Li Wen-Zhe, Xiong Yu, Wang Tian-Kun, Chen Yan-Yan, Wan Song-Lin, Li Lu-Yao, Xu Meng, Tong Jing-Jing, Qian Qun, Jiang Cong-Qing, Liu Wei-Cheng
Department of Colorectal and Anal Surgery (Clinical Center for Pelvic Floor Surgery), Clinical Center of Constipation and Pelvic Floor Disease of Wuhan, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Quality Control Center of Colorectal and Anal Surgery of Health Commission of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China.
Department of Radiation and Medical Oncology for Esophageal Mediastinal and Lymphatic Tumors, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China.
World J Gastroenterol. 2024 Dec 7;30(45):4817-4835. doi: 10.3748/wjg.v30.i45.4817.
Obstructed defecation syndrome (ODS) represents the most prevalent form of chronic constipation, affecting a diverse patient population, leading to numerous complications, and imposing a significant burden on healthcare resources. Most ODS patients have insufficient rectal propulsion, but the exact mechanism underlying the pathogenesis of ODS remains unclear.
To explore the molecular mechanism underlying the pathogenesis of ODS.
A total of 30 pairs of rectal samples were collected from patients with ODS (ODS group) or grade IV prolapsed hemorrhoids without constipation (control group) for quantitative proteomic and bioinformatic analysis. Subsequently, 50 pairs of paraffin-embedded rectal specimens were selected for immunohistochemistry and immunofluorescence studies to validate the analysis results. Human intestinal smooth cell contractile function experiments and electrophysiological experiments were conducted to verify the physiological functions of target proteins. Cellular ultrastructure was detected using transmission electron microscopy.
In comparison to the control group, the expression level of dystrophin (DMD) in rectal specimens from ODS patients was markedly reduced. This finding was corroborated using immunohistochemistry and immunofluorescence techniques. The diminished expression of DMD compromised the contractile function of intestinal smooth muscle cells. At the molecular level, nucleoporin protein 153 and L-type voltage-gated calcium channel were found to be overexpressed in intestinal smooth muscle cells exhibiting downregulated DMD expression. Electrophysiological experiments confirmed an excessive influx of calcium ions into these cells. Moreover, vacuolar-like structures which may be associated with excessive calcium influx were observed in the cells by transmission electron microscopy.
Decreased DMD expression in intestinal smooth muscle may upregulate L-type voltage-gated calcium channel expression, leading to excessive calcium influx which may cause a decrease in rectal propulsion, thereby contributing to the pathogenesis of ODS.
排便障碍综合征（ODS）是慢性便秘最常见的形式，影响着不同的患者群体，导致多种并发症，并给医疗资源带来沉重负担。大多数ODS患者直肠推进力不足，但ODS发病机制的确切原因仍不清楚。
探讨ODS发病机制的分子机制。
从ODS患者（ODS组）或无便秘的IV度脱垂性痔患者（对照组）中收集30对直肠样本，进行定量蛋白质组学和生物信息学分析。随后，选取50对石蜡包埋的直肠标本进行免疫组织化学和免疫荧光研究，以验证分析结果。进行人肠道平滑肌收缩功能实验和电生理实验，以验证靶蛋白的生理功能。使用透射电子显微镜检测细胞超微结构。
与对照组相比，ODS患者直肠标本中肌营养不良蛋白（DMD）的表达水平明显降低。免疫组织化学和免疫荧光技术证实了这一发现。DMD表达的降低损害了肠道平滑肌细胞的收缩功能。在分子水平上，发现核孔蛋白153和L型电压门控钙通道在DMD表达下调的肠道平滑肌细胞中过表达。电生理实验证实钙离子过度流入这些细胞。此外，通过透射电子显微镜在细胞中观察到可能与钙离子过度流入有关的空泡样结构。
肠道平滑肌中DMD表达降低可能上调L型电压门控钙通道表达，导致钙离子过度流入，这可能导致直肠推进力下降，从而促成ODS的发病机制。
