The role of club cell phenoconversion and migration in idiopathic pulmonary fibrosis

Fukumoto, Jutaro; Soundararajan, Ramani; Leung, Joseph C.K.; Cox, Ruan; Mahendrasah, Sanjay; Muthavarapu, Neha; Herrin, Travis; Czachor, Alexander; Tan, Lee Charles; Hosseinian, Nima; Patel, Priyanshi; Gone, Jayanthraj; Breitzig, Mason; Cho, Young; Cooke, Andrew; Galam, Lakshmi; Narala, Venkata Ramireddy; Pathak, Yashwant; Lockey, Richard F.; Kolliputi, Narasaiah

doi:10.18632/aging.101115

Cited by 25 publications

(32 citation statements)

References 26 publications

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“…9F & H). These results are compatible with our previous work showing abnormal distribution and arrangement of claudin-10-positive club cells in IPF lung [6]. To corroborate the relationship of the abnormal behavior of club cells with IPF pathogenesis, the amounts of claudin-10 were examined using western blotting.…”

Section: Resultssupporting

confidence: 91%

“…Recent advances in molecular and cellular biology have led to a consensus that continually damaged type II alveolar epithelial cells (AECs) serve as a trigger for IPF [4]. Compared to type II AECs, the role for club cells in IPF pathology is unclear and has been largely deemphasized until recently [5,6]. The relative difficulty of obtaining a pure population of primary club cells, compared to type II AECs, has also hindered our understanding of club cell behavior in IPF development.…”

Section: Introductionmentioning

confidence: 99%

“…Alveolar bronchiolization, a process of proliferation and alveolar migration of club cells and other bronchiolar epithelial cell types, has been documented since the 1970s [7]. Its potential relevance to pulmonary fibrosis has been examined in IPF as well as animal models of lung fibrosis [6,8,9]. A systematic lineage tracing approach supports the concept that migration of club cells is an inherent repair system [10], however a recent report by Akram et al suggests that the migratory club cells contribute to IPF progression by promoting lung epithelial cell death [5].…”

Section: Introductionmentioning

confidence: 99%

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Oxidative stress induces club cell proliferation and pulmonary fibrosis in Atp8b1 mutant mice

Fukumoto

Leung

Cox

et al. 2019

Aging

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Atp8b1 (ATPase, aminophospholipid transporter, class I, type 8B, member 1) is a cardiolipin transporter in the apical membrane of lung epithelial cells. While the role of Atp8b1 in pneumonia-induced acute lung injury (ALI) has been well studied, its potential role in oxidative stress-induced ALI is poorly understood. We herein show that Atp8b1G308V/G308V mice under hyperoxic conditions display exacerbated cell apoptosis at alveolar epithelium and aberrant proliferation of club cells at bronchiolar epithelium. This hyperoxia-induced ambivalent response in Atp8b1G308V/G308V lungs was followed by patchy distribution of non-uniform interstitial fibrosis at late recovery phase under normoxia. Since this club cell abnormality is commonly observed between Atp8b1G308V/G308V lungs under hyperoxic conditions and IPF lungs, we characterized this mouse fibrosis model focusing on club cells. Intriguingly, subcellular morphological analysis of IPF lungs, using transmission electron microscopy (TEM), revealed that metaplastic bronchiolar epithelial cells in fibrotic lesions and deformed type II alveolar epithelial cells (AECs) in alveoli with mild fibrosis, have common morphological features including cytoplasmic vacuolation and dysmorphic lamellar bodies. In conclusion, the combination of Atp8b1 mutation and hyperoxic insult serves as a novel platform to study unfocused role of club cells in IPF.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oxidative stress induces club cell proliferation and pulmonary fibrosis in Atp8b1 mutant mice

Fukumoto

Leung

Cox

et al. 2019

Aging

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“…In regard to the ontology of the MUC5B + club cells migrating to the alveoli in IPF, our previous study demonstrated that MUC5B is highly expressed in normal human small airway club cells [ 3 ], i.e., SCGB1A1 + MUC5B + club cells in broncholarization of the IPF lung might be the result of migration of club cells from human small airway epithelium [ 20 , 36 ]. Another possibility might be the small airway BC, since: (1) human small airway BC can differentiate into SCGB1A1 + MUC5B + club cells [ 3 ]; and (2) there are increased numbers of BC in the lower respiratory tract of the IPF lung [ 20 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of club cell biology in idiopathic pulmonary fibrosis

