The Novel Compound SUL-138 Counteracts Endothelial Cell and Kidney Dysfunction in Sepsis by Preserving Mitochondrial...

Area of Science:

• Mitochondrial biology
• Immunology
• Pharmacology

Background:

• Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response.
• Mitochondrial dysfunction is a critical factor in the development of organ damage during sepsis.
• Targeting mitochondrial protection offers a potential therapeutic strategy for sepsis.

Purpose of the Study:

• To investigate the efficacy of SUL-138, a novel mitochondrial protective compound, in preclinical models of sepsis.
• To assess SUL-138's impact on mitochondrial function, inflammation, and organ dysfunction.

Main Methods:

• Sepsis models were established using lipopolysaccharide (LPS)-challenged human umbilical vein endothelial cells (HUVECs) and cecal ligation and puncture (CLP)-induced sepsis in mice.
• Mitochondrial function (membrane potential, oxygen consumption, oxidative stress) and inflammatory markers (cytokines, chemokines) were measured.
• Organ dysfunction was assessed using specific biomarkers (NGAL, urea) and histological analysis.

Main Results:

• In LPS-challenged HUVECs, SUL-138 preserved mitochondrial function and enhanced cell survival.
• In CLP-induced sepsis mice, SUL-138 limited kidney mitochondrial dysfunction and reduced markers of kidney injury (NGAL, urea).
• SUL-138 modulated the expression of key inflammatory mediators, including IL-1β and IL-6, in both cellular and animal models, and reduced plasma IL-6 and TNF-α levels.

Conclusions:

• SUL-138 demonstrates significant mitochondrial protective effects in sepsis models.
• SUL-138 treatment mitigates organ dysfunction and systemic inflammation associated with sepsis.
• SUL-138 represents a promising therapeutic candidate for sepsis management by targeting mitochondrial integrity.