Sox9-expressing cells promote regeneration after radiation-induced lung injury via the PI3K/AKT pathway

Chen, Shuang; Li, Kang; Zhong, Xinqi; Wang, Ganping; Wang, Xiaocheng; Cheng, Maosheng; Chen, Jie; Chen, Zhi; Chen, Jianwen; Zhang, Caihua; Xiong, Guanglei; Xu, Xiuyun; Chen, Demeng; Li, Heping; Peng, Liang

doi:10.1186/s13287-021-02465-9

Cited by 10 publications

(4 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on the findings that inhibition of the NLRP3 inflammasome alleviated epithelial remodeling in the distal lung, the reparative and regenerative behaviors of cells in this region in response to silica challenge were investigated. SOX9 and SOX2 are important factors related to lung repair and regeneration (41,42), and SOX9 + SOX2 + progenitor cells play a major role in embryonic lung branching morphogenesis by specifying proximal-distal fate (43). In terminal bronchiole, SOX9/SOX2 double-positive cells were not detected in the control or MCC950-only group but were abundant in the silica-treated group on day 7 (Fig.…”

Section: Silica-induced Nlrp3 Inflammasome Activation Causes Abnormal...mentioning

confidence: 89%

NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis

Zhou,

Zhang,

Liu

et al. 2024

Int J Mol Med

View full text Add to dashboard Cite

NOD-like receptor protein 3 (NLRP3) inflammasome is closely related to silica particle-induced chronic lung inflammation but its role in epithelial remodeling, repair and regeneration in the distal lung during development of silicosis remains to be elucidated. The present study aimed to determine the effects of the NLRP3 inflammasome on epithelial remodeling and cellular regeneration and potential mechanisms in the distal lung of silica-treated mice at three time points. Pulmonary function assessment, inflammatory cell counting, enzyme-linked immunosorbent assay, histological and immunological analyses, hydroxyproline assay and western blotting were used in the study. Single intratracheal instillation of a silica suspension caused sustained NLRP3 inflammasome activation in the distal lung. Moreover, a time-dependent increase in airway resistance and a decrease in lung compliance accompanied progression of pulmonary fibrosis. In the terminal bronchiole, lung remodeling including pyroptosis (membrane-distributed GSDMD + ), excessive proliferation (Ki67 + ), mucus overproduction (mucin 5 subtype AC and B) and epithelial-mesenchymal transition (decreased E-Cadherin + and increased Vimentin + ), was observed by immunofluorescence analysis. Notably, aberrant spatiotemporal expression of the embryonic lung stem/progenitor cell markers SOX2 and SOX9 and ectopic distribution of bronchioalveolar stem cells were observed in the distal lung only on the 7th day after silica instillation (the early inflammatory phase of silicosis). Western blotting revealed that the Sonic hedgehog/Glioma-associated oncogene (Shh/Gli) and Wnt/β-catenin pathways were involved in NLRP3 inflammasome activation-mediated epithelial remodeling and dysregulated regeneration during the inflammatory and fibrotic phases. Overall, sustained NLRP3 inflammasome activation led to epithelial remodeling in the distal lung of mice. Moreover, understanding the spatiotemporal profile of dysregulated epithelial repair and regeneration may provide a novel therapeutic strategy for inhalable particle-related chronic inflammatory and fibrotic lung disease.

show abstract

Section: Silica-induced Nlrp3 Inflammasome Activation Causes Abnormal...mentioning

confidence: 89%

NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis

Zhou,

Zhang,

Liu

et al. 2024

Int J Mol Med

View full text Add to dashboard Cite

show abstract

“…SOX9 could activate the PI3K/AKT signaling pathway and promote cellular proliferation while blocking the PI3K/AKT signaling pathway using inhibitors greatly inhibited the regenerative ability of Sox9-expressing cells [69,70]. Previous results have also shown that cells expressing transcription factor Sox9 were an important factor in the repair and regeneration of radiation-induced lung injury [71]. Furthermore, SOX-9 was involved in regeneration and repair through activation of the PI3K/AKT signaling pathway, suggesting that SOX9 may be a potential clinical therapeutic target in patients with thoracic malignancies.…”

