Numerous intestinal pathologies involve breakdown of the intestinal barrier, including Inflammatory Bowel Diseases and ischemia/reperfusion injury. Damage to the intestinal barrier leads to immune system activation, resulting in further damage to the intestinal epithelium; this generates a positive feedback-loop leading to sustained intestinal injury. Current therapies focus on treating the symptoms of intestinal damage or suppressing the immune system, and do not treat the underlying intestinal damage. This work explores the role of mu opioid receptor (MOR) signaling in the protection and recovery from acute intestinal injury. MOR signaling is responsible for the analgesic properties of opiates such as morphine. This work establishes for the first time that MOR signaling promotes intestinal epithelial survival and restitution during and after acute intestinal injury, using multiple models of injury in two different animal species. In zebrafish larvae, we created a model of acute intestinal injury using the non-steroidal anti-inflammatory drug (NSAID) glafeinine, which was shown to involve induction of cell stress with blockade of proper endoplasmic reticulum (ER) and mitochondrial stress responses, leading to intestinal epithelial cell (IEC) apoptosis. Administration of the MOR agonist DALDA protected against this injury by restoring the proper cellular stress responses. In mice, we established that DALDA administration could protect and enhance recovery from a chemical (dextran sodium sulfate) model of acute colitis. This effect correlated with increased IEC STAT3 phosphorylation, an effect known to be protective in the intestine. Additionally, we established that DALDA administration protected mice from small intestine ischemia/reperfusion-induced injury. Using an IEC-specific MOR knockout strain of mice that we developed, we established that the DALDA-mediated protection was due to IEC-specific MOR signaling. Pharmacological blockade of PI3K signaling demonstrated that MOR-mediated protection from ischemia/reperfusion injury is also PI3K-dependent. Together, this work establishes for the first time that enterocyte-mediated MOR signaling is intestinal-protective, engaging numerous, likely related pathways in the intestinal epithelium. This suggests that opioid-based therapy should be explored in patients for the treatment pathologies involving intestinal injury.
|Commitee:||Graves, Lee, Harden, Thomas Kendall, Nackley, Andrea, Sartor, Ryan Barton|
|School:||The University of North Carolina at Chapel Hill|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 74/01(E), Dissertation Abstracts International|
|Subjects:||Pharmacology, Medicine, Pathology|
|Keywords:||Acute injury, Colitis, Mu opioid receptors, Pi3k, Stat3, Wound healing, Zebrafish|
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