Kianian Mandana, Kelly Melanie E M, Zhou Juan, Hung Orlando, Cerny Vladimir, Rowden Geoffrey, Lehmann Christian
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada Department of Anesthesia, Dalhousie University, Halifax, NS, Canada.
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Clin Hemorheol Microcirc. 2014;58(2):333-42. doi: 10.3233/CH-131668.
Impairment of the intestinal microcirculation in endotoxemia may cause a deterioration of the mucosal barrier function thus releasing intraluminal bacteria and their toxins into the systemic circulation. In clinical sepsis this mechanism may influence disease severity and outcome. The aim of the study was to investigate the impact of cannabinoid receptor 1 (CB1R) modulation within the intestinal microcirculation with regard to leukocyte activation and capillary perfusion, and on intestinal histology in experimental endotoxemia in rats.
Endotoxemia was induced by intravenous lipopolysaccharide (LPS) administration. We studied 5 groups of animals: controls (CON), LPS, LPS + CB1R agonist (ACEA, 2.5 mg/kg), LPS + CB1R antagonist (AM281, 2 mg/kg) and LPS + CB1R agonist (ACEA, 2.5 mg/kg) + CB1R antagonist (AM281, 2 mg/kg). Intestinal intravital microscopy (IVM) was performed two hours following LPS/placebo administration. Intestinal leukocyte adhesion in submucosal venules and functional capillary density (FCD) of the intestinal wall was quantified using IVM. Histological changes were assessed using a standardized injury score.
After two hours of endotoxemia, we observed a significant increase of leukocyte adhesion in intestinal submucosal venules. Administration of the CB1R antagonist in endotoxemic animals significantly reduced the number of adhering leukocytes (p < 0.05). The CB1R agonist did not further increase leukocyte adhesion. FCD was significantly improved by the CB1R antagonist (p < 0.05). Administration of the CB1R agonist, ACEA, reversed the beneficial effect of the CB1R antagonist, AM281.
CB1R inhibition significantly improved intestinal microcirculation by reducing leukocyte adhesion and increasing FCD in acute endotoxemia in rats. The data supports the involvement of the CB1R signaling in leukocyte activation during sepsis. Drugs targeting the CB1R may have therapeutic potential in systemic inflammation, such as sepsis.
内毒素血症时肠道微循环受损可能导致黏膜屏障功能恶化，从而使肠腔内细菌及其毒素释放进入体循环。在临床脓毒症中，这一机制可能影响疾病的严重程度和预后。本研究的目的是探讨肠道微循环中大麻素受体1（CB1R）调节对内毒素血症大鼠白细胞活化、毛细血管灌注以及肠道组织学的影响。
通过静脉注射脂多糖（LPS）诱导内毒素血症。我们研究了5组动物：对照组（CON）、LPS组、LPS + CB1R激动剂（ACEA，2.5 mg/kg）组、LPS + CB1R拮抗剂（AM281，2 mg/kg）组以及LPS + CB1R激动剂（ACEA，2.5 mg/kg）+ CB1R拮抗剂（AM281，2 mg/kg）组。在给予LPS/安慰剂后两小时进行肠道活体显微镜检查（IVM）。使用IVM对黏膜下小静脉中的肠道白细胞黏附以及肠壁的功能性毛细血管密度（FCD）进行定量。使用标准化损伤评分评估组织学变化。
内毒素血症两小时后，我们观察到肠道黏膜下小静脉中白细胞黏附显著增加。在内毒素血症动物中给予CB1R拮抗剂可显著减少黏附白细胞的数量（p < 0.05）。CB1R激动剂并未进一步增加白细胞黏附。CB1R拮抗剂使FCD显著改善（p < 0.05）。给予CB1R激动剂ACEA可逆转CB1R拮抗剂AM281的有益作用。
在大鼠急性内毒素血症中，抑制CB1R可通过减少白细胞黏附并增加FCD显著改善肠道微循环。数据支持CB1R信号传导参与脓毒症期间的白细胞活化。靶向CB1R的药物在全身性炎症如脓毒症中可能具有治疗潜力。
