Novel Agents in the Treatment of Intestinal Failure: Humoral Factors

Yang, Hua; Teitelbaum, Daniel H.

doi:10.1053/j.gastro.2005.08.059

Cited by 17 publications

(8 citation statements)

References 57 publications

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“…Previous studies by our group have shown that IEL play an important role in the maintenance of the gut barrier function and in the support of intestinal EC growth 6, 7, 11, 13, 31. Several studies have indicated that EC may have an important role in mucosal immune responses by helping to regulate IEL phenotype and function 20, 22.…”

Section: Discussionmentioning

confidence: 92%

Intestinal Specific Overexpression of Interleukin-7 Attenuates the Alternation of Intestinal Intraepithelial Lymphocytes After Total Parenteral Nutrition Administration

Yang

Gumucio

Teitelbaum³

2008

Annals of Surgery

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Total parenteral nutrition (TPN), with the complete removal of enteral nutrition, results in marked changes in intestinal intraepithelial lymphocyte (IEL) function and phenotype. Previous work shows that TPN results in a loss of intestinal epithelial cell (EC)-derived interleukin-7 (IL-7), and this loss may play an important role in development of such TPN-associated IEL changes. To further understand this relation, we generated a transgenic mouse (IL-7 vill ), which over-expresses IL-7 specifically in intestinal ECs. We hypothesized that this localized over-expression would attenuate many of the observed TPN-associated IEL changes. Our study showed that TPN administration led to significant changes in IEL phenotype, including a marked decline in the CD8αβ+, CD4+, and αβ-TCR+ populations. IEL basal proliferation decreased 1.7-fold compared to Controls. TPN administration in wild-type mice resulted in several changes in IEL-derived cytokine expression. IL-7 vill mice given TPN, however, maintained IEL proliferation, as well as sustaining normal IEL numbers and phenotype. We conclude that specific intestinal IL-7 over-expression significantly attenuated many IEL changes in IEL phenotype and function after TPN administration. These findings suggest a mechanism by which TPN results in observed IEL changes.

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Section: Discussionmentioning

confidence: 92%

Intestinal Specific Overexpression of Interleukin-7 Attenuates the Alternation of Intestinal Intraepithelial Lymphocytes After Total Parenteral Nutrition Administration

Yang

Gumucio

Teitelbaum³

2008

Annals of Surgery

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“…Furthermore, also EGFR expression has found to be significantly increased after SBR only in the D-SBR group. EGFR has been shown to be of crucial importance for postresectional intestinal adaptation [31,[42][43][44]. Stimulation of EGFR in vivo was found to result in an enhancement, whereas its' inhibition led to attenuation of post-resectional intestinal adaptation [42].…”

Section: Discussionmentioning

confidence: 99%

Intestinal epithelial cell proliferation is dependent on the site of massive small bowel resection

et al. 2007

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Early intestinal adaptation after massive small bowel resection (SBR) is driven by increased epithelial cell (EC) proliferation. There is a clear clinical difference in the post-operative course of patients after the loss of proximal (P) compared to distal (D) small bowel. This study examined the effects of the site of SBR on post-resectional intestinal adaptation, and investigated the potential mechanisms involved. C57BL/6J mice (n = 7/group) underwent: (1) 60% P-SBR, (2) 60% D-SBR, (3) 60% mid (M)-SBR and (4) SHAM-operation (transection/reanastomosis). Mice were sacrificed at 7 days after surgery and ECs and adjacent mucosal lymphocytes (IELs) isolated. Adaptation was assessed in both jejunum and ileum by quantification of villus height, crypt depth, villus cell size, crypt cell size (microns), goblet cell number, and EC proliferation (%BrdU incorporation). Proliferation signalling pathways including keratinocyte growth factor (KGF)/KGFR(1), IL-7/IL-7R, and epidermal growth factor receptor (EGFR) were measured by RT-PCR. Expression of IL-7 was further analysed by immunofluorescence. Data were analyzed using ANOVA. All three SBR models led to significant increases in villus height, crypt depth, goblet cell numbers and EC proliferation rate when compared to respective SHAM groups. The strongest morphometric changes were found for jejunal segments after M-SBR and for ileal segments after P-SBR. Furthermore, morphometric analysis showed that at 1-week post-resection a tremendous increase in EC numbers occurred in jejunal villi (cell hyperplasia), whereas a significant increase in EC size predominated in ileal villi (cell hypertrophy). mRNA expression of KGF, KGFR(1), IL-7R, and EGFR showed a significant increase only after D-SBR, whereas IL-7 increased significantly after SBR in all investigated models, and this was confirmed by immunofluorescence studies. Early intestinal adaptation shows distinct differences depending on the site of SBR, and is predominately driven by cell hyperplasia in jejunal villi and cell hypertrophy in ileal villi. However, the exact mechanisms, which guide these signalling pathways are still unclear.

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“…IEL act as the initial lymphoid defense layer against intraluminal foreign antigens (7), and may be of critical importance for proper functioning of the mucosal immune system (35). Previous studies by our group have shown that IEL play an important role in the maintenance of the gut barrier function and support intestinal EC growth (42)(43)(44)(45)47). There is an average of 10 -20 IEL per 100 villi EC in human small intestine (11).…”

Section: Introductionmentioning

confidence: 99%

Intestinal epithelial cell-derived interleukin-7: a mechanism for the alteration of intraepithelial lymphocytes in a mouse model of total parenteral nutrition

Yang¹,

Sun²,

Haxhija³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Total parenteral nutrition (TPN), with the absence of enteral nutrition, results in profound changes to both intestinal epithelial cells (EC) as well as the adjacent intraepithelial lymphocyte (IEL) population. Intestinal EC are a rich source of IL-7, a critical factor to support the maintenance of several lymphoid tissues, and TPN results in marked EC changes. On this basis, we hypothesized that TPN would diminish EC-derived IL-7 expression and that this would contribute to the observed changes in the IEL population. Mice received enteral food and intravenous crystalloid solution (control group) or TPN. TPN administration significantly decreased EC-derived IL-7 expression, along with significant changes in IEL phenotype; decreased IEL proliferation; and resulted in a marked decrease in IEL numbers. To better determine the relevance of TPN-related changes in IL-7, TPN mice supplemented with exogenous IL-7 or mice allowed ad libitum feeding and treated with exogenous administration of anti-IL-7 receptor (IL-7R) antibody were also studied. Exogenous IL-7 administration in TPN mice significantly attenuated TPN-associated IEL changes, whereas blocking IL-7R in normal mice resulted in several similar changes in IEL to those observed with TPN. These findings suggest that a decrease in EC-derived IL-7 expression may be a contributing mechanism to account for the observed TPN-associated IEL changes.

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Novel Agents in the Treatment of Intestinal Failure: Humoral Factors

Cited by 17 publications

References 57 publications

Intestinal Specific Overexpression of Interleukin-7 Attenuates the Alternation of Intestinal Intraepithelial Lymphocytes After Total Parenteral Nutrition Administration

Intestinal Specific Overexpression of Interleukin-7 Attenuates the Alternation of Intestinal Intraepithelial Lymphocytes After Total Parenteral Nutrition Administration

Intestinal epithelial cell proliferation is dependent on the site of massive small bowel resection

Intestinal epithelial cell-derived interleukin-7: a mechanism for the alteration of intraepithelial lymphocytes in a mouse model of total parenteral nutrition

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