Obstruction-initiated mechanotranscription in colonic smooth muscle cells

梗阻启动的结肠平滑肌细胞机械转录(摘要) 肠梗阻是影响儿童和成人的重大健康挑战。数不胜数 病理情况，包括粘连、癌症和先天性巨结肠，会导致肠梗阻。 我的直觉。不管最初的梗阻原因如何，其后果基本相同：近端梗阻 随着肠腔内容物和气体的积累，肠段过度伸展。随后，一个 发生了一系列的功能和形态变化。这些包括运动功能改变，降低 平滑肌的收缩能力和肌层厚度的增加(肥大)，并与 症状如腹胀、呕吐、腹部痉挛和便秘，并可能导致 肠衰竭。不幸的是，这些变化背后的分子机制尚不清楚。我们的 假说是肠道口中机械拉伸到阻塞部位会激活特定的信号。 改变平滑肌基因表达的途径(机械转录)，以及改变的基因表达 导致收缩能力受损和肌肉肥大。大鼠局灶性脑缺血模型的初步研究 梗阻表明结肠梗阻导致环氧合酶-2(COX-2)的急剧增加 在梗阻前近端结肠段的SMC特异性表达 收缩功能减退和肥大的开始。此外，我们还发现， COX-2的诱导是机械拉伸，因为COX-2在非拉伸状态下的表达不增加 梗阻远端的节段，以及结肠环状肌条或结肠SMC的体外伸展 诱导COX-2的表达和前列腺素(PG)PGE2的释放。COX-2 众所周知，环氧合酶-2产生的前列腺素能影响平滑肌的收缩和促进细胞增殖。 因此，我们的具体目标是：1)研究牵张诱导的环氧合酶-2在结肠中的作用 梗阻引起的收缩功能损害和平滑肌肥大中的平滑肌细胞； 牵张诱导结肠环COX-2表达的机械转录机制研究 SMCS；3)确定COX-2抑制剂和机械转录阻滞剂是否预防和/或缓解 大鼠的肠梗阻相关症状。进一步的研究表明，机械转录也可能参与其中。 在其他伸展相关的运动障碍中，如失弛缓症和胃轻瘫，缺乏放松的下半身 食道括约肌和幽门括约肌与食道扩张和动力减退有关 体部和胃窦部。综上所述，我们关于机械转录调控肠道SMC的假设 功能，并在阻塞性疾病的病理生理学中起关键作用是新的。我们的建议是 期望建立牵张诱导的COX-2在梗阻运动减慢和肥大中的关键作用。 这在临床上具有重要意义，因为COX-2抑制剂和机械转录阻滞剂 梗阻和其他牵张相关运动障碍的治疗潜力。

Obstruction-initiated mechanotranscription in colonic smooth muscle cells (Abstract) Bowel obstruction is a significant health challenge that affects children as well as adults. Numerous pathological conditions, including adhesions, carcinomas, and Hirschsprung's disease, result in obstruction in the gut. Regardless of the initial cause of obstruction, the consequences are largely the same: the proximal segment of the gut is over-stretched with the accumulation of the luminal contents and gas. Subsequently, a series of functional and morphological changes occurs. These include altered motility function, decreased smooth muscle contractility and increased thickness of muscle layer (hypertrophy), and are responsible for symptoms such as abdominal bloating, vomiting, abdominal cramps, and constipation, and may lead to intestinal failure. Unfortunately, the molecular mechanisms underlying these changes are not known. Our hypothesis is that mechanical stretch in the gut oral to the site of obstruction activates specific signaling pathways to alter smooth muscle gene expression (mechanotranscription), and the altered gene expression leads to impaired contractility and muscular hypertrophy. Preliminary studies in a rat model of partial obstruction demonstrated that colon obstruction leads to a dramatic increase of cyclooxygenase-2 (COX-2) expression specifically in the smooth muscle cells (SMC) of the colon segment proximal to obstruction before the onset of impaired contractility and hypertrophy. Furthermore, we identified that the initial trigger for the induction of COX-2 is mechanical stretch because COX-2 expression is not increased in the un-stretched segment distal to obstruction, and because in vitro stretch of the colonic circular muscle strips or colonic SMCs in primary culture induces marked expression of COX-2 and release of prostaglandin (PG) PGE2. The COX-2 and COX-2-generated PGs are well known to affect smooth muscle contractility and promote cell proliferation. Therefore, our specific aims are to: 1) investigate the role of stretch-induced COX-2 expression in the colonic smooth muscle cells in obstruction-initiated contractility impairments and smooth muscle hypertrophy; 2) investigate the mechanotranscription mechanism of stretch-induced COX-2 expression in the colonic circular SMCs; 3) determine whether COX-2 inhibitors and the mechanotrancription blockers prevent and/or alleviate obstruction-related symptoms in rats. Further studies indicate that mechanotranscription may also be involved in other stretch-related motility disorders such as achalasia and gastroparesis, where lack of relaxation of lower esophageal sphincter and pylorus sphincter is associated with distension and hypomotility in the esophageal body and antrum, respectively. In summary, our hypothesis that mechanotranscription regulates gut SMC function, and plays a critical role in the pathophysiology of obstructive disorders is novel. Our proposal is expected to establish a critical role of stretch-induced COX-2 in hypo-motility and hypertrophy in obstruction. This is clinically significant because COX-2 inhibitors and mechanotranscription blockers would have therapeutic potentials in obstruction and other stretch-related motility disorders.