Lu Chen, Zhu Hongxia, Lu Haiqian, Xie Xianjing, Tong Ling, Li Yujia, Qian Zhida
The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.
PLoS One. 2024 Dec 17;19(12):e0312413. doi: 10.1371/journal.pone.0312413. eCollection 2024.
Colitis is a complex multifactorial disease with an unknown aetiology that mainly manifests as chronic refractory colon transmission disorders. Smooth muscle, the main source of colon transmission power, consists of not only smooth muscle cells (SMCs) but also PDGFRα+ cells that mediate smooth muscle relaxation and ICCs that mediate contraction. PDGFRα+ cells and their unique small conductance Ca2+-activated K (SK3) channels are crucial in regulating colonic transit by exerting inhibitory effects. In this study, the contributions of the SK3 signalling pathway in PDGFRα+ cells to colitis-induced colonic transit dysmotility were investigated in DSS-induced colitis mice. An experiment was conducted to record the transmission of waves during smooth muscle contraction in the colon, using a colonic migrating motor complex(CMMC). Western blotting was utilized for protein expression detection, while PCR was employed for gene expression analysis. Immunofluorescence staining was used to detect the co-localization of SK3 channels with PDGFRα+ cells. In the colitis group, the weight of mice was reduced, the length of colon was shortened, and the disease activity index (DAI) was significantly increased. In the CMMC experiment, colon transmission was significantly disrupted in the colitis group compared to the control group, with a consistent colonic transmission amplitude and frequency. The sensitivity of mice with colitis to SK3 antagonists and agonists (apamin and CyPPA) was lower than that of the control group in CMMC experiment. The expression levels of mRNA and protein of PDGFRα and SK3 channels in colon of mice with colitis were decreased. Less SK3 channel colocalization with PDGFRα+ cells was observed in the colitis mouse group than in the control group. The findings indicated that colonic transit disorder in DSS-induced colitis mice is caused by the down-regulation of PDGFRα+ cells / SK3 channel expression.
结肠炎是一种病因不明的复杂多因素疾病，主要表现为慢性难治性结肠传输障碍。平滑肌是结肠传输动力的主要来源，不仅由平滑肌细胞（SMC）组成，还包括介导平滑肌舒张的PDGFRα+细胞和介导收缩的ICC。PDGFRα+细胞及其独特的小电导钙激活钾（SK3）通道通过发挥抑制作用对调节结肠运输至关重要。在本研究中，在DSS诱导的结肠炎小鼠中研究了PDGFRα+细胞中SK3信号通路对结肠炎诱导的结肠运输运动障碍的作用。进行了一项实验，使用结肠移行性运动复合体（CMMC）记录结肠平滑肌收缩期间的波传播。采用蛋白质印迹法检测蛋白质表达，采用PCR进行基因表达分析。免疫荧光染色用于检测SK3通道与PDGFRα+细胞的共定位。在结肠炎组中，小鼠体重减轻，结肠长度缩短，疾病活动指数（DAI）显著增加。在CMMC实验中，与对照组相比，结肠炎组的结肠传输明显中断，结肠传输幅度和频率一致。在CMMC实验中，结肠炎小鼠对SK3拮抗剂和激动剂（蜂毒明肽和环匹阿尼酸）的敏感性低于对照组。结肠炎小鼠结肠中PDGFRα和SK3通道的mRNA和蛋白质表达水平降低。与对照组相比，在结肠炎小鼠组中观察到SK3通道与PDGFRα+细胞的共定位较少。研究结果表明，DSS诱导的结肠炎小鼠的结肠运输障碍是由PDGFRα+细胞/SK3通道表达下调引起的。
