CANNABINOID 2 RECEPTOR MODULATION IN EXPERIMENTAL MODELS OF SEPSIS

Abstract

Sepsis is a critical disease where a dysregulated immune response causes multi-organ dysfunction, leading to organ failure and eventual mortality. Early in the course of sepsis, the microcirculation of the intestine is impaired, leading to tissue hypoperfusion, ischemia and hypoxic cell death, particularly in the inner layer of the intestinal wall, i.e. the mucosa. Once this anatomical and immunological barrier is compromised, intraluminal pathogens can enter the bloodstream and further exacerbate the immune dysregulation. The aim of our research was to examine the impact of cannabinoid 2 receptor modulation on the intestinal microcirculation in different acute murine models of experimental sepsis. In an endotoxemia model, activation of the CB2 receptor either through direct agonist (HU308) or enzyme inhibition (URB597 or JZL184) was able to ablate the excessive leukocyte recruitment caused by LPS administration. In a clinically relevant model of sepsis (colon ascendens stent peritonitis – CASP), JZL184 administration was able to minimize the increase in leukocyte adhesion caused by the peritonitis, as well as to improve capillary perfusion of the intestinal mucosa. The use of JZL184 in CB2 receptor knockout mice showed modest reduction in leukocyte recruitment caused by LPS administration indicating the activation of alternative pathways in CB2 receptor knockout mice. Overall the effects of activating the CB2 receptor during acute septic models shows some beneficial effects by minimizing the exaggerated inflammatory response.