polarized epithelial–endothelial coculture exhibits mature barrier function, appropriate intercellular junction staining, and epithelial‐to‐endothelial transmission of inflammatory stimuli such as polyinosine:polycytidylic acid (poly(I:C)). Further, exposure to influenza A virus PR8 and human beta‐coronavirus OC43 initiates a dose‐dependent inflammatory response that propagates from the epithelium to endothelium. While this model focuses on the air–blood barrier, the underside seeding method is generalizable to various coculture tissue models for scalable, physiologic screening.

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Ontogeny and Biology of Human Small Airway Epithelial Club Cells

Abstract: These observations provide novel insights into the molecular phenotype and biologic functions of the human club cell population and identify basal cells as the human progenitor cells for club cells.

Cited by 83 publications

References 49 publications

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

Transcriptional analysis identifies novel biomarkers associated with successful ex-vivo perfusion of human donor lungs

A High‐Throughput Distal Lung Air–Blood Barrier Model Enabled By Density‐Driven Underside Epithelium Seeding

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