Shannon W Longshore

Washington University in St. Louis, Saint Louis, MO, United States

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Publications (10)17.94 Total impact

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    ABSTRACT: Adaptation following massive intestinal loss is characterized by increased villus height and crypt depth. Previously, we demonstrated that p21-null mice do not adapt after small bowel resection (SBR). As retinoblastoma protein (Rb) levels are elevated in p21-null crypt cells, we first sought to determine whether Rb is required for normal adaptation. Next, we tested whether Rb expression is responsible for blocked adaptation in p21-nulls. Genetically manipulated mice and wild-type (WT) littermates underwent either 50% SBR or sham operation. The intestine was harvested at 3, 7, or 28 days later and intestinal adaptation was evaluated. Enterocytes were isolated and protein levels evaluated by Western blot and quantified by optical density. Rb-null mice demonstrated increased villus height, crypt depth, and proliferative rate at baseline, but there was no further increase following SBR. Deletion of one Rb allele lowered Rb expression and restored resection-induced adaptation responses in p21-null mice. Rb is specifically required for resection-induced adaptation. Restoration of adaptation in p21-null mice by lowering Rb expression suggests a crucial mechanistic role for Rb in the regulation of intestinal adaptation by p21.
    Journal of Gastrointestinal Surgery 01/2012; 16(1):148-55; discussion 155. · 2.36 Impact Factor
  • Journal of Surgical Research - J SURG RES. 01/2011; 165(2):287-287.
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    ABSTRACT: In vitro supplementation of the bile salt, taurodeoxycholic acid (TDCA), has been shown to stimulate proliferation and prevent intestinal apoptosis in IEC-6 cells. We hypothesize that addition of TDCA to a rodent liquid diet will be protective against induced intestinal injury. C57Bl6 mice were fed a liquid diet with or without 50-mg/(kg d) TDCA supplementation. After 6 days, the mice were injected with lipopolysaccharide (LPS) (10 mg/kg) to induce intestinal injury. Specimens were obtained 24 hours later and evaluated for intestinal apoptosis, crypt proliferation, and villus length. A separate cohort of animals was injected with LPS (25 mg/kg) and followed 7 days for survival. Mice whose diet was supplemented with TDCA had significantly increased survival. After LPS-induced injury, mice supplemented with TDCA showed decreased intestinal apoptosis by both H&E and caspase-3. They also had increased intestinal proliferation by 5-bromo-2'deoxyuridine staining and increased villus length. Dietary TDCA supplementation alleviates mucosal damage and improves survival after LPS-induced intestinal injury. Taurodeoxycholic acid is protective of the intestinal mucosa by increasing resistance to injury-induced apoptosis, stimulating enterocyte proliferation, and increasing villus length. Taurodeoxycholic acid supplementation also results in an increased survival benefit. Therefore, bile acid supplementation may potentially protect the intestine from injury or infection.
    Journal of Pediatric Surgery 06/2010; 45(6):1256-65. · 1.38 Impact Factor
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    ABSTRACT: The magnitude of intestinal adaptation is considered to correlate with the extent of small bowel resection (SBR). However, this association has never been tested in mice. We sought to test the hypothesis that a greater SBR will induce a greater adaptation response. C57/B6 mice underwent 50% SBR, 75% SBR, or sham operation and were killed on postoperative day 7. The magnitude of adaptation was compared between 50% SBR and 75% SBR as changes in villus height, crypt depth, as well as rates of apoptosis and proliferation. Seventy-five percent SBR led to decreased survival and increased weight loss compared with 50% SBR. The remnant ileum of both 50% SBR and 75% SBR displayed similar crypt expansion, enhanced villi, and increased apoptotic indices. Proliferation rates increased after 50% and 75% SBR equally. Models of resection greater than 50% in mice result in greater morbidity and mortality and do not magnify the adaptation response to massive SBR. The use of more extreme resection models does not appear to provide added benefit for investigating mechanisms of intestinal adaptation.
    Journal of Pediatric Surgery 06/2010; 45(6):1274-9. · 1.38 Impact Factor
