Sang Lee

Boston Children's Hospital, Boston, Massachusetts, United States

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Publications (15)64.23 Total impact

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    ABSTRACT: This study compared the effects of total parenteral nutrition (TPN) by central vein with or without fat provided at maintenance energy requirement on fatty acid metabolism, de novo lipogenesis, and the risk of hepatic and systemic inflammation in rats. Study 1 was conducted in 2 groups: high glucose (HG), where fat-free TPN was given at maintenance levels of 180 kcal/(kg d), and low glucose (LG), where fat-free TPN containing 30% fewer calories at 126 kcal/(kg d) was provided by reducing 54 kcal/(kg d) from parenteral glucose. Study 2 contained 3 TPN groups: 1 LG group at 126 kcal/(kg d) and 2 groups at 180 kcal/(kg d) with 30% of total calories (54 kcal/[kg d]) either from soybean or fish oil emulsion. In both studies, animals fed a chow diet ad libitum were included. Plasma and hepatic triglyceride and phospholipid fatty acid profiles, enzymes indicating hepatic injury, and C-reactive protein levels (CRP) reflecting systemic injury were measured. In study 1, evidence of de novo lipogenesis was noted in LG and was more prominent in HG with elevation of CRP in HG. In study 2, de novo lipogenesis was reduced by adding either fat to LG to achieve maintenance energy levels. Moreover, adding fat as soybean oil but not fish oil significantly increased plasma and hepatic triglyceride and also elevated aspartate aminotransferase and CRP levels, reflecting inflammation. Thus, in rats, either hypocaloric feeding as glucose-based TPN or TPN provided at maintenance energy levels with the addition of fish oil limits hepatic lipid accumulation and prevents the evidence of hepatic and systemic injury found with maintenance level TPN as glucose only or glucose plus soybean oil.
    Metabolism: clinical and experimental 02/2011; 60(2):195-205. · 3.10 Impact Factor
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    ABSTRACT: Interactions between developmental signaling pathways govern the formation and function of stem cells. Prostaglandin (PG) E2 regulates vertebrate hematopoietic stem cells (HSC). Similarly, the Wnt signaling pathway controls HSC self-renewal and bone marrow repopulation. Here, we show that wnt reporter activity in zebrafish HSCs is responsive to PGE2 modulation, demonstrating a direct interaction in vivo. Inhibition of PGE2 synthesis blocked wnt-induced alterations in HSC formation. PGE2 modified the wnt signaling cascade at the level of beta-catenin degradation through cAMP/PKA-mediated stabilizing phosphorylation events. The PGE2/Wnt interaction regulated murine stem and progenitor populations in vitro in hematopoietic ES cell assays and in vivo following transplantation. The relationship between PGE2 and Wnt was also conserved during regeneration of other organ systems. Our work provides in vivo evidence that Wnt activation in stem cells requires PGE2, and suggests the PGE2/Wnt interaction is a master regulator of vertebrate regeneration and recovery.
    Cell 04/2009; 136(6):1136-47. · 31.96 Impact Factor
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    ABSTRACT: Bile duct obstruction and subsequent cholestasis produces hepatocellular injury and an inflammatory response. Fatty acid constitution of cell membranes plays a major role in the inflammatory cascade. Omega-3 fatty acids are antiinflammatory. We proposed that omega-3 fatty acid supplementation would reduce hepatocellular damage and cell death in a model of murine common bile duct ligation. Mice underwent bile duct ligation and were administered either control soy diet (omega-6) or Menhaden diet (omega-3), and parameters of liver injury were measured at postoperative days 1, 4, and 8. Serum was analyzed for liver function tests. Liver tissue was scored for histologic necrosis and inflammation, and apoptosis was qualitatively measured. At day 8, comparing control and Menhaden, liver function tests were not significantly different. The H&E slides were analyzed and scored. At day 4, the mean necrosis scores for the Menhaden-fed group was 0.01 +/- 0.028 and 0.46 +/- 0.108 for the soy-fed group (P = .001) and at day 8, 0.420 +/- 0.107 and 1.22 +/- 0.132 (P < .001). The mean portal inflammation score for day 4 Menhaden-fed and soy-fed mice was 1.40 +/- 0.245 for both groups (P = 1.00) and for day 8, 1.80 +/- 0.200 and 2.80 +/- 0.200 (P = .008). At day 1, the median terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling scores of the Menhaden vs soy group were 6.0 and 0.0 (P < .001); day 4, 24.0 and 3.0 (P < .001); and day 8, 0.0 and 3.0 (P < .001), respectively. Although there appears to be a trend toward biochemical protection and a marked reduction of necrosis and inflammation, there was no significant liver function test difference between control and Menhaden groups. Considering our data of blunted histologic hepatotoxicity with omega-3 fatty acid supplementation, we hypothesize that this may be a method of reducing long-term complications of liver injury secondary to diseases of cholestasis such as biliary atresia, namely fibrosis and cirrhosis.
