Phillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathway
Acute lung injury (ALI) is a severe pulmonary disorder of sepsis with high clinical incidence and mortality. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-cysteinyl aspartate specific prote...
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| Format: | Article |
| Language: | English |
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China Science Publishing & Media Ltd.
2024-10-01
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| Series: | Acta Biochimica et Biophysica Sinica |
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| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2024161 |
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| author | Ji Chen Hao Xiaoyan Li Zhiyi Liu Jiaxing Yan Hanyu Ma Ketao Li Ling Zhang Liang |
| author_facet | Ji Chen Hao Xiaoyan Li Zhiyi Liu Jiaxing Yan Hanyu Ma Ketao Li Ling Zhang Liang |
| author_sort | Ji Chen |
| collection | DOAJ |
| description | Acute lung injury (ALI) is a severe pulmonary disorder of sepsis with high clinical incidence and mortality. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-cysteinyl aspartate specific proteinase 1-gasdermin D (GSDMD)-dependent pyroptosis of alveolar epithelial cells (AECs) has emerged as a crucial contributor to ALI during sepsis. Phillyrin (PHI), a natural lignan isolated from the traditional Chinese herbal medicine Forsythia suspensa, has been shown to have anti-inflammatory, antioxidant and antiviral properties. However, little is known about the protective role and potential mechanism of PHI in sepsis-induced ALI, and it is uncertain whether the protective effect of PHI in sepsis-induced ALI is connected to pyroptosis. This study aims to examine the preventive effects of PHI on sepsis-induced ALI via the inhibition of NLRP3/caspase-1/GSDMD-mediated pyroptosis in AECs. Our findings demonstrate that preadministration of PHI successfully reduces sepsis-induced pulmonary edema, systemic/pulmonary inflammation, and pulmonary histological damage in lung tissues, bronchoalveolar lavage fluid, and the serum of septic mice. Intriguingly, PHI preadministration suppresses sepsis-induced protein expressions of pyroptosis-specific markers, especially their active forms. In vitro assays show that PHI pretreatment also protects type II AECs (MLE-12) from lipopolysaccharide-induced pyroptosis by preventing the activation of the pyroptosis signaling pathway. The results from molecular docking and surface plasmon resonance reveal that PHI has a significant affinity for direct binding to the GSDMD protein, suggesting that GSDMD is a potential pharmacological target for PHI. In conclusion, PHI can prevent sepsis-triggered ALI by effectively suppressing the activation of the canonical pyroptosis signaling pathway and pyroptosis of AECs. |
| format | Article |
| id | doaj-art-e31c7eb76f2a4a1ebe0f87a36e832a08 |
| institution | OA Journals |
| issn | 1672-9145 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | China Science Publishing & Media Ltd. |
| record_format | Article |
| series | Acta Biochimica et Biophysica Sinica |
| spelling | doaj-art-e31c7eb76f2a4a1ebe0f87a36e832a082025-08-20T01:55:33ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452024-10-015744746210.3724/abbs.202416120d259ccPhillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathwayJi Chen0Hao Xiaoyan1Li Zhiyi2Liu Jiaxing3Yan Hanyu4Ma Ketao5Li Ling6Zhang Liang7["Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi 832003, China"]["Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi 832003, China"]["Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi 832003, China"]["Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi 832003, China"]["Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi 832003, China"]["Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi 832003, China","NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, the first Affiliated Hospital, Shihezi University, Shihezi 832008, China"]["Medical Teaching Experimental Center, School of Medicine, Shihezi University, Shihezi 832003, China"]["Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi 832003, China","NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, the first Affiliated Hospital, Shihezi University, Shihezi 832008, China"]Acute lung injury (ALI) is a severe pulmonary disorder of sepsis with high clinical incidence and mortality. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-cysteinyl aspartate specific proteinase 1-gasdermin D (GSDMD)-dependent pyroptosis of alveolar epithelial cells (AECs) has emerged as a crucial contributor to ALI during sepsis. Phillyrin (PHI), a natural lignan isolated from the traditional Chinese herbal medicine Forsythia suspensa, has been shown to have anti-inflammatory, antioxidant and antiviral properties. However, little is known about the protective role and potential mechanism of PHI in sepsis-induced ALI, and it is uncertain whether the protective effect of PHI in sepsis-induced ALI is connected to pyroptosis. This study aims to examine the preventive effects of PHI on sepsis-induced ALI via the inhibition of NLRP3/caspase-1/GSDMD-mediated pyroptosis in AECs. Our findings demonstrate that preadministration of PHI successfully reduces sepsis-induced pulmonary edema, systemic/pulmonary inflammation, and pulmonary histological damage in lung tissues, bronchoalveolar lavage fluid, and the serum of septic mice. Intriguingly, PHI preadministration suppresses sepsis-induced protein expressions of pyroptosis-specific markers, especially their active forms. In vitro assays show that PHI pretreatment also protects type II AECs (MLE-12) from lipopolysaccharide-induced pyroptosis by preventing the activation of the pyroptosis signaling pathway. The results from molecular docking and surface plasmon resonance reveal that PHI has a significant affinity for direct binding to the GSDMD protein, suggesting that GSDMD is a potential pharmacological target for PHI. In conclusion, PHI can prevent sepsis-triggered ALI by effectively suppressing the activation of the canonical pyroptosis signaling pathway and pyroptosis of AECs.https://www.sciengine.com/doi/10.3724/abbs.2024161phillyrinsepsisacute lung injuryalveolar epithelial cellspyroptosis |
| spellingShingle | Ji Chen Hao Xiaoyan Li Zhiyi Liu Jiaxing Yan Hanyu Ma Ketao Li Ling Zhang Liang Phillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathway Acta Biochimica et Biophysica Sinica phillyrin sepsis acute lung injury alveolar epithelial cells pyroptosis |
| title | Phillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathway |
| title_full | Phillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathway |
| title_fullStr | Phillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathway |
| title_full_unstemmed | Phillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathway |
| title_short | Phillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathway |
| title_sort | phillyrin prevents sepsis induced acute lung injury through inhibiting the nlrp3 caspase 1 gsdmd dependent pyroptosis signaling pathway |
| topic | phillyrin sepsis acute lung injury alveolar epithelial cells pyroptosis |
| url | https://www.sciengine.com/doi/10.3724/abbs.2024161 |
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