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    ABSTRACT: The structural and functional changes during intestinal adaptation are necessary to compensate for the sudden loss of digestive and absorptive capacity after massive intestinal resection. When the adaptive response is inadequate, short bowel syndrome (SBS) ensues and patients are left with the requirement for parenteral nutrition and its associated morbidities. Several hormones have been studied as potential enhancers of the adaptation process. The effects of growth hormone, insulin-like growth factor-1, epidermal growth factor, and glucagon-like peptide 2 on adaptation have been studied extensively in animal models. In addition, growth hormone and glucagon-like peptide 2 have shown promise for the treatment of SBS in clinical trials in human beings. Several lesser studied hormones, including leptin, corticosteroids, thyroxine, testosterone, and estradiol, are also discussed.
    Seminars in Pediatric Surgery 02/2010; 19(1):35-43. · 2.40 Impact Factor
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    Zhaohua Qiu, Shannon W Longshore, Brad W Warner, David A Rudnick
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    ABSTRACT: Liver mass is regulated in precise proportion to body mass in health and is restored by regeneration following acute injury. Despite extensive experimental analyses, the mechanisms involved in this regulation have not been fully elucidated. Previous investigations suggest that signals from the bowel may play an important role. The purpose of the studies reported here was to determine the effect of proximal partial small bowel resection on liver mass in a murine model. Mice were subjected to a 50% proximal small bowel resection or sham surgery followed by primary anastomosis, then sacrificed at serial times for determination of liver:body mass ratio and analyses of liver tissue. Liver:body weight ratio was significantly decreased 72 h after small bowel resection, and this decrease correlated with reduced functional liver mass as assessed by determination of total hepatic tissue protein and alanine transaminase (ALT) activity. Liver from bowel-resected animals demonstrated increased expression of LC3-II, a marker of autophagy, and also of pro-apoptotic Bax compared to anti-apoptotic Bcl-2. These data support a role for signals from the intestine in liver mass regulation, and they have potential implications regarding the pathogenesis of liver injury following small bowel resection.
    Journal of Gastrointestinal Surgery 09/2009; 13(12):2176-82. · 2.36 Impact Factor
  • S W Longshore, D Wakeman, M McMellen, B W Warner
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    ABSTRACT: Intestinal adaptation after massive short bowel resection (SBR) is characterized structurally by an increase in intestinal wet weight, protein, DNA content, villus height, crypt depth, and absorptive surface area. These structural characteristics are driven by a proliferative stimulus that increases crypt cell division and augments cellular progression along the crypt-villus axis. Functional characteristics of adaptation include an upregulation of NA+/Glucose cotransporters, Na+/H+ exchangers, and other enzymes involved in digestion and absorption. The combination of structural and functional adaptation are physiologic live-saving events that compensate for the sudden loss of digestive and absorptive capacity in the remnant intestine. If intestinal adaptation does not occur or is inadequate, a lifelong dependence on parenteral nutrition will ensue, which ultimately results in devastating cholestatic liver dysfunction. Several mediators are thought to play an influential role in postresection small bowel adaptation, including intraluminal nutrients, gastrointestinal secretions, hormones, growth factors, and other genetic/biochemical factors. A thorough understanding of the mechanisms that drive intestinal adaptation will be essential in the development of novel and innovative therapies that result in saving lives.
    Minerva pediatrica 07/2009; 61(3):239-51. · 0.64 Impact Factor
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    ABSTRACT: Adaptive growth of the intestinal mucosa in response to massive gut loss is fundamental for autonomy from parenteral nutrition. Although angiogenesis is essential for cellular proliferation in other tissues, its relevance to intestinal adaptation is unknown. We tested the hypothesis that resection-induced adaptation is associated with new blood vessel growth. Male C57Bl/6 mice underwent either a 50% small bowel resection or a sham (transection and reanastomosis) operation. After 1, 3, or 7 days, capillary density within the intestinal villi was measured using confocal microscopy. A messenger RNA reverse-transcriptase polymerase chain reaction (RT-PCR) array was used to determine angiogenic gene expression during adaptation. Mice that underwent small bowel resection had a significantly increased capillary density compared to sham-operated mice at postoperative day 7. This morphological alteration was preceded by significant alterations in 5 candidate genes at postoperative day 3. New vessel blood growth is observed in the adapting intestine after massive small bowel loss. This response appears to follow rather than initiate the adaptive alterations in mucosal morphology that are characteristic of adaptation. A better understanding of this progress and the signaling factors involved may improve therapeutic options for children with short gut syndrome.
