UMR-PNCA, Université Paris-Saclay, AgroParisTech, INRAE, 91120 Palaiseau, France.
Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, 93000 Bobigny, France.
Int J Mol Sci. 2023 May 31;24(11):9554. doi: 10.3390/ijms24119554.
Inflammatory bowel diseases are chronic inflammation of the intestinal mucosa characterized by relapsing-remitting cycle periods of variable duration. Infliximab (IFX) was the first monoclonal antibody used for the treatment of Crohn's disease and ulcerative colitis (UC). High variability between treated patients and loss of IFX efficiency over time support the further development of drug therapy. An innovative approach has been suggested based on the presence of orexin receptor (OX1R) in the inflamed human epithelium of UC patients. In that context, the aim of this study was to compare, in a mouse model of chemically induced colitis, the efficacy of IFX compared to the hypothalamic peptide orexin-A (OxA). C57BL/6 mice received 3.5% dextran sodium sulfate (DSS) in drinking water for 5 days. Since the inflammatory flare was maximal at day 7, IFX or OxA was administered based on a curative perspective at that time for 4 days using intraperitoneal injection. Treatment with OxA promoted mucosal healing and decreased colonic myeloperoxidase activity, circulating concentrations of lipopolysaccharide-binding protein, IL-6 and tumor necrosis factor alpha (TNFα) and decreased expression of genes encoding cytokines in colonic tissues with better efficacy than IFX allowing for more rapid re-epithelization. This study demonstrates the comparable anti-inflammatory properties of OxA and IFX and shows that OxA is efficient in promoting mucosal healing, suggesting that OxA treatment is a promising new biotherapy.
炎症性肠病是一种以反复发作、缓解为特征的肠道黏膜慢性炎症,其持续时间长短不一。英夫利昔单抗(IFX)是首个用于治疗克罗恩病和溃疡性结肠炎(UC)的单克隆抗体。在接受治疗的患者之间存在高度变异性,并且随着时间的推移 IFX 的效率会降低,这支持进一步开发药物治疗。基于 UC 患者炎症人上皮细胞中存在食欲素受体(OX1R),提出了一种创新的方法。在这种情况下,本研究的目的是在化学诱导的结肠炎小鼠模型中比较 IFX 与下丘脑肽食欲素-A(OxA)的疗效。C57BL/6 小鼠在饮用水中接受 3.5%葡聚糖硫酸钠(DSS)5 天。由于炎症爆发在第 7 天达到最大值,因此基于治愈的观点,在那时用腹腔内注射方式给予 IFX 或 OxA 治疗 4 天。与 IFX 相比,OxA 治疗可促进黏膜愈合,降低结肠髓过氧化物酶活性、循环脂多糖结合蛋白、IL-6 和肿瘤坏死因子-α(TNFα)的浓度,并降低结肠组织中编码细胞因子的基因表达,其疗效更好,可更快地重新上皮化。本研究证明了 OxA 和 IFX 具有相似的抗炎特性,并表明 OxA 可有效促进黏膜愈合,提示 OxA 治疗是一种有前途的新型生物疗法。