Association of the RAGE/RAGE-ligand axis with interstitial lung disease and its acute exacerbation

Yamaguchi, Kakuhiro; Iwamoto, Hiroshi; Sakamoto, Shinjiro; Horimasu, Yasushi; Masuda, Takeshi; Miyamoto, Shintaro; Nakashima, Toshikatsu; Fujitaka, Kazunori; Hamada, Hironobu; Hattori, Noboru

doi:10.1016/j.resinv.2022.04.004

Cited by 9 publications

(5 citation statements)

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“…Additionally, SFTPA1, a C‐type lectin, which binds to specific carbohydrate moieties on lipids and the surface of microorganisms, is essential in the defense against respiratory pathogens 25–27 while the pulmonary‐associated surfactant protein C encoded by SFTPC is a marker for COVID‐19 patients with high viral loads 28 . AGER, predominantly expressed in ACs (Figure 2C), is a multiligand receptor interacting with AGE and other molecules implicated in lung homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease, and regulates diverse pathways including MyD88‐dependent, nuclear receptors, TNF‐α, ERK1/2 and p38 MAPK, and p53/TP53 pathways 29–32 . Following interaction with S100A12, AGER triggers the activation of mononuclear phagocytes, lymphocytes, and endothelium by generating key proinflammatory mediators 33 .…”

Section: Resultsmentioning

confidence: 99%

“…28 AGER, predominantly expressed in ACs (Figure 2C), is a multiligand receptor interacting with AGE and other molecules implicated in lung homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease, and regulates diverse pathways including MyD88-dependent, nuclear receptors, TNF-α, ERK1/2 and p38 MAPK, and p53/TP53 pathways. [29][30][31][32] Following interaction with S100A12, AGER triggers the activation of mononuclear phagocytes, lymphocytes, and endothelium by generating key proinflammatory mediators. 33 Indeed, AGER-related pathways are activated by SARS-CoV-2 infection and are implicated in COVID-19 lung pathology.…”

Section: Sars-cov-2 Infection Alters the Cell Compositions Of Major P...mentioning

confidence: 99%

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Molecular and immune signatures, and pathological trajectories of fatal COVID‐19 lungs defined by in situ spatial single‐cell transcriptome analysis

Das

Meng

Liu

et al. 2023

Journal of Medical Virology

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Despite intensive studies during the last 3 years, the pathology and underlying molecular mechanism of coronavirus disease 2019 (COVID‐19) remain poorly defined. In this study, we investigated the spatial single‐cell molecular and cellular features of postmortem COVID‐19 lung tissues using in situ sequencing (ISS). We detected 10 414 863 transcripts of 221 genes in whole‐slide tissues and segmented them into 1 719 459 cells that were mapped to 18 major parenchymal and immune cell types, all of which were infected by SARS‐CoV‐2. Compared with the non‐COVID‐19 control, COVID‐19 lungs exhibited reduced alveolar cells (ACs) and increased innate and adaptive immune cells. We also identified 19 differentially expressed genes in both infected and uninfected cells across the tissues, which reflected the altered cellular compositions. Spatial analysis of local infection rates revealed regions with high infection rates that were correlated with high cell densities (HIHD). The HIHD regions expressed high levels of SARS‐CoV‐2 entry‐related factors including ACE2, FURIN, TMPRSS2 and NRP1, and co‐localized with organizing pneumonia (OP) and lymphocytic and immune infiltration, which exhibited increased ACs and fibroblasts but decreased vascular endothelial cells and epithelial cells, mirroring the tissue damage and wound healing processes. Sparse nonnegative matrix factorization (SNMF) analysis of niche features identified seven signatures that captured structure and immune niches in COVID‐19 tissues. Trajectory inference based on immune niche signatures defined two pathological routes. Trajectory A primarily progressed with increased NK cells and granulocytes, likely reflecting the complication of microbial infections. Trajectory B was marked by increased HIHD and OP, possibly accounting for the increased immune infiltration. The OP regions were marked by high numbers of fibroblasts expressing extremely high levels of COL1A1 and COL1A2. Examination of single‐cell RNA‐seq data (scRNA‐seq) from COVID‐19 lung tissues and idiopathic pulmonary fibrosis (IPF) identified similar cell populations consisting mainly of myofibroblasts. Immunofluorescence staining revealed the activation of IL6‐STAT3 and TGF‐β‐SMAD2/3 pathways in these cells, likely mediating the upregulation of COL1A1 and COL1A2 and excessive fibrosis in the lung tissues. Together, this study provides a spatial single‐cell atlas of cellular and molecular signatures of fatal COVID‐19 lungs, which reveals the complex spatial cellular heterogeneity, organization, and interactions that characterized the COVID‐19 lung pathology.

