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Resetting proteostasis with ISRIB promotes epithelial differentiation to attenuate pulmonary fibrosis.

ABSTRACT: Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy, we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.

SUBMITTER: Watanabe S

PROVIDER: S-EPMC8157939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis

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Resetting Proteostasis of CIRBP with ISRIB Suppresses Neural Stem Cell Apoptosis under Hypoxic Exposure

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Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [AT2]

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Project description: Not available

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Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis

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Project description:Astragalus polysaccharides (APS), the active ingredients isolated from the plant Astragalus, have been reported to have numerous biological activities, including anti‑inflammatory and antitumor activities. However, the effect of APS on pulmonary fibrosis (PF) remains unknown. The present study aimed to evaluate the protective effect of APS against PF and to explore its underlying mechanisms by using in vivo and in vitro models. A mouse in vivo model of bleomycin‑induced PF and an in vitro model of transforming growth factor β1 (TGF‑β1)‑stimulated human lung epithelial A549 cells were established. Histopathologic examination and collagen deposition were investigated by hematoxylin and eosin staining and Masson staining, and by detecting the hydroxyproline content. The expression of related genes was analyzed by western blotting, reverse transcription‑quantitative (RT‑q) PCR, immunofluorescence and immunohistochemistry. The results from the in vivo mouse model demonstrated that treatment with APS could ameliorate collagen deposition and reduce fibrotic area and hydroxyproline content in the matrix. Furthermore, APS significantly inhibited the epithelial‑mesenchymal transition (EMT), as evidenced by an increased level of E‑cadherin and a decreased expression of vimentin and alpha smooth muscle actin. Furthermore, APS treatment significantly decreased TGF‑β1‑induced EMT and NF‑κB pathway activation in vitro. The results from the present study provided new insights on PF regression via the anti‑fibrotic effects of APS.

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