Related Experiment Video
Updated: Jul 31, 2026
Colon Ascendens Stent Peritonitis CASP - a Standardized Model for Polymicrobial Abdominal Sepsis
Published on: December 18, 2010
Blocking P2X7 receptor with AZ 10606120 exacerbates vascular hyperpermeability and inflammation in murine
Jamie E Meegan1, Padmini Komalavilas2, Joyce Cheung-Flynn2
1Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Abstract:
Sepsis is a devastating disease with high morbidity and mortality and no specific treatments. The pathophysiology of sepsis involves a hyperinflammatory response and release of damage-associated molecular patterns (DAMPs), including adenosine triphosphate (ATP), from activated and dying cells. Purinergic receptors activated by ATP have gained attention for their roles in sepsis, which can be pro- or anti-inflammatory depending on the context. Current data regarding the role of ATP-specific purinergic receptor P2X7 (P2X7R) in vascular function and inflammation during sepsis are conflicting, and its role on the endothelium has not been well characterized. In this study, we hypothesized that the P2X7R antagonist AZ 10606120 (AZ106) would prevent endothelial dysfunction during sepsis. As proof of concept, we first demonstrated the ability of AZ106 (10 µM) to prevent endothelial dysfunction in intact rat aorta in response to IL-1β, an inflammatory mediator upregulated during sepsis. Likewise, blocking P2X7R with AZ106 (10 µg/g) reduced the impairment of endothelial-dependent relaxation in mice subjected to intraperitoneal injection of cecal slurry (CS), a model of polymicrobial sepsis. However, contrary to our hypothesis, AZ106 did not improve microvascular permeability or injury, lung apoptosis, or illness severity in mice subjected to CS. Instead, AZ106 elevated spleen bacterial burden and circulating inflammatory markers. In conclusion, antagonism of P2X7R signaling during sepsis appears to disrupt the balance between its roles in inflammatory, antimicrobial, and vascular function.
Insights
Blocking the P2X7 receptor (P2X7R) with AZ10606120 (AZ106) did not improve sepsis outcomes in mice. Instead, it increased bacterial burden and inflammation, suggesting P2X7R plays a complex role in sepsis.
Area of Science:
- Immunology
- Vascular Biology
- Pharmacology
Background:
- Sepsis is a life-threatening condition with no specific treatments, characterized by hyperinflammation and the release of damage-associated molecular patterns like adenosine triphosphate (ATP).
- Purinergic receptors, activated by ATP, have complex roles in sepsis, and the specific function of the P2X7 receptor (P2X7R) on endothelial cells remains unclear.
- Conflicting data exists regarding P2X7R's role in sepsis-induced vascular dysfunction and inflammation.
Purpose of the Study:
- To investigate the effect of the P2X7R antagonist AZ10606120 (AZ106) on endothelial dysfunction during sepsis.
- To determine if blocking P2X7R signaling can ameliorate sepsis-induced vascular injury, organ damage, and overall illness severity.
Main Methods:
- Demonstrated AZ106's ability to prevent endothelial dysfunction in rat aorta ex vivo.
- Administered AZ106 to mice subjected to polymicrobial sepsis induced by cecal slurry (CS).
- Assessed endothelial-dependent relaxation, microvascular permeability, lung apoptosis, illness severity, spleen bacterial burden, and circulating inflammatory markers.
Main Results:
- AZ106 prevented endothelial dysfunction in rat aorta and improved endothelial-dependent relaxation in septic mice.
- Contrary to the hypothesis, AZ106 did not improve microvascular permeability, lung apoptosis, or reduce illness severity in septic mice.
- AZ106 treatment led to increased spleen bacterial burden and elevated circulating inflammatory markers in septic mice.
Conclusions:
- Antagonism of P2X7R signaling during sepsis does not improve overall disease outcomes.
- P2X7R plays a multifaceted role in sepsis, influencing inflammatory, antimicrobial, and vascular functions.
- Blocking P2X7R may disrupt the delicate balance of these functions, potentially worsening sepsis progression.
