GDF15 Aggravates Sepsis-Induced Coagulopathy and is Associated with PI3K/AKT/mTOR Signaling Changes

Area of Science:

• Biomedical research
• Molecular biology
• Pathophysiology

Background:

• Sepsis is a life-threatening condition characterized by dysregulated host response to infection.
• Coagulation dysfunction, inflammation, and multi-organ damage are hallmarks of sepsis progression.
• The role of Growth Differentiation Factor 15 (GDF15) in sepsis pathophysiology remains incompletely understood.

Purpose of the Study:

• To investigate the role of GDF15 in sepsis-induced coagulation dysfunction, inflammation, and organ damage.
• To elucidate the underlying molecular mechanisms, particularly the involvement of the PI3K/AKT/mTOR signaling pathway.
• To evaluate GDF15 as a potential therapeutic target in a preclinical sepsis model.

Main Methods:

• Established a cecal ligation and puncture (CLP)-induced sepsis model in Sprague-Dawley rats.
• Utilized adenovirus vectors for GDF15 overexpression and knockdown.
• Administered a PI3K inhibitor (LY294002) to assess pathway involvement.
• Measured serum biomarkers, coagulation parameters, inflammatory cytokines, and assessed organ damage via histology.

Main Results:

• Elevated GDF15 levels in CLP rats correlated with increased apoptosis, endothelial injury, coagulopathy, inflammation, and multi-organ damage.
• GDF15 overexpression exacerbated sepsis phenotypes, while GDF15 knockdown or PI3K inhibition ameliorated them.
• GDF15 significantly activated the PI3K/AKT/mTOR signaling pathway, which was implicated in its detrimental effects.

Conclusions:

• GDF15 plays a significant role in exacerbating coagulopathy, inflammation, and multi-organ damage in sepsis.
• The PI3K/AKT/mTOR pathway is a key mediator of GDF15's detrimental effects in sepsis.
• GDF15 represents a potential therapeutic target for sepsis, though further human validation is required.