Extracellular ATP drives systemic inflammation, tissue damage and mortality.

Area of Science:

• Biochemistry
• Immunology
• Pathophysiology

Background:

• Systemic inflammatory response syndromes (SIRS) result from infectious or sterile insults, causing excessive inflammation and organ damage.
• Inflammasome-dependent cytokines, like interleukin-1β, are crucial in SIRS-induced multiple organ dysfunction syndrome (MODS) and mortality.
• Extracellular adenosine triphosphate (ATP) is an in vitro activator of inflammasomes, suggesting a role in SIRS pathogenesis.

Purpose of the Study:

• To investigate the potential of removing extracellular ATP to prevent tissue damage and mortality in a murine model of LPS-induced inflammation.
• To elucidate the role of extracellular ATP in both inflammasome-dependent and independent inflammatory pathways during SIRS.

Main Methods:

• Utilized a murine lipopolysaccharide (LPS)-induced inflammation model.
• Administered systemic apyrase to remove extracellular ATP.
• Administered suramin, a P2 purinergic receptor antagonist, for comparison.
• Assessed levels of IL-1β, TNF, IL-10, and indicators of cellular damage, apoptosis, and intestinal barrier integrity.

Main Results:

• Extracellular ATP demonstrated a significant pro-inflammatory role in the LPS-induced SIRS model.
• Apyrase treatment effectively prevented the accumulation of IL-1β, TNF, and IL-10, alongside reducing cellular disintegration, mitochondrial damage, apoptosis, and intestinal barrier disruption.
• Suramin treatment showed some beneficial effects but failed to prevent overall morbidity and mortality, unlike apyrase.

Conclusions:

• Systemic extracellular ATP removal is a promising therapeutic strategy to mitigate inflammatory damage and toxicity in SIRS.
• The beneficial effects of ATP removal extend beyond inflammasome inhibition, impacting inflammasome-independent cytokines and cellular integrity.