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Section: Resultsmentioning

confidence: 99%

Section: Sars-cov-2 Infection Alters the Cell Compositions Of Major P...mentioning

confidence: 99%

Molecular and immune signatures, and pathological trajectories of fatal COVID‐19 lungs defined by in situ spatial single‐cell transcriptome analysis

Das

Meng

Liu

et al. 2023

Journal of Medical Virology

View full text Add to dashboard Cite

show abstract

“…AGER, predominantly expressed in ACs (Fig. 2C), is a multiligand receptor interacting with AGE and other molecules implicated in lung homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer’s disease, and regulates diverse pathways including MyD88-dependent, nuclear receptors, TNF-α, ERK1/2 and p38 MAPK, and p53/TP53 pathways [20–23]. Following interaction with S100A12, AGER triggers the activation of mononuclear phagocytes, lymphocytes, and endothelium by generating key pro- inflammatory mediators [24].…”

Section: Resultsmentioning

confidence: 99%

Cellular and molecular heterogeneities and signatures, and pathological trajectories of fatal COVID-19 lungs defined by spatial single-cell transcriptome analysis

Das

Meng

Liu

et al. 2023

Preprint

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Despite intensive studies during the last 3 years, the pathology and underlying molecular mechanism of coronavirus disease 2019 (COVID-19) remain poorly defined. Here, we examined postmortem COVID-19 lung tissues by spatial single-cell transcriptome analysis (SSCTA). We identified 18 major parenchymal and immune cell types, all of which are infected by SARS-CoV-2. Compared to the non-COVID-19 control, COVID-19 lungs have reduced alveolar cells (ACs), and increased innate and adaptive immune cells. Additionally, 19 differentially expressed genes in both infected and uninfected cells across the tissues mirror the altered cellular compositions. Spatial analysis of local infection rates revealed regions with high infection rates that are correlated with high cell densities (HIHD). The HIHD regions express high levels of SARS-CoV-2 entry-related factors including ACE2, FURIN, TMPRSS2, and NRP1, and co-localized with organizing pneumonia (OP) and lymphocytic and immune infiltration that have increased ACs and fibroblasts but decreased vascular endothelial cells and epithelial cells, echoing the tissue damage and wound healing processes. Sparse non-negative matrix factorization (SNMF) analysis of neighborhood cell type composition (NCTC) features identified 7 signatures that capture structure and immune niches in COVID-19 tissues. Trajectory inference based on immune niche signatures defined two pathological routes. Trajectory A progresses with primarily increased NK cells and granulocytes, likely reflecting the complication of microbial infections. Trajectory B is marked by increased HIHD and OP, possibly accounting for the increased immune infiltration. The OP regions are marked by high numbers of fibroblasts expressing extremely high levels of COL1A1 and COL1A2. Examination of single-cell RNA-seq data (scRNA-seq) from COVID-19 lung tissues and idiopathic pulmonary fibrosis (IPF) identified similar cell populations primarily consisting of myofibroblasts. Immunofluorescence staining revealed the activation of IL6-STAT3 and TGF-β-SMAD2/3 pathways in these cells, which likely mediate the upregulation of COL1A1 and COL1A2, and excessive fibrosis in the lung tissues. Together, this study provides an SSCTA atlas of cellular and molecular signatures of fatal COVID-19 lungs, revealing the complex spatial cellular heterogeneity, organization, and interactions that characterized the COVID-19 lung pathology.

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“…1. Additionally, there are many other factors, such as the receptor for advanced glycation end product [68], adipose-derived mesenchymal stem cells [69], etc., need to be further investigated. However, given that existing models do not fully recapitulate physiologic findings in AE-IPF [48], functional studies examining host-microbiome interactions as well as better models of AE-PF are needed.…”

Section: The Pathogenesis Of Ae-ipfmentioning

confidence: 99%

Animal models of acute exacerbation of pulmonary fibrosis

Ye,

Zhang,

et al. 2023

Respir Res

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive scarring interstitial lung disease with an unknown cause. Some patients may experience acute exacerbations (AE), which result in severe lung damage visible on imaging or through examination of tissue samples, often leading to high mortality rates. However, the etiology and pathogenesis of AE-IPF remain unclear. AE-IPF patients exhibit diffuse lung damage, apoptosis of type II alveolar epithelial cells, and an excessive inflammatory response. Establishing a reliable animal model of AE is critical for investigating the pathogenesis. Recent studies have reported a variety of animal models for AE-IPF, each with its own advantages and disadvantages. These models are usually established in mice with bleomycin-induced pulmonary fibrosis, using viruses, bacteria, small peptides, or specific drugs. In this review, we present an overview of different AE models, hoping to provide a useful resource for exploring the mechanisms and targeted therapies for AE-IPF.

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Association of the RAGE/RAGE-ligand axis with interstitial lung disease and its acute exacerbation

Cited by 9 publications

References 90 publications

Molecular and immune signatures, and pathological trajectories of fatal COVID‐19 lungs defined by in situ spatial single‐cell transcriptome analysis

Molecular and immune signatures, and pathological trajectories of fatal COVID‐19 lungs defined by in situ spatial single‐cell transcriptome analysis

Cellular and molecular heterogeneities and signatures, and pathological trajectories of fatal COVID-19 lungs defined by spatial single-cell transcriptome analysis

Animal models of acute exacerbation of pulmonary fibrosis

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