Abstract
We have been conducting basic experiments on sepsis to gain further understanding of its pathophysiology and treatment. Guinea pig endotoxaemia models were used due to their LPS induced biological response and simple experimental procedure. We particularly focused on bowel movement paralysis after administration of LPS. We found that the peak reaction of intestinal tract relaxation was observed at 2-3 hours after administration of LPS in the guinea pig endotoxaemia model. During this period, there was a variety of ongoing inflammatory responses. We investigated bowel movement by using agonists and antagonists assumed to affect intestinal tract movement within the signal cascade. We carried out experiments using anandamide and 2-arachidonoilglycerol, which are endocannabinoids, as agonists; and used the following antagonists: polymyxin B immobilized fiber, which absorbs LPS; TAK-242, a TLR4 inhibitor; AM281 and rimonabant, which are CB1 receptor inhibitors; and meloxicam, a COX-2 inhibitor. It was observed that administration of cannabinoids induced bowel movement paralysis, as did LPS administration. LPS-induced bowel movement paralysis was significantly inhibited with pretreatment with each inhibitor. Based on these examinations, it is anticipated that endocannabinoids and arachidonate metabolites mediate bowel movement paralysis. It was also found that since PMX and TAK-242 had larger effects in the regulation of the paralysis, it is effective to eliminate causative substances within the early phase of sepsis. When treating sepsis patients, it is necessary to take into consideration the above mentioned mediators acting in the background to sepsis. Previous studies showed that treatments such as single mediator inhibition did not obtain good results, and inhibition of multiple mediators seems to be required.
