Paracrine SPARC signaling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis

Conforti, Franco; Ridley, Robert; Brereton, Christopher J.; Alzetani, Aiman; Johnson, Benjamin C.; Marshall, Ben G; Fletcher, Sophie; Ottensmeier, Christian; Richeldi, Luca; Skipp, Paul; Wang, Yihua; Jones, Mark G.; Davies, Donna E.

doi:10.1038/s41420-020-0289-9

Cited by 30 publications

(28 citation statements)

References 76 publications

(79 reference statements)

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“…In dataset GSE92592 ( 10 ), SPARC levels are increased in IPF tissues compared with control lungs ( p < 0.01; Fig. 5 C ; Table 1 ), consistent with our recent report ( 11 ). Further analysis of GSE99621 ( 12 ) showed that SPARC expression is increased not only in scarred but also in those macroscopically unaffected (normal-appearing) regions of IPF lung ( p < 0.05; Fig.…”

Section: Resultssupporting

confidence: 91%

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Bidirectional epithelial–mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis

Yao

Zhou

et al. 2021

Journal of Biological Chemistry

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Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2 to 4 years. Injury to and/or dysfunction of the alveolar epithelium is strongly implicated in IPF disease initiation, but the factors that determine whether fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that zinc finger E-box-binding homeobox 1–mediated epithelial–mesenchymal transition in human alveolar epithelial type II (ATII) cells augments transforming growth factor-β–induced profibrogenic responses in underlying lung fibroblasts via paracrine signaling. Here, we investigated bidirectional epithelial–mesenchymal crosstalk and its potential to drive fibrosis progression. RNA-Seq of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced epithelial–mesenchymal transition identified many differentially expressed genes including those involved in cell migration and extracellular matrix regulation. We confirmed that paracrine signaling between RAS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a zinc finger E-box-binding homeobox 1–tissue plasminogen activator axis. In a reciprocal fashion, paracrine signaling from transforming growth factor-β–activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially through the secreted protein acidic and rich in cysteine, which may signal via the epithelial growth factor receptor via epithelial growth factor–like repeats. Together, these data identify that aberrant bidirectional epithelial–mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining profibrotic signals.

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Section: Resultssupporting

confidence: 91%

“…We recently reported that paracrine SPARC signaling from IPFFs dysregulates alveolar epithelial barrier integrity ( 11 ). We therefore hypothesized that SPARC might also mediate RAS activation in ATII cells during fibroblast–epithelial crosstalk.…”

Section: Resultsmentioning

confidence: 99%

Bidirectional epithelial–mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis

Yao

Zhou

et al. 2021

Journal of Biological Chemistry

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“…For instance, AEC2 exposed to IPF fibroblast-conditioned media lead to aberrant epithelialization, a surrogate of IPF-related bronchiolization. In this study, further secretome analysis identified SPARC as key paracrine mediator of fibroblast-induced epithelial activation ( Conforti et al, 2020 ). In parallel, bronchiolar smooth muscle cell progenitors in the distal mesenchyme produce WNT-dependent FGF10, allowing distal lung to repair after injury via differentiation of bronchial stem cells ( Volckaert et al, 2011 ).…”

Section: Epithelium–mesenchyme Crosstalk In Respiratory Diseasesmentioning

confidence: 78%

Epithelial Barrier Dysfunction in Chronic Respiratory Diseases

2021

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Mucosal surfaces are lined by epithelial cells, which provide a complex and adaptive module that ensures first-line defense against external toxics, irritants, antigens, and pathogens. The underlying mechanisms of host protection encompass multiple physical, chemical, and immune pathways. In the lung, inhaled agents continually challenge the airway epithelial barrier, which is altered in chronic diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, or pulmonary fibrosis. In this review, we describe the epithelial barrier abnormalities that are observed in such disorders and summarize current knowledge on the mechanisms driving impaired barrier function, which could represent targets of future therapeutic approaches.

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“…RTqPCR was performed as previously described 3,50,51…”

Section: Reverse Transcription Quantitative Polymerase Chain Reaction (Rtqpcr)mentioning

confidence: 99%

Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis

Brereton

Zhou

et al. 2021

Preprint

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Extracellular matrix (ECM) stiffening with downstream activation of mechanosensitive pathways is strongly implicated in fibrosis. We previously reported that altered collagen nanoarchitecture is a key determinant of pathogenetic ECM structure-function in human fibrosis (Jones et al., 2018). Here, through human tissue, bioinformatic and ex vivo studies we show that hypoxia-inducible factor (HIF) pathway activation is a critical pathway for this process regardless of oxygen status (pseudohypoxia). Whilst TGFβ increased rate of fibrillar collagen synthesis, HIF pathway activation was required to dysregulate post-translational modification of fibrillar collagen, promoting 'bone-type' cross-linking, altering collagen nanostructure, and increasing tissue stiffness. In vitro, knock down of Factor Inhibiting HIF (FIH) or oxidative stress caused pseudohypoxic HIF activation in normal fibroblasts. In contrast, endogenous FIH activity was reduced in fibroblasts from patients with lung fibrosis in association with significantly increased normoxic HIF pathway activation. In human lung fibrosis tissue, HIF mediated signalling was increased at sites of active fibrogenesis whilst subpopulations of IPF lung mesenchymal cells had increases in both HIF and oxidative stress scores. Our data demonstrate that oxidative stress can drive pseudohypoxic HIF pathway activation which is a critical regulator of pathogenetic collagen-structure function in fibrosis.

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Paracrine SPARC signaling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis

Cited by 30 publications

References 76 publications

Bidirectional epithelial–mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis

Bidirectional epithelial–mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis

Epithelial Barrier Dysfunction in Chronic Respiratory Diseases

Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis

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