The role of the cannabinoid system in sepsis

There is growing evidence for an involvement of the cannabinoid system in the pathogenesis of sepsis. In-vitro, immune cell activation increases endocannabinoid release and reduces metabolic breakdown. The net result of this increased endocannabinoid activity may contribute to some of the cardiovascular changes seen in sepsis. In this thesis studies investigating the effects of sepsis on the human immunological-endocannabinoid system are described, first using an in-vitro model of sepsis and secondly in patients admitted to Intensive Care with a diagnosis of sepsis. Q-PCR and mass spectrometry technology were employed to measure receptor mRNA expression and lipid concentrations respectively. In the in-vitro model using polymorphonuclear cells from healthy volunteers, non-stimulated cells expressed mRNA for CB2, CB1 and the controversial third cannabinoid receptor (GPR55). Moreover, a septic stimulus (lipopolysaccharide) caused endocannabinoid and entourage lipid release, along with marked upregulation of CB2 and GPR55 mRNA expression. In the clinical study, the concentrations of some endocannabinoids were increased in patients with sepsis compared to samples taken after recovery. However, lower anandamide and oleoylethanolamide concentrations were associated with increased needs for therapeutic medical interventions (vasoconstrictor drugs, renal replacement therapy and invasive ventilation). These data suggest that endocannabinoids produced by immunocytes may be protective during sepsis. Higher concentrations of endocannabinoids were associated with less cardiovascular instability, renal dysfunction and requirement for invasive ventilation. This might be explained by the anti-inflammatory effects of endocannabinoids. Together, these data support the development of a cannabinoid drug with anti-inflammatory, analgesic and anxiolytic properties as a potential adjunctive treatment for patients with sepsis.