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.

Public Health Relevance

Bowel obstruction may be caused by numerous pathological conditions, and represents a significant health challenge affecting adults and children. We find that obstruction-initiated mechanical stretch leads to marked induction of COX-2 molecule in gut smooth muscle cells, and the increased COX-2 expression accounts for obstruction-related motility changes and bowel thickening. We are expected to find that the use of COX-2 inhibitors may be a novel therapeutic target in obstruction and other stretch-related motility disorders, such as achalasia, gastroparesis, chronic constipation, and Hirschsprung's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK082563-04
Application #
8293276
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Carrington, Jill L
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$326,153
Indirect Cost
$112,981
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Lin, You-Min; Li, Feng; Shi, Xuan-Zheng (2014) Mechanical stress is a pro-inflammatory stimulus in the gut: in vitro, in vivo and ex vivo evidence. PLoS One 9:e106242
Shi, Xuan-Zheng; Sarna, Sushil K (2013) Cell culture retains contractile phenotype but epigenetically modulates cell-signaling proteins of excitation-contraction coupling in colon smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 304:G337-45
Lin, Y-M; Li, F; Shi, X-Z (2012) Mechano-transcription of COX-2 is a common response to lumen dilation of the rat gastrointestinal tract. Neurogastroenterol Motil 24:670-7, e295-6
Lin, You-Min; Sarna, Sushil K; Shi, Xuan-Zheng (2012) Prophylactic and therapeutic benefits of COX-2 inhibitor on motility dysfunction in bowel obstruction: roles of PGE? and EP receptors. Am J Physiol Gastrointest Liver Physiol 302:G267-75
Shi, Xuan-Zheng; Lin, You-Min; Powell, Don W et al. (2011) Pathophysiology of motility dysfunction in bowel obstruction: role of stretch-induced COX-2. Am J Physiol Gastrointest Liver Physiol 300:G99-G108