Cannabinoid CB1 receptor and its endogenous lipid mediator 2-AG alleviates severity in a pancreatitis-associated lung injury mouse model

Acute pancreatitis (AP) is a leading cause of gastrointestinal hospital admissions, with a rising incidence. Current therapies fail to address the systemic inflammatory response and organ failure, particularly associated with acute respiratory distress syndrome (ARDS) in AP-induced cases. Endocannabinoids-arachidonic acid-derived lipid mediators-influence the inflammatory response. This study investigates the role of the endocannabinoid system, specifically the cannabinoid receptor 1 (CB1) and its primary endogenous ligand, the 2-arachidonoylglycerol (2AG), in pancreatitis-associated acute lung injury (ALI). We hypothesize the role of CB1/2AG in the systemic impact of AP; suggesting that CB1 signaling with 2AG could mitigate AP severity. Measurement of endocannabinoids in plasma of AP patients and healthy controls via HPLC-MS revealed elevated 2AG levels in mild AP, significantly reduced in severe AP patients, indicating a protective role. An in vivo cerulein-AP mouse model showed that the enzymes involved in 2AG production are regulated, triggering a down-production of 2AG. The exogenous administration of 2AG and JZL184, an inhibitor of the enzyme involved in 2AG degradation, controlled AP-ALI. Elevating 2AG levels reduced plasma amylase and lung inflammation (TNFα, IL1β, IFNγ). Neutrophil recruitment and mobilization were enhanced in blood and peritoneal cavity, respectively. Strikingly, 2AG inhibited lung damage assessed by histology. Notably, rising 2AG proved systemic and local anti-inflammatory effects, suggesting its protective role in AP-ALI. 2AG evokes potent lung anti-inflammatory effects in an in vivo mouse model of AP. The findings propose 2AG as a potential therapeutic for early-stage pancreatitis patients to prevent progression to severe forms and subsequent ARDS.