The long-term objective is to open new strategies to reduce the development of postoperative ileus (POI) occurring after abdominal surgery involving manipulation of the bowel by increasing the understanding of neuro-immune mechanisms in rodent experimental models of POI. Besides causing significant discomfort to patients (bloating, nausea, emesis, and abdominal pain), POI hampers recovery and constitutes the most common reason for delaying discharge from the hospital after surgery, thus incurring a substantial socio- economical burden. Recent reviews of treatment modalities point out the lack of efficient preventive therapy and our poor understanding of pathophysiological mechanisms. We will test the hypothesis, based on data obtained during the last granting period and novel preliminary data, that abdominal surgery recruits stress- related mechanisms, most prominently corticotropin releasing factor (CRF) receptor 2 (CRF2) system in the brain and the gut, which contributes to orchestrate alterations in extrinsic and myenteric neuronal activity and local inflammatory response leading to impairment of gut propulsive motor function. This will be achieved by 1) characterizing the expression of CRF ligands (CRF and urocortins, Ucns), CRF receptors and their splice variants at selective brain nuclei regulating autonomic outflow to the colon and establishing the functional relevance of brain CRF2 receptors in colonic POI using pharmacological approach; 2) assessing the up- regulation of Ucns/CRF2 system within the colon and related increased release of nitric oxide from neurons and resident macrophages, thereby decreasing colonic motility; 3) establishing that activation of brain CRF pathways in response to abdominal surgery induces stimulation of sympathetic outflow and inhibition of vagal activity and counteracting these autonomic changes improves POI by restoring myenteric neuronal activity and curtailing the local inflammatory response. The approaches to achieve these aims will dwell on new technical advances recently made in our laboratories including key molecular probes to assess gene expression of rodent CRF ligands and CRF1 and CRF2 receptors and novel receptor variants that we have cloned, the use of laser captured microdissected brain nuclei, the ability to monitor increase in neuronal activity in the brain and myenteric neurons using functional Fos immunohistochemistry along with real-time monitoring of colonic motility with novel non-invasive methods of Mikrotip pressure sensor in conscious rodents, pharmacological tools (selective CRF receptor subtype agonists and antagonists) and transgenic mouse models . The characterization of CRF/Ucns signaling pathways in the brain and the gut that contribute to POI induced by abdominal surgery will enable us to uncover novel mechanisms in the pathogenesis of POI. This experimental research is relevant to the VA patient care mission as part of the medical research priority area that relates to stress, trauma and disorders of the gastrointestinal system, which is particularly pertinent as an increasing number of combat veterans deployed in war zone suffered traumatic injuries that required surgery.
NARRATIVE This research directed to uncover mechanisms underlying the pathogenesis of postoperative ileus linked with abdominal surgery is relevant to the patient care mission as part of the medical research priority area that relates to stress, trauma and disorders of the gastrointestinal system, which is particularly pertinent as a number of veterans deployed in war zone undergo injuries requiring surgery and the high incidence of veterans undergoing abdominal surgery for removal of malignancies, bariatric surgery or other conditions.