The proposed surgical research addresses critical mechanisms in maintenance of an intact intestinal mucosal barrier, and in S1P, a potential therapy to preserve this function in critically ill patients. Critical illness, particularly in surgical patients, is very common, and a high percentage of patients in the intensive care units incur stress-related injuries to their very vulnerable GI mucosa, leading to barrier dysfunction. This leads to malnutrition, translocation of bacteria, immune dysregulation, and fluid and electrolyte disorders. Despite the medical advances of the past few decades, therapies for these gastrointestinal injuries are, for the most part, conservative, as there is no current pharmacologic therapy available. The bioactive sphingolipid sphingosine-1-phosphate (S1P) has recently demonstrated significant effects on endothelial cells in promoting important biological functions, such as survival of injured cells, reparative proliferation of cells, and especially preservation of barrier function. S1P's effects are mediated through specific cell surface receptors (S1PR) which govern intracellular cytoskeletal organization and in particular regulate the organization and function of the adherens and tight junction proteins. We have demonstrated in both previously published work and in our preliminary data that S1P modulates biological functions critical to maintenance of GI barrier function by mechanisms that have not previously been studied, and which may differ significantly from those that govern endothelial barrier function. We therefore propose to investigate whether S1P promotes intestinal epithelial cell barrier integrity through increased adherens and tight junction protein expression and function, mediated primarily by extracellular S1P interaction with G-protein coupled receptors. To study this we will 1) Define the role of S1P in regulating the expression of intestinal barrier proteins using in vitro cell culture, 2) Determine the mechanism by which S1P promotes intestinal barrier function using in vitro cell culture, and 3) Determine whether S1P can maintain barrier integrity in in vivo models (human and mouse) of barrier dysfunction. We postulate that S1P modulates biological functions critical to maintenance of GI barrier function by mechanisms that have not previously been studied, and which may differ significantly from those that govern endothelial barrier function. Further, if the intracellular and intercellular mechanisms that mediate these effects are better delineated, this pathway can be targeted so as to attenuate, prevent, or even reverse GI mucosal barrier dysfunction in critically ill veterans.
Abnormalities in gastrointestinal mucosal healing contribute the pathophysiology of several diseases such as postsurgical healing, trauma, stress ulceration and gastritis, and inflammatory bowel disease among many others. Unfortunately, these are exceedingly common in the Veteran population, including nearly every patient in our intensive care unit, and contribute greatly to their morbidity and mortality. Pharmacologic therapies have been seen to benefit care tremendously, as in the targeting of stomach acid production by proton pump inhibitors, greatly reducing the need for additional surgeries and improved outcomes in these same patients. If we can similarly target the pathway inhibiting mucosal healing, then this would potentially facilitate recovery in septic Veteran patients.
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