Venara Aurélien, Duchalais Emilie, Dariel Anne, Aubert Philippe, Durand Tony, Meurette Guillaume, Rolli-Derkinderen Malvyne, Hamy Antoine, Neunlist Michel
TENS - The enteric nervous system in gut and brain disorders, INSERM U1235, 44093, Nantes, France.
L'UNAM, University of Angers, Angers, France.
World J Surg. 2018 Apr;42(4):953-964. doi: 10.1007/s00268-017-4266-2.
Postoperative ileus (POI) is observed in 20-30% of patients undergoing colorectal cancer surgery, despite enhanced recovery programs (ERPs). Cyclooxygenase (COX)-2 is identified as a key enzyme in POI, but other arachidonic acid pathway enzymes have received little attention despite their potential as selective targets to prevent POI. The objectives were to compare the expression of arachidonic acid metabolism (AAM) enzymes (1) between patients who underwent colorectal cancer surgery and followed an ERP or not (NERP), (2) and between ERP patients who experimented POI or not and (3) to determine the ability of antagonists of these pathways to modulate contractile activity of colonic muscle.
This was a translational study. Main outcome measures were gastrointestinal motility recovery data, mRNA expressions of key enzymes involved in AAM (RT-qPCR) and ex vivo motility values of the circular colon muscle. Twenty-eight prospectively included ERP patients were compared to eleven retrospectively included NERP patients that underwent colorectal cancer surgery.
ERP reduced colonic mucosal COX-2, microsomal prostaglandin E synthase (mPGES1) and hematopoietic prostaglandin D synthase (HPGDS) mRNA expression. mPGES1 and HPGDS mRNA expression were significantly associated with ERP compliance (respectively, r2 = 0.25, p = 0.002 and r2 = 0.6, p < 0.001). In muscularis propria, HPGDS mRNA expression was correlated with GI motility recovery (p = 0.002). The pharmacological inhibition of mPGES1 increased spontaneous ex vivo contractile activity in circular muscle (p = 0.03).
The effects of ERP on GI recovery are correlated with the compliance of ERP and could be mediated at least in part by mPGES1, HPGDS and COX-2. Furthermore, mPGES1 shows promise as a therapeutic target to further reduce POI duration among ERP patients.
尽管有强化康复计划（ERP），但在20%-30%接受结直肠癌手术的患者中仍会出现术后肠梗阻（POI）。环氧化酶（COX）-2被认为是POI中的关键酶，但其他花生四烯酸途径的酶尽管有作为预防POI的选择性靶点的潜力，却很少受到关注。目的是比较花生四烯酸代谢（AAM）酶的表达：（1）在接受结直肠癌手术并遵循ERP或未遵循ERP（非ERP）的患者之间；（2）在经历或未经历POI的ERP患者之间；（3）确定这些途径的拮抗剂调节结肠肌肉收缩活性的能力。
这是一项转化研究。主要观察指标为胃肠动力恢复数据、AAM中关键酶的mRNA表达（逆转录定量聚合酶链反应）以及结肠环肌的体外动力值。将28名前瞻性纳入的ERP患者与11名回顾性纳入的接受结直肠癌手术的非ERP患者进行比较。
ERP降低了结肠黏膜COX-2、微粒体前列腺素E合酶（mPGES1）和造血前列腺素D合酶（HPGDS）的mRNA表达。mPGES1和HPGDS的mRNA表达与ERP依从性显著相关（分别为r2 = 0.25，p = 0.002和r2 = 0.6，p < 0.001）。在固有肌层中，HPGDS的mRNA表达与胃肠动力恢复相关（p = 0.002）。mPGES1的药理抑制增加了结肠环肌的体外自发收缩活性（p = 0.03）。
ERP对胃肠恢复的影响与ERP依从性相关，并且可能至少部分由mPGES1、HPGDS和COX-2介导。此外，mPGES1有望成为进一步缩短ERP患者POI持续时间的治疗靶点。
