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Published on: November 27, 2019
Gasdermin D Inhibitor Necrosulfonamide Alleviates Lipopolysaccharide/D-galactosamine-induced Acute Liver Failure in
Yi-Long Wu1, Wei-Jie Ou2, Ming Zhong3,4
1Endoscopy Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
Background And Aims:
Acute liver failure (ALF) is associated with high mortality. Gasdermin D (GSDMD) is the executioner of pyroptosis and is involved in the pathophysiology of immune dysregulation This study investigated the role of the GSDMD inhibitor necrosulfonamide (NSA) in ALF.
Methods:
An ALF model was established by lipopolysaccharide/D-galactosamine challenge in C57BL/6J mice. Mice were divided into four groups: normal controls (control group), ALF group (ALF group), dimethyl sulfoxide group (DMSO group), and NSA intervention group (NSA group). Survival was monitored, liver damage was determined by hematoxylin and eosin staining, and serum alanine aminotransferase (ALT). Underlying mechanisms were explored by quantitative real-time PCR, western blotting, and enzyme-linked immunosorbent assays.
Results:
Pyroptosis was activated in ALF model mice. Mice treated with GSDMD inhibitor NSA developed less severe liver failure. NSA reduced the expression of GSDMD, NLRP3, cleaved caspase-1, cleaved caspase-11, and secretion of interleukin-1 beta in ALF mice model.
Conclusions:
Pyroptosis was activated in ALF. NSA alleviated ALF via the pyroptosis pathway.
Insights
Necrosulfonamide (NSA), a Gasdermin D (GSDMD) inhibitor, significantly reduced liver damage in acute liver failure (ALF) mouse models by suppressing pyroptosis. This finding highlights NSA
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- Acute liver failure (ALF) presents a significant mortality risk.
- Gasdermin D (GSDMD) is a key mediator of pyroptosis, a programmed cell death pathway implicated in immune dysregulation and ALF pathogenesis.
Purpose of the Study:
- To investigate the therapeutic potential of necrosulfonamide (NSA), a GSDMD inhibitor, in mitigating ALF.
- To elucidate the role of the pyroptosis pathway in ALF and its modulation by NSA.
Main Methods:
- An ALF mouse model was induced using lipopolysaccharide/D-galactosamine.
- Mice were treated with NSA or a vehicle control (DMSO).
- Survival, liver injury (histopathology, ALT levels), and molecular markers of pyroptosis (GSDMD, NLRP3, caspase-1, caspase-11, IL-1β) were assessed.
Main Results:
- Pyroptosis was demonstrably activated in the ALF mouse model.
- NSA treatment led to reduced liver damage and improved survival in ALF mice.
- NSA administration suppressed the expression of GSDMD, NLRP3, cleaved caspase-1, and cleaved caspase-11, and reduced IL-1β secretion.
Conclusions:
- Pyroptosis is a critical pathway in the development of ALF.
- NSA effectively alleviates ALF by inhibiting the pyroptosis pathway, suggesting its potential as a therapeutic agent.
