A phosphatidylinositol 3-kinase inhibitor strongly suppressed pulmonary vascular remodeling of allergic vasculitis in a murine model

Oikawa, Yuka; Sasaki, Nobuyuki; Niisato, Miyuki; Nakamura, Yutaka; Yamauchi, Kohei

doi:10.3109/01902148.2016.1157226

Cited by 7 publications

(7 citation statements)

References 26 publications

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“…Recent studies indicate that inhibition of the Akt/mTOR pathway can impair EOS chemotaxis and recruitment, decrease EOS longevity and responsiveness, and attenuate eosinophilic inflammation [ 50 , 51 ]. Inhibition of the Akt/mTOR pathway can also downregulate tissue remodeling during allergic airway inflammation [ 52 ]. However, we found no correlation between activation of the Akt/mTOR pathway and eosinophilic inflammation or tissue remodeling.…”

Section: Discussionmentioning

confidence: 99%

The Roles of Autophagy, Mitophagy, and the Akt/mTOR Pathway in the Pathogenesis of Chronic Rhinosinusitis with Nasal Polyps

Wang

Zhou

Liu

et al. 2022

Journal of Immunology Research

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The pathogenesis of CRSwNP is complex and unclear. CRSwNP is subdivided into two types based on the infiltration of EOSs: eCRSwNP and noeCRSwNP. This study was designed to seek the role of autophagy, mitophagy, and Akt/mTOR pathway in these two subtypes of CRSwNP. This study included 29 patients with CRSwNP and 9 controls. The levels of autophagy, mitophagy, and Akt/mTOR pathway-related proteins in nasal tissues were quantified using western blot analysis. Levels of eosinophilic inflammation-related cytokines in nasal tissues were quantified by enzyme-linked immunosorbent assay. Immunohistochemistry was also used to evaluate autophagy, mitophagy, and Akt/mTOR pathway-related protein expression and distribution in nasal polyps and control tissues. Transmission electron microscopy was used to detect the formation of autophagosomes and mitochondrial autophagosomes. Masson’s trichrome and periodic acid–Schiff Alcian blue staining were used to evaluate the severity of tissue remodeling. The expression of p-Akt/Akt and p-mTOR/mTOR was upregulated in patients with eCRSwNP or noeCRSwNP. Beclin 1, PINK1, BNIP3, and FUNDC1 levels were significantly reduced in the nasal polyps of patients with eCRSwNP or noeCRSwNP. Autophagosomes and mitochondrial autophagosomes formed less frequently in the nasal polyps of patients with eCRSwNP or noeCRSwNP. Levels of IL-4, IL-5, IL-13, and ECP and the eotaxins CCL11, CCL24, and CCL26 were elevated in the nasal polyps of patients with eCRSwNP or noeCRSwNP. Tissue remodeling is enhanced in patients with eCRSwNP or noeCRSwNP. The Akt/mTOR pathway, eosinophilic inflammation, and tissue remodeling are activated in the nasal polyps of patients with eCRSwNP or noeCRSwNP. The downregulation of autophagy and mitophagy is also observed in eosinophilic and noneosinophilic nasal polyps. The targeting of mitophagy may provide new therapeutic options for different endotypes of CRSwNP.

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Section: Discussionmentioning

confidence: 99%

The Roles of Autophagy, Mitophagy, and the Akt/mTOR Pathway in the Pathogenesis of Chronic Rhinosinusitis with Nasal Polyps

Wang

Zhou

Liu

et al. 2022

Journal of Immunology Research

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“…Inhibition of the PI3K/Akt/mTOR pathway can inhibit the chemotaxis and recruitment of EOS, reduce the survival time and response of EOS, and decrease the production of EOS-related ribonuclease, thereby attenuating eosinophilic in ammation [9]. In addition, inhibition of the PI3K/Akt/mTOR pathway can inhibit tissue remodeling in allergic airway in ammation [10]. However, few studies have investigated the PI3K/Akt/mTOR pathway in nasal in ammation, although some have focused on hypoxia-inducible factor-1α, a downstream factor of this pathway [11].…”

Section: Discussionmentioning

confidence: 99%

The role of autophagy regulated by the PI3K/AKT/mTOR pathway and innate lymphoid cells in eosinophilic chronic sinusitis with nasal polyps

