Air pollutants, genetic susceptibility and risk of incident idiopathic pulmonary fibrosis

Cui, Fei-Peng; Sun, Yu; Xie, Junqing; Li, Dankang; Wu, Mingyang; Song, Lulu; Hu, Yonghua; Tian, Yaohua

doi:10.1183/13993003.00777-2022

Cited by 43 publications

(29 citation statements)

References 38 publications

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“…IL11 acts as master regulator in RA, orchestrating the CXCL dominated inflammatory response. IL11 with its bi-inflammatory signaling capacity has been described to be involved in a range of chronic inflammatory lung diseases, including asthma, COPD and IPF (Cui et al, 2022). Furthermore, it has gathered attention as potential therapeutic targeting (Ng et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Cytokine signaling converging onIL11in ILD fibroblasts provokes aberrant epithelial differentiation signatures

Kastlmeier

Rodriguez

Cabanis

et al. 2022

Preprint

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Fibrotic interstitial lung disease (ILD) is a group of lung disorders characterized by the accumulation of extracellular matrix, ultimately resulting in the destruction of the pulmonary scaffold. Continuous mesenchyme-derived profibrotic signaling perpetuates the remodeling process, specifically targeting the epithelial cell compartment, thereby destroying the gas exchange area. Studies that address this detrimental crosstalk between lung epithelial cells and fibroblasts are key to understanding ILD.With the aim of identifying functionally relevant targets that drive lung mesenchymal-epithelial crosstalk and their potential as new avenues to therapeutic strategies, we developed a 3D organoid co-culture system based on human induced pluripotent stem cell (hiPSC)-derived alveolar epithelial type 2 cells (iAT2s) and lung fibroblasts from ILD patients as well as IMR-90 controls. While organoid formation capacity and organoid size was comparable in the presence of ILD or control lung fibroblasts, metabolic activity was significantly increased in ILD co-cultures. Alveolar organoids cultured with ILD fibroblasts further demonstrated reduced stem cell function supported by reducedSurfactant Protein C (SFTPC)gene expression together with an aberrant basaloid-prone differentiation program indicated by elevatedCadherin 2 (CDH2), Bone Morphogenic Protein 4 (BMP4)andVimentin (VIM)transcription.In order to identify key mediators of the misguided mesenchymal-to-epithelial crosstalk with a focus on disease-relevant inflammatory processes, we used secretome mass spectrometry to identify key signals secreted by end stage ILD lung fibroblasts. Over 2000 proteins were detected in a single-shot experiment with 47 differentially upregulated proteins when comparing ILD and non-Chronic Lung Disease (CLD) control fibroblasts.The secretome profile was dominated by chemokines of the C-X-C motif family, including CXCL1, CXCL-3, and -8, all interfering with (epithelial) growth factor signaling orchestrated by Interleukin 11 (IL11), steering fibrogenic cell-cell communication, and proteins regulating extracellular matrix remodeling including epithelial-to-mesenchymal transition (EMT). When in turn treating 3D monocultures of iAT2s with IL11 we recapitulated the co-culture results obtained with primary ILD fibroblasts including changes in metabolic activity as well as organoid formation capacity and size.In summary, our analysis identified mesenchyme-derived mediators likely contributing to the disease-perpetuating mesenchymal-to-epithelial crosstalk in ILD by using sophisticated alveolar organoid co-cultures indicating the importance of cytokine-driven aberrant epithelial differentiation and confirmed IL11 as a key player in ILD using an unbiased approach.Abstract Figure

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Section: Resultsmentioning

confidence: 99%

Cytokine signaling converging onIL11in ILD fibroblasts provokes aberrant epithelial differentiation signatures

Kastlmeier

Rodriguez

Cabanis

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Air pollution is increasingly recognized as an integral risk factor for fibrotic interstitial lung disease (fILD) or interstitial lung abnormality (ILA) incidence, baseline severity, progression, acute exacerbations, hospitalizations and mortality 1–23 …”

Section: Figurementioning

confidence: 99%

“…Of 24 studies investigating the impact of air pollution on fILD‐related outcomes, only 10 (42%) incorporated socio‐economic covariates in any analyses (Figure 1A). 1–24 Furthermore, the specific socio‐economic covariates included in these studies vary widely in their composition and ability to capture such a multifaceted social determinant of health (Figure 1B). It is imperative that future work establishes robust and reproducible methods for considering the synergistic impacts of environmental and socio‐economic factors in patients with fILD.…”

Section: Figurementioning

confidence: 99%

“…How do these different pollutants interact, and do compositional differences in PM 2.5 between different geographic regions explain some of the differences in lung function outcomes between studies? 9,17,19 How do we disentangle the relationship between SES and air pollution to better define the impact of these risk factors in patients with fILD? What are the molecular mechanisms underlying pollution impacts in patients with fILD and how do these interact with genetic risk factors for disease incidence and progression? 15 While some may consider the question of whether air pollution adversely impacts patients with fILD answered, there remain many new roadways to explore.…”

Section: Figurementioning

confidence: 99%

“…What are the molecular mechanisms underlying pollution impacts in patients with fILD and how do these interact with genetic risk factors for disease incidence and progression? 15 While some may consider the question of whether air pollution adversely impacts patients with fILD answered, there remain many new roadways to explore. KEYWORDS air pollution, idiopathic pulmonary fibrosis, interstitial lung disease, nitrogen dioxide, particulate matter, socio-economic status…”

mentioning

confidence: 99%

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