Total parenteral nutrition (TPN) is frequently used for surgical and trauma patients who cannot tolerate enteral feedings. A number of alterations occur in the intestinal mucosa with TPN, including loss of mucosal barrier function and villus atrophy, which may contribute to increased septic complications, commonly seen in patients on TPN. TPN leads to a number of changes in the intestinal intraepithelial lymphocytes (IEL) - which reside in the epithelial layer of the gut. This includes an increased IEL expression of interferon gamma (IFN-gamma), which mediates a loss of epithelial barrier function, and up-regulates epithelial cell (EC) apoptosis. TPN also results in a significant decline in IEL-derived keratinocyte growth factor (KGF) expression, which contributes to the development of mucosal atrophy with TPN. The causative factors leading to these IEL changes are unknown. An important factor for IEL development and function is EC expression of interleukin 7 (IL-7). EC-derived IL- 7 is significantly decreased with TPN administration, and this may contribute to the observed changes in IEL phenotype and function. The overlying aim of this proposal is to further understand how TPN-associated IEL changes affect alterations in epithelial physiology, and to understand the mechanisms which lead to these changes. The following aims are proposed: 1) Examine the mechanisms by which IEL-derived cytokines mediate the TPN-associated loss of epithelial barrier function, using Ussing chamber measurements. 2) Determine if the decline in EC-derived IL-7, with TPN, leads to IEL phenotype and functional changes. This will be approached by both the removal of IL-7, as well as the creation of IL-7 over-expressing mice. 3) Test the hypothesis that alterations in IEL-derived cytokine and KGF expression, with TPN administration, lead to changes in EC-derived IL-7. 4) Investigate the contributions of nutritional substrates and gut peptides in the development of TPN-associated changes in IEL phenotype and function. Factors will include glutamine, arginine, epidermal growth factor and gastrin-releasing peptide. These experiments will both advance understanding of IEL/EC interactions, as well as explain the observed findings of mucosal atrophy and epithelial barrier leak that occur during TPN. This may lead to methods to prevent such problems.
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