Section: Discussionmentioning

confidence: 99%

Effects of Therapeutic Platelet-Rich Plasma on Overactive Bladder via Modulating Hyaluronan Synthesis in Ovariectomized Rat

Chueh

Juan

et al. 2023

IJMS

View full text Add to dashboard Cite

Postmenopausal women who have ovary hormone deficiency (OHD) may experience urological dysfunctions, such as overactive bladder (OAB) symptoms. This study used a female Sprague Dawley rat model that underwent bilateral ovariectomy (OVX) to simulate post-menopause in humans. The rats were treated with platelet-rich plasma (PRP) or platelet-poor plasma (PPP) after 12 months of OVX to investigate the therapeutic effects of PRP on OHD-induced OAB. The OVX-treated rats exhibited a decrease in the expression of urothelial barrier-associated proteins, altered hyaluronic acid (hyaluronan; HA) production, and exacerbated bladder pathological damage and interstitial fibrosis through NFƘB/COX-2 signaling pathways, which may contribute to OAB. In contrast, PRP instillation for four weeks regulated the inflammatory fibrotic biosynthesis, promoted cell proliferation and matrix synthesis of stroma, enhanced mucosal regeneration, and improved urothelial mucosa to alleviate OHD-induced bladder hyperactivity. PRP could release growth factors to promote angiogenic potential for bladder repair through laminin/integrin-α6 and VEGF/VEGF receptor signaling pathways in the pathogenesis of OHD-induced OAB. Furthermore, PRP enhanced the expression of HA receptors and hyaluronan synthases (HAS) enzymes, reduced hyaluronidases (HYALs), modulated the fibroblast-myofibroblast transition, and increased angiogenesis and matrix synthesis via the PI3K/AKT/m-TOR pathway, resulting in bladder remodeling and regeneration.

show abstract

“…SOX9 has an established importance to alveolar regenerative populations, with early phase human work already underway to therapeutically target these cells ( 28 ). Most in vivo lung studies, to date, of SOX9 have focussed upon this role of SOX9 ( 43, 44 ). Our results here indicate SOX9 has an importance to lung injury and fibrosis reaching beyond this.…”

Section: Discussionmentioning

confidence: 99%

SOX9-regulated matrix proteins predict poor outcomes in patients with COVID-19 and pulmonary fibrosis

Pearmain,

Jokl,

Simpson

et al. 2024

Preprint

View full text Add to dashboard Cite

Pulmonary fibrosis is an increasing and major cause of death worldwide. Understanding the cellular and molecular mechanisms underlying the pathophysiology of lung fibrosis may lead to urgently needed diagnostic and prognostic strategies for the disease. SOX9 is a core transcription factor that has been associated with fibrotic disease, however its role and regulation in acute lung injury and/or fibrosis have not been fully defined. In this study we apply a hypothesis based approach to uncover unique SOX9-protein signatures associated with both acute lung injury and fibrotic progression. Using in vivo models of lung injury in the presence or absence of SOX9, our study shows SOX9 is essential to the damage associated response of alveolar epithelial cells from an early time-point in lung injury. In parallel, as disease progresses, SOX9 is responsible for regulating tissue damaging ECM production from pro-fibrotic fibroblasts. In determining the in vivo role of SOX9 we identified secreted ECM components downstream of SOX9 as markers of acute lung injury and fibrosis. To underscore the translational potential of our SOX9-regulated markers, we analysed serum samples from acute COVID19, post COVID19 and idiopathic pulmonary fibrosis (IPF) patient cohorts. Our hypothesis driven SOX9-panels showed significant capability in all cohorts at identifying patients who had poor disease outcomes. This study shows that SOX9 is functionally critical to disease in acute lung injury and pulmonary fibrosis and its regulated pathways have diagnostic, prognostic and therapeutic potential in both COVID19 and IPF disease.

show abstract

Sox9-expressing cells promote regeneration after radiation-induced lung injury via the PI3K/AKT pathway

Cited by 10 publications

References 26 publications

NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis

NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis

Effects of Therapeutic Platelet-Rich Plasma on Overactive Bladder via Modulating Hyaluronan Synthesis in Ovariectomized Rat

SOX9-regulated matrix proteins predict poor outcomes in patients with COVID-19 and pulmonary fibrosis

Contact Info

Product

Resources

About