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Background/purpose: Intestinal adaptation is a compensatory response to massive small bowel loss in which there are increased numbers of absorptive enterocytes. However, the generation of secretory epithelial cell subtypes in this process has not been investigated. The purpose of this study was to examine the adaptive changes of several small intestinal cell lineage changes in response to massive small bowel resection (SBR)., Methods: A 75% SBR or sham operation was performed on male Sprague-Dawley rats. On postoperative day 7, the remnant ileum was harvested and immunohistochemical staining for goblet, Paneth, and enteroendocrine cells was performed. Cell subtypes were evaluated as cells per micrometer of villus/crypt length and compared among operations., Results: A significant increase in goblet cell density occurred after SBR. Intestinal resection did not alter the number of Paneth and enteroendocrine cells. In additional experiments, inhibition of epidermal growth factor receptor signaling was associated with a diminished goblet cell density., Conclusions: The adaptive response of the intestine to massive bowel loss results in an expansion of the goblet cell population in addition to greater numbers of absorptive enterocytes. Although the mechanism and purpose for selective expansion of these stem cell-derived lineages are not presently known, epidermal growth factor receptor signaling appears to be a common pathway.

Prior studies of intestinal adaptation after massive small bowel resection (SBR) have focused on growth factors and their effects on amplification of the gut mucosa. Because adaptive changes have also been described in intestinal smooth muscle, we sought to determine the effect of targeted smooth muscle growth factor overexpression on resection-induced intestinal adaptation. Male transgenic mice with smooth muscle cell overexpression of insulin-like growth factor I (IGF-I) by virtue of an alpha-smooth muscle actin promoter were obtained. SMP8 IGF-I transgenic (IGF-I TG) and nontransgenic (NT) littermates underwent 50% proximal SBR or sham operation and were then killed after 3 or 28 days. NT mice showed the expected alterations in mucosal adaptive parameters after SBR, such as increased wet weight and villus height. The IGF-I TG mice had inherently taller villi, which did not increase significantly after SBR. In addition, IGF-I TG mice had a 50% postresection persistent increase in remnant intestinal length, which was associated with an early decline and later increase in relative mucosal surface area. These results indicate that growth factor overexpression within the muscularis layer of the bowel wall induces significant postresection adaptive intestinal lengthening and a unique mucosal response. IGF-I signaling within the muscle wall may play an important role in the pathogenesis of resection-induced adaptation.

Background: Adaptation after massive smallbowel resection (SBR) is associated with increased cell turnover, increased rates of enterocyte proliferation, and apoptosis. Epidermal growth factor receptor (EGFR) inhibition attenuates adaptation and increases apoptosis. Intestinal levels of bax appear to correlate with EGFR signaling. This study tested the hypothesis that bax is required for the exaggerated postresection apoptosis induced by perturbed EGFR signaling., Methods: Waved-2 mice with impaired EGFR signaling were crossbred with bax-null mice. Offspring were subjected to either 50% proximal SBR or sham operation (bowel transection and reanastomosis). After 7 days, parameters of adaptation (villus height, wet weight), proliferation (% Ki-67 immunostaining of crypt cells), and apoptosis (# apoptotic bodies per crypt) were recorded in the remnant ileum., Results: Enterocyte apoptosis was increased in waved-2 mice and prevented in bax-null mice after SBR. The accelerated apoptosis in the waved-2 mice was rescued in the context of deficient bax expression. Other parameters of adaptation were restored in the bax-null/waved-2 mice., Conclusion: Bax is required for the induction of postresection enterocyte apoptosis. Defective EGFR signaling augments resection-induced enterocyte apoptosis via a mechanism that also requires bax expression. These data implicate a link between EGFR signaling and bax in the genesis of postresection apoptosis and adaptation., (Copyright 2004 Elsevier Inc.)