et al. 2020

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Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic fibrotic lung disease with an irreversible decline of lung function. “Bronchiolization”, characterized by ectopic appearance of airway epithelial cells in the alveolar regions, is one of the characteristic features in the IPF lung. Based on the knowledge that club cells are the major epithelial secretory cells in human small airways, and their major secretory product uteroglobin (SCGB1A1) is significantly increased in both serum and epithelial lining fluid of IPF lung, we hypothesize that human airway club cells contribute to the pathogenesis of IPF. By assessing the transcriptomes of the single cells from human lung of control donors and IPF patients, we identified two SCGB1A1 + club cell subpopulations, highly expressing MUC5B, a significant genetic risk factor strongly associated with IPF, and SCGB3A2, a marker heterogeneously expressed in the club cells, respectively. Interestingly, the cellular proportion of SCGB1A1 + MUC5B + club cells was significantly increased in IPF patients, and this club cell subpopulation highly expressed genes related to mucous production and immune cell chemotaxis. In contrast, though the cellular proportion did not change, the molecular phenotype of the SCGB1A1 + SCGB3A2 high club cell subpopulation was significantly altered in IPF lung, with increased expression of mucins, cytokine and extracellular matrix genes. The single cell transcriptomic analysis reveals the cellular and molecular heterogeneity of club cells, and provide novel insights into the biological functions of club cells in the pathogenesis of IPF.

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“…This hypothesis may explain the widely shared clinical observations that human lung cancer commonly develops during post-middle age in relatively peripheral regions of the lung. Idiopathic pulmonary fibrosis (IPF) is also a representative age-associated lung disease, in which 1) hyperplastic epithelial cells expressing ⌬Np63 are observed at bronchiolo-alveolar junctions (4), 2) elevated alveolar epithelial cell (AEC) apoptosis is frequently juxtaposed with hyperplastic cells (25), and 3) immature epithelial cells with club cell markers are widely distributed in various patterns (13). Observations in the current study suggest that age-associated functional deterioration of type II AECs is temporally related to expansion of epithelial progenitors in the distal lung, consistent with the histopathological features of IPF.…”

Section: C503mentioning

confidence: 99%

Altered expression of p63 isoforms and expansion of p63- and club cell secretory protein-positive epithelial cells in the lung as novel features of aging

Fukumoto

Patil

Krishnamurthy

et al. 2019

American Journal of Physiology-Cell Physiology

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Aging is a key contributor for subclinical progression of late-onset lung diseases. Basal, club, and type II alveolar epithelial cells (AECs) are lung epithelial progenitors whose capacities of differentiation are extensively studied. The timely transition of these cells in response to environmental changes helps maintain the intricate organization of lung structure. However, it remains unclear how aging affects their behavior. This paper demonstrates that the protein expression profiles of a type II AEC marker, prosurfactant protein C (pro-SPC), and a basal cell marker, p63, are altered in the lungs of 14-mo-old versus 7- to 9-wk-old mice. Expression of NH2-terminal-truncated forms of p63 (ΔNp63), a basal cell marker, and claudin-10, a club cell marker, in cytoplasmic extracts of lungs of 14-mo-old mice was upregulated. In contrast, nuclear expression of full-length forms of p63 (TAp63) decreases with age. These alterations in protein expression profiles coincide with dramatic changes in lung functions including compliance. Whole tissue lysates of middle-aged versus aged rhesus monkey lungs display similar age-associated alterations in pro-SPC expression. An age-associated decrease of TAp63 in nuclear lysates was observed in aged monkey group. Moreover, the lungs of 14-mo-old versus 7- to 9-wk-old mice display a wider spreading of ΔNp63-positive CCSP-positive bronchiolar epithelial cells. This expansion did not involve upregulation of Ki67, a representative proliferation marker. Collectively, it is postulated that 1) this expansion is secondary to a transition of progenitor cells committed to club cells from ΔNp63-negative to ΔNp63-positive status, and 2) high levels of cytoplasmic ΔNp63 expression trigger club cell migration.

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The role of club cell phenoconversion and migration in idiopathic pulmonary fibrosis

Cited by 25 publications

References 26 publications

Oxidative stress induces club cell proliferation and pulmonary fibrosis in Atp8b1 mutant mice

Oxidative stress induces club cell proliferation and pulmonary fibrosis in Atp8b1 mutant mice

Dysregulation of club cell biology in idiopathic pulmonary fibrosis

Altered expression of p63 isoforms and expansion of p63- and club cell secretory protein-positive epithelial cells in the lung as novel features of aging

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