    Journal of Pediatric Surgery 07/2009; 44(6):1077-82; discussion 1083. · 1.38 Impact Factor
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    ABSTRACT: After small bowel resection (SBR), adaptation is initiated in intestinal crypts where stem cells reside. Prior studies revealed SBR-induced enterocyte proliferation requires the expression of p21(waf1/cip1). As deficient expression of p21(waf1/cip1) has been shown to result in reduced numbers of hematopoietic stem cells. We sought to test the hypothesis that p21(waf1/cip1)deficiency similarly perturbs the intestinal stem cell population after SBR. Control (n = 21; C57Bl/6) and p21(waf1/cip1)-null mice (n = 30) underwent 50% proximal SBR or sham operation. After 3 days, the ileum was harvested and the crypt stem cell population evaluated by counting crypt base columnar cells on histologic sections, determining the expression of Musashi-1 and Lgr5, and profiling the transcriptional expression of 84 known stem cell genes. There were no significant differences in crypt base columnar cells, expression of Musashi-1 or Lgr5, or in stem cell gene expression after SBR in control mice. Furthermore, there were no differences in these markers between controls and p21(waf1/cip1)-null mice. In contrast with bone marrow stem cells, the stem cell population of the gut is unaffected by deficient expression of p21(waf1/cip1). Additional mechanisms for the role of p21(waf1/cip1) in small bowel proliferation and adaptation after massive SBR must be considered.
    Journal of Pediatric Surgery 07/2009; 44(6):1065-71; discussion 1071. · 1.38 Impact Factor
  • Jun Guo, Shannon Longshore, Rajalakshmi Nair, Brad W Warner
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    ABSTRACT: The function of retinoblastoma protein (pRb) in the regulation of small intestine epithelial cell homeostasis has been challenged by several groups using various promoter-based Cre transgenic mouse lines. Interestingly, different pRb deletion systems yield dramatically disparate small intestinal phenotypes. These findings confound the function of pRb in this dynamic tissue. In this study, Villin-Cre transgenic mice were crossed with Rb (flox/flox) mice to conditionally delete pRb protein in small intestine enterocytes. We discovered a novel hyperplasia phenotype as well as ectopic cell cycle reentry within villus enterocytes in the small intestine. This phenotype was not seen in other pRb family member (p107 or p130) null mice. Using a newly developed crypt/villus isolation method, we uncovered that expression of pRb was undetectable, whereas proliferating cell nuclear antigen, p107, cyclin E, cyclin D3, Cdk2, and Cdc2 were dramatically increased in pRb-deficient villus cells. Cyclin A, cyclin D1, cyclin D2, and Cdk4/6 expression was not affected by absent pRb expression. pRb-deficient villus cells appeared capable of progressing to mitosis but with higher rates of apoptosis. However, the cycling villus enterocytes were not completely differentiated as gauged by significant reduction of intestinal fatty acid-binding protein expression. In summary, pRb, but not p107 or p130, is required for maintaining the postmitotic villus cell in quiescence, governing the expression of cell cycle regulatory proteins, and completing of absorptive enterocyte differentiation in the small intestine.
    Journal of Biological Chemistry 12/2008; 284(1):134-40. · 4.65 Impact Factor

Publication Stats

80 Citations
17.94 Total Impact Points

Institutions

  • 2008–2012
    • Washington University in St. Louis
      • Department of Surgery
      Saint Louis, MO, United States
  • 2010
    • California State University, Sacramento
      Sacramento, California, United States
  • 2009–2010
    • University of Washington Seattle
      • Division of Pediatric Surgery
      Seattle, WA, United States
    • CSU Mentor
      Long Beach, California, United States
    • Cincinnati Children's Hospital Medical Center
      • Division of Pediatric General and Thoracic Surgery
      Cincinnati, OH, United States