Background: After massive small bowel resection (SBR), increased rates of enterocyte apoptosis are observed in the remnant bowel via a mechanism requiring bax gene expression. This study tested the hypothesis that adaptive mucosal growth could be enhanced by the novel strategy of preventing postresection enterocyte apoptosis., Methods: Male bax-null and corresponding wild-type (WT) mice underwent a 50% proximal SBR or sham operation (bowel transaction with reanastomosis alone). Mice were killed after a full adaptation interval of 1 month. Adaptation was measured in the remnant ileum as alterations in villus height, crypt depth, and wet weight. Rates of enterocyte proliferation were derived by immunostaining of crypt enterocytes for Ki-67 and apoptosis by the presence of apoptosis bodies., Results: The expected increase in enterocyte apoptosis after SBR occurred in the WT mice but was unchanged in the bax-null mice. Despite the prevention of postresection apoptosis in the bax-null mice, all parameters of adaptation and proliferation increased equally after SBR in both groups of mice., Conclusions: Bax deficiency prevents the increase in enterocyte apoptosis that occurs after massive SBR throughout the entire adaptation period. Attenuation of postresection enterocyte apoptosis does not augment mucosal adaptation to massive intestinal loss.

Background: After massive small bowel resection (SBR), the remnant bowel adapts by increasing enterocyte proliferation and apoptosis. The purpose of this study was to investigate the relevance of luminal bacteria on postresection intestinal cell turnover., Methods: Male germ-free (GF) and normally colonized control rats underwent either a 75% mid-SBR or sham operation. In other experiments, normally colonized control rats were given antibiotics in the drinking water. After 7 days, the remnant ileum was harvested and adaptation verified by alterations in wet weight, crypt depth, and villus height. Proliferation and apoptosis were measured in crypts as the percent of crypt cells staining for Ki-67 or the number of apoptotic bodies per crypt., Results: Both GF and control rats demonstrated significant increases in all adaptive parameters. Proliferation was increased after SBR in both groups, but significantly greater in the GF animals over control. This response could not be recapitulated after antibiotic treatment. Apoptosis increased equally after SBR in all groups., Conclusion: Resection-induced intestinal adaptation occurs normally in GF animals. Epithelial-microbial interactions are probably not involved in the activation of enterocyte apoptosis. The germ-free studies offer the possibility that luminal bacteria may attenuate the proliferative response of the enterocyte to massive small bowel resection.

Intestinal adaptation following small bowel resection (SBR) is associated with greater rates of enterocyte apoptosis by unknown mechanism(s). Because postresection adaptation is associated with increased translocation of luminal bacteria, we sought to characterize the role for the extrinsic, death receptor pathway for the activation of enterocyte apoptosis after massive SBR. We first performed SBR or sham operations in mice, and the temporal expression of caspases 8, 9, and 3, death receptors tumor necrosis factor receptor-1 (TNFR1) and Fas and corresponding ligands (TNF and Fas ligand) was determined in the remnant intestine at various postoperative time points. Ileal TNFR1 and Fas expression were then measured after SBR in the setting of increased (waved-2 mice) or decreased (exogenous EGF administration) apoptosis. Finally, intestinal adaptation and apoptosis were recorded in the remnant ileum after SBR in TNFR1-null and Fas-null mice. The expression of death receptor family proteins and caspases demonstrated only modest changes after SBR and did not correlate with the histological appearance of apoptosis. In the setting of accelerated apoptosis, TNFR1 and Fas expression were paradoxically decreased. Apoptotic and adaptive responses were preserved in both TNFR1-null and Fas-null mice. These results suggest that the mechanism for increased enterocyte apoptosis following massive SBR does not appear to involve the extrinsic, death receptor-mediated pathway.

Background/purpose: After small bowel resection (SBR), serum induces proliferation in rat intestinal epithelial cells (RIEC-6). This study was designed to elucidate the effects of postoperative time interval, site, and magnitude of SBR on RIEC-6 proliferation., Methods: Serum was collected from rats at various times after a 75% mid-SBR or sham operation and added to RIEC-6 cells and growth determined over 5 days. In other experiments, cell growth was recorded in the presence of serum from rats after 25%, 50%, or 75% SBR, or after jejunal or ileal SBR., Results: SBR serum enhanced RIEC-6 cell proliferation as early as 12 hours after resection. The extent of SBR directly correlated with the level of adaptation; however, the effects on cell growth by the serum were similar. SBR serum induced proliferation equally after either proximal or distal resection., Conclusions: Serum contains a factor that stimulates intestinal cell proliferation soon after SBR but independent of the degree or site of intestinal resection. Although humoral factor(s) play a role in the early induction of enterocyte proliferation after SBR, further modulation of adaptation to varied lengths or sites of intestinal resection are probably governed by mechanisms independent of factors that circulate in the serum.