    Journal of Pediatric Surgery 12/2008; 43(11):2010-5. · 1.38 Impact Factor
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    ABSTRACT: Rib lesions in the pediatric population are rare but significant processes and are often neoplastic. All patients with primary rib lesions evaluated by the Department of Surgery at Children's Hospital Boston from 1992 to 2005 were studied. The patient's diagnosis, sex, symptoms and their duration, radiologic evaluation, biopsy status, surgical procedure, and follow-up were assessed. Thirty-three patients, ages 3 to 23 years (median, 12.7 years), were evaluated. Sixteen patients (48%) had benign and 17 (52%) had malignant lesions. Within the benign cohort of 16 patients, there were 6 osteochondromas, 4 aneurysmal bone cysts, and 2 fibrous dysplasias as well as 1 of each of the following: enchondroma, periosteal chondroma, eosinophilic granuloma, and chondrophyte. Within the malignant cohort of 17 patients, 13 were diagnosed with Ewing's sarcoma, 3 with osteogenic sarcoma, and 1 with chondrosarcoma. The sex distribution for the malignant group was 11 (65%) females and 6 (35%) males. Rib tumors are rare entities in the pediatric population. However, a significant number of rib lesions are malignant. Therefore, proper diagnosis and expeditious treatment are critical.
    Journal of Pediatric Surgery 11/2008; 43(10):1781-5. · 1.38 Impact Factor
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    ABSTRACT: Developmental signaling pathways hold the keys to unlocking the promise of adult tissue regeneration, and to inhibiting carcinogenesis. Patients with mutations in the Adenomatous Polyposis Coli (APC) gene are at increased risk of developing hepatoblastoma, an embryonal form of liver cancer, suggesting that Wnt affects hepatic progenitor cells. To elucidate the role of APC loss and enhanced Wnt activity in liver development, we examined APC mutant and wnt inducible transgenic zebrafish. APC(+/-) embryos developed enlarged livers through biased induction of hepatic gene programs and increased proliferation. Conversely, APC(-/-) embryos formed no livers. Blastula transplantations determined that the effects of APC loss were cell autonomous. Induction of wnt modulators confirmed biphasic consequences of wnt activation: endodermal pattern formation and gene expression required suppression of wnt signaling in early somitogenesis; later, increased wnt activity altered endodermal fate by enhancing liver growth at the expense of pancreas formation; these effects persisted into the larval stage. In adult APC(+/-) zebrafish, increased wnt activity significantly accelerated liver regeneration after partial hepatectomy. Similarly, liver regeneration was significantly enhanced in APC(Min/+) mice, indicating the conserved effect of Wnt pathway activation in liver regeneration across vertebrate species. These studies reveal an important and time-dependent role for wnt signaling during liver development and regeneration.
    Developmental Biology 06/2008; 320(1):161-74. · 3.87 Impact Factor
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    ABSTRACT: Fish oil, a rich source of omega-3 fatty acids, has never been used as the sole source of lipid in clinical practice for fear of development of essential fatty acid deficiency, as it lacks the believed requisite levels of linoleic acid, an omega-6 fatty acid. The objectives of this study were to establish biochemical standards for fish oil as the sole fat and to test the hypothesis that fish oil contains adequate amounts of omega-6 fatty acids to prevent essential fatty acid deficiency. Forty mice were divided into 2 groups that were either pair fed or allowed to eat ad libitum. In each group, 4 subgroups of 5 mice were fed 1%, 5%, and 10% fish oil diets by weight or a control soybean diet for 9 weeks. Blood was collected at 4 time points, and fatty acid analysis was performed. Food intake and weight status were monitored. All groups but the pair-fed 1% fish oil group gained weight, and the 5% fish oil group showed the highest caloric efficiency in both pair-fed and ad libitum groups. Fatty acid profiles for the 1% fish oil group displayed clear essential fatty acid deficiency, 5% fish oil appeared marginal, and 10% and soybean oil diets were found to prevent essential fatty acid deficiency. Fish oil enhances growth through higher caloric efficiency. We established a total omega-6 fatty acid requirement of between 0.30% and 0.56% of dietary energy, approximately half of the conventionally believed 1% as linoleic acid. This can presumably be attributed to the fact that fish oil contains not only a small amount of linoleic acid, but also arachidonic acid, which has greater efficiency to meet omega-6 fatty acid requirements.
    Metabolism 06/2008; 57(5):698-707. · 3.10 Impact Factor
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    ABSTRACT: Matrix metalloproteinases (MMPs), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) are mediators of liver regeneration. To determine whether MMPs are required for normal hepatic regeneration, we performed 67% hepatectomies on mice treated with a broad-spectrum MMP-inhibitor, and assessed the effect on liver regeneration and urinary MMP activity. Mice were subjected to sham operations, 67% hepatectomy, or 67% hepatectomy plus treatment with the broad-spectrum MMP inhibitor Marimastat. Urine collected preoperatively and for 8 d postoperatively was tested for MMP-2 and MMP-9 activity using zymography. Serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, TNF-alpha, IL-6, and hepatocyte growth factor levels were measured. Liver sections were analyzed by CD31 immunohistochemistry and microvessel density. Mitotic index and proliferating cell nuclear antigen labeling index were determined. The mean regenerating liver weight on postoperative day 8 was 0.72 +/- 0.01 grams for the hepatectomy Marimastat group, and 0.83 +/- 0.02 grams for the hepatectomy control group (P < 0.001). Urinary MMP-9 activity was elevated during hepatic regeneration, and decreased on postoperative day 8 when the liver returned to its preoperative mass. In contrast, urine from hepatectomy Marimastat mice, in which liver regeneration was successfully inhibited, showed consistently low levels of MMP-2 and MMP-9 activity. The hepatectomy Marimastat group also exhibited elevated serum IL-6 levels on post-operative day 8, while serum TNF-alpha soluble receptor II levels were unchanged. Hepatocyte growth factor levels were not significantly different between the control hepatectomy and hepatectomy Marimastat groups at days 2, 4, and 8. Liver microvessel density was reduced in the hepatectomy Marimastat group at day 4. Mitotic index and proliferating cell nuclear antigen index were significantly decreased in the Marimastat hepatectomy group at post-operative day 2. The broad-spectrum MMP-inhibitor Marimastat inhibits liver regeneration. Microvessel density is reduced at day 4. Furthermore, urinary MMP-9 is elevated during liver regeneration, and this effect is not observed when regeneration is inhibited by the broad-spectrum MMP-inhibitor Marimastat.
    Journal of Surgical Research 05/2008; 145(2):192-8. · 2.02 Impact Factor
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    ABSTRACT: Parenteral nutrition-associated liver disease can be a progressive and fatal entity in children with short-bowel syndrome. Soybean-fat emulsions provided as part of standard parenteral nutrition may contribute to its pathophysiology. We compared safety and efficacy outcomes of a fish-oil-based fat emulsion in 18 infants with short-bowel syndrome who developed cholestasis (serum direct bilirubin level of > 2 mg/dL) while receiving soybean emulsions with those from a historical cohort of 21 infants with short-bowel syndrome who also developed cholestasis while receiving soybean emulsions. The primary end point was time to reversal of cholestasis (3 consecutive measurements of serum direct bilirubin level of < or = 2 mg/dL). Among survivors, the median time to reversal of cholestasis was 9.4 and 44.1 weeks in the fish-oil and historical cohorts, respectively. Subjects who received fish-oil-based emulsion experienced reversal of cholestasis 4.8 times faster than those who received soybean emulsions and 6.8 times faster in analysis adjusted for baseline bilirubin concentration, gestational age, and the diagnosis of necrotizing enterocolitis. A total of 2 deaths and 0 liver transplantations were recorded in the fish-oil cohort and 7 deaths and 2 transplantations in the historical cohort. The provision of fish-oil-based fat emulsion was not associated with essential fatty acid deficiency, hypertriglyceridemia, coagulopathy, infections, or growth delay. Parenteral fish-oil-based fat emulsions are safe and may be effective in the treatment of parenteral nutrition-associated liver disease.
    PEDIATRICS 03/2008; 121(3):e678-86. · 4.47 Impact Factor
  • Journal of pediatric gastroenterology and nutrition 03/2008; 46(2):224-5; author reply 225. · 2.18 Impact Factor
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    ABSTRACT: To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions. In the United States, complications from adhesions cost $1 billion and account for 846,000 inpatient days annually. Endothelial mitogens, such as VEGF, are up-regulated during adhesion formation. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor properties, may prevent or reduce postoperative abdominal adhