Enterococcus faecalis Translocation in Sepsis: Fibrinolysis and Mitochondrial Dysfunction Drive Lung Injury

Area of Science:

• Microbiology and Immunology
• Pathophysiology of Sepsis
• Mitochondrial Biology

Background:

• Sepsis often leads to acute lung injury (ALI), characterized by inflammation and mitochondrial dysfunction.
• Gut-derived bacteria can translocate to the lungs during sepsis, contributing to injury.
• The host fibrinolytic system's role in sepsis-induced ALI is not fully understood.

Purpose of the Study:

• To investigate the role of Enterococcus faecalis in sepsis-induced ALI.
• To elucidate the mechanisms by which E. faecalis exacerbates lung injury, focusing on the fibrinolytic system and mitochondrial function.
• To evaluate the therapeutic potential of targeting fibrinolysis and mitochondrial dysfunction.

Main Methods:

• Utilized a cecal ligation and puncture (CLP) mouse model combined with E. faecalis pulmonary infection.
• Assessed fibrinolytic activity, fibrin degradation products (FDP), and expression of tight junction proteins (ZO-1, occludin).
• Evaluated mitochondrial function (ultrastructure, ATP synthesis, ROS levels) and lung histology.
• Tested the efficacy of aminocaproic acid (fibrinolysis inhibitor) and MitoTEMPO (mitochondrial protector) as monotherapies and in combination.

Main Results:

• E. faecalis exacerbated ALI by activating the host fibrinolytic system, increasing plasmin activity and FDP levels.
• Intestinal barrier integrity was compromised, indicated by reduced ZO-1 and occludin expression.
• Mitochondrial dysfunction, including ultrastructural damage, impaired ATP synthesis, and increased ROS, was observed.
• Aminocaproic acid and MitoTEMPO treatments attenuated fibrinolysis, preserved mitochondrial function, and reduced lung damage.
• Combination therapy demonstrated the most significant protective effects, improving lung histology and reducing inflammation markers.

Conclusions:

• Enterococcus faecalis exploits the host fibrinolytic system for pulmonary translocation, leading to mitochondrial damage and exacerbating sepsis-induced ALI.
• Targeting the fibrinolytic system and mitochondrial dysfunction represents a promising therapeutic strategy for sepsis-induced ALI.
• Combination therapy offers superior protection against sepsis-induced lung injury.