Background: After massive small bowel resection (SBR), enterocyte apoptosis is elevated and inversely correlates with epidermal growth factor receptor (EGFR) signaling. The purpose of the current study was to determine whether EGFR manipulation affects the expression of specific bcl-2 family members., Methods: A 50% proximal SBR or sham operation was performed in 3 groups of mice control, after exogenous EGF, or mutant mice with defective EGFR signaling (waved-2). Apoptotic index (no. of apoptotic bodies per crypt), and bax (pro-apoptosis) and bcl-w (anti-apoptosis) protein expression was measured in the remnant ileum after 12, 24, and 72 hours., Results: Waved-2 mice with defective EGFR showed the greatest increase in apoptosis and altered the ratio of bax to bcl-w in favor of apoptosis after SBR. Conversely, EGF prevented the expected increase in apoptosis after SBR by shifting the ratio of bax to bcl-w in favor of cell survival., Conclusions: After massive small bowel resection, inhibition of the EGFR accelerates the rate of apoptosis and modifies the expression of specific bcl-2 family members to favor apoptosis. These results further support a specific mechanistic pathway for the regulation of enterocyte apoptosis after SBR via EGFR signaling.

The maintenance of long-term venous access is critical to the livelihood of children in a variety of clinical situations, especially those who are dependent on parenteral nutrition. Whereas the traditional routes of either peripheral or central venous access are initially adequate, most of these sites eventually succumb to the pitfalls associated with long-term venous access. This review provides a comprehensive and multidisciplinary approach to the management of reoperative venous access with regard to preoperative planning and imaging and specific techniques in interventional radiology and surgery., (Copyright 2003 Elsevier Inc. All rights reserved.)

Background/purpose: Epidermal growth factor (EGF) and its receptor (EGFR) are key components in the genesis of adaptation after small bowel resection (SBR). Within intestinal homogenates, EGFR expression is increased after SBR; however, the exact cells responsible for altered EGFR expression are unknown. In this study, laser capture microdissection (LCM) microscopy was used to elucidate the specific cellular compartment(s) responsible for postresection changes in EGFR expression., Methods: Male ICR mice underwent a 50% proximal SBR or sham operation. After 3 days, frozen sections were taken from the remnant ileum. Individual cells from villi, crypt, muscularis, and mesenchymal compartments were isolated by LCM. EGFR mRNA expression for each cell compartment was quantified using real-time polymerase chain reaction (PCR)., Results: EGFR expression was increased after SBR within the crypt (2-fold) and muscularis compartments (3-fold). There were no changes detected after SBR in the villus tips or mesenchymal compartments., Conclusions: Increased expression of EGFR in crypts directly correlates with the zone of cell proliferation and supports the hypothesis that EGFR signaling is crucial for the mitogenic stimulus for adaptation. The finding of increased EGFR expression in the muscular compartment is novel and may implicate a role for EGFR as a mediator of the muscular hyperplasia seen after massive SBR., (Copyright 2003, Elsevier Science (USA). All rights reserved.)

Background: In vivo, intestinal adaptation after massive small bowel resection (SBR) requires a functional epidermal growth factor (EGF) receptor (EGFR). In vitro studies have shown that serum from mice after SBR induces rat intestinal epithelial cells to proliferate. This study tested the hypothesis that the proliferative response to SBR serum is mediated by EGFR signaling., Methods: Serum was collected from male Sprague-Dawley rats 7 days after 75% SBR or sham operation. Rat intestinal epithelial cells were incubated in the presence of sham or SBR serum. Total EGFR expression and phosphorylation of several EGFR downstream pathways were determined by Western blotting. In other experiments, a specific EGFR inhibitor (ZD1839) was added and cell growth determined over 5 days., Results: SBR serum significantly increased total EGFR expression (3-fold) over sham operation and consistently activated the phosphatidylinositol 3-kinase pathway. Furthermore, SBR serum markedly augmented rat intestinal epithelial cell growth, an effect that was abolished by EGFR inhibition., Conclusions: SBR serum contains a factor or factors that stimulates proliferation of intestinal epithelial cells by an EGFR and phosphatidylinositol 3-kinase signaling mechanism. These data recapitulate in vivo studies supporting the hypothesis that EGFR is a central mediator of postresection intestinal adaptation. This in vitro model may provide a novel means to gain insight into the pathophysiology of intestinal adaptation.