title: Inhibition of endocannabinoid degradation in experimental endotoxemia reduces leukocyte adhesion and improves capillary perfusion in the gut.
abstract: BACKGROUND
  Changes in leukocyte-endothelial and microvascular perfusion are hallmark events in inflammation. Thus, protection of the intestinal microcirculation represents a pivotal therapeutic target in systemic inflammation and sepsis. The endocannabinoid system (ECS) modulates a number of critical homeostatic functions and has been associated with anti-inflammatory responses. Our study aimed to examine intestinal leukocyte adhesion and capillary perfusion following selective inhibition of the endocannabinoid degradation enzyme, fatty acid amide hydrolase (FAAH), in experimental sepsis (endotoxemia).
  
  
  METHODS
  Five groups of rats were used: controls, endotoxemia [lipopolysaccharide (LPS)], FAAH inhibitor URB597 (0.3 mg/kg)+LPS, URB597 (0.6 mg/kg)+LPS, and URB597 (0.6 mg/kg)+cannabinoid 2 receptor (CB2R) antagonist (AM630)+LPS. After 2 h, intravital microscopy was performed to quantify intestinal leukocyte recruitment and functional capillary density (FCD), as well as macrohemodynamic monitoring and histological examinations.
  
  
  RESULTS
  LPS induced a significant increase in leukocyte adhesion in collecting and postcapillary submucosal venules and a decrease in intestinal FCD. URB597 pretreatment prevented the LPS-induced increase in leukocyte adhesion in intestinal venules and a decrease in intestinal FCD. The administration of the CB2R inhibitor, AM630, with URB597 reversed the protective effects of URB597 on the LPS-induced increase in leukocyte adhesion in intestinal venules, but not URB597's effect on the intestinal FCD.
  
  
  CONCLUSIONS
  FAAH inhibition prevents the LPS-induced increase in leukocyte adhesion and improves the capillary perfusion of the gut. This might be mediated in part by CB2R activation. Our study encourages further investigation into the therapeutic potential of drugs targeting the ECS in sepsis.
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Mandana
authors: M
authors: Kianian
authors: Nadia A
authors: NA
authors: Al-Banna
authors: Melanie E M
authors: ME
authors: Kelly
authors: Christian
authors: C
authors: Lehmann
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002196:Capillaries / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002448:Cell Adhesion; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D019446:Endotoxemia / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001549:Benzamides; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D063388:Endocannabinoids; D007211:Indoles; D008070:Lipopolysaccharides; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C094023:iodopravadoline