Zhou

Wang

et al. 2022

Preprint

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The PI3K/Akt/mTOR pathway and autophagy are important physiological processes. But their roles in eCRSwNP remains controversial. In this study, we used the eCRSwNP mouse model, PI3K/Akt/mTOR pathway inhibitors, and autophagy inhibitors and activators to investigate the regulatory effects of the PI3K/Akt/mTOR pathway on autophagy, and their effects on eosinophilic inflammation, and tissue remodeling. The role of ILC2s in eCRSwNP was also studied, and the relationship between ILC2s and autophagy was preliminarily determined. Our results show that eosinophilic inflammation in eCRSwNP mice could be inhibited by promoting the autophagy; otherwise, eosinophilic inflammation could be promoted. Meanwhile, inhibition of the PI3K/Akt/mTOR pathway can further promote autophagy and inhibit eosinophilic inflammation. Meanwhile, inhibiting the PI3K/Akt/mTOR pathway and promoting autophagy can reduce the number of ILC2s and the severity of tissue remodeling in the nasal polyps of eCRSwNP mice. We conclude that the PI3K/Akt/mTOR pathway plays roles in eosinophilic inflammation and tissue remodeling of eCRSwNP, in part by regulating the level of autophagy. The downregulation of autophagy is a pathogenesis of eCRSwNP; therefore, the recovery of normal autophagy levels might be a new target for eCRSwNP therapy. Furthermore, autophagy might inhibit eosinophilic inflammation and tissue remodeling, in part by reducing the number of ILC2s.

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“…Currently, there are various technologies that can visualize analytes in ex vivo lung samples. These include Masson's trichrome and hematoxylin and eosin (H&E) staining for histopathology, [1][2][3][4]6,7 immunohistochemistry and immunofluorescence for detecting cellular protein abundances, 5,7 ex vivo computed tomography (CT) for regional quantitative analysis of targeted fluorescent substances 10 and tissuecleared light sheet fluorescence microscopy for precise cellular-level mapping of targeted analytes. 10 While most of these techniques offer high spatial resolution at the cellular level, CT scans provide the additional benefit of three-dimensional scanned images, however, they do not provide molecular information.…”

Section: Introductionmentioning

confidence: 99%

“…Despite the anatomical and physiological differences between mice and humans, murine models are often used in pulmonary research to study fibrosis, 1‐3 chronic obstructive pulmonary disease, 4 hypoplasia, 5 eosinophilic granulomatous polyangiitis 6 and toxic acetaminophen exposure 7 . Analytical technologies provide insight into lung diseases, in both humans and murine models, enabling the potential translation of knowledge and applications to human disease 8 .…”

Section: Introductionmentioning

confidence: 99%

Mass spectrometry imaging protocol for spatial mapping of lipids, N‐glycans and peptides in murine lung tissue

Ngai,

Briggs,

Mittal

et al. 2024

Rapid Comm Mass Spectrometry

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RationaleThe application of matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI‐MSI) to murine lungs is challenging due to the spongy nature of the tissue. Lungs consist of interconnected air sacs (alveoli) lined by a single layer of flattened epithelial cells, which requires inflation to maintain its natural structure. Therefore, a protocol that is compatible with both lung instillation and high spatial resolution is essential to enable multi‐omic studies on murine lung disease models using MALDI‐MSI.Methods and resultsTo maintain the structural integrity of the tissue, murine lungs were inflated with 8% (w/v) gelatin for lipid MSI of fresh frozen tissues or 4% (v/v) paraformaldehyde neutral buffer for N‐glycan and peptide MSI of FFPE tissues. Tissues were sectioned and prepared for enzymatic digestion and/or matrix deposition. Glycerol‐free PNGase F was applied for N‐glycan MSI, while Trypsin Gold was applied for peptide MSI using the iMatrixSpray and ImagePrep Station, respectively. For lipid, N‐glycan and peptide MSI, α‐cyano‐4‐hydroxycinnamic acid matrix was deposited using the iMatrixSpray. MS data were acquired with 20 μm spatial resolution using a timsTOF fleX MS instrument followed by MS fragmentation of lipids, N‐glycans and peptides. For lipid MSI, trapped ion mobility spectrometry was used to separate isomeric/isobaric lipid species. SCiLS™ Lab was used to visualize all MSI data. For analyte identification, MetaboScape®, GlycoMod and Mascot were used to annotate MS fragmentation spectra of lipids, N‐glycans and tryptic peptides, respectively.ConclusionsOur protocol provides instructions on sample preparation for high spatial resolution MALDI‐MSI, MS/MS data acquisition and lipid, N‐glycan and peptide annotation and identification from murine lungs. This protocol will allow non‐biased analyses of diseased lungs from preclinical murine models and provide further insight into disease models.

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A phosphatidylinositol 3-kinase inhibitor strongly suppressed pulmonary vascular remodeling of allergic vasculitis in a murine model

Abstract: The PI3K inhibitor, ZSTK474 suppressed pulmonary vascular remodeling in the murine model of allergic vasculitis with eosinophil infiltration. PI3K signal transduction may have a critical role in the immunological process that induces allergic vasculitis.

Cited by 7 publications

References 26 publications

The Roles of Autophagy, Mitophagy, and the Akt/mTOR Pathway in the Pathogenesis of Chronic Rhinosinusitis with Nasal Polyps

The Roles of Autophagy, Mitophagy, and the Akt/mTOR Pathway in the Pathogenesis of Chronic Rhinosinusitis with Nasal Polyps

The role of autophagy regulated by the PI3K/AKT/mTOR pathway and innate lymphoid cells in eosinophilic chronic sinusitis with nasal polyps

Mass spectrometry imaging protocol for spatial mapping of lipids, N‐glycans and peptides in murine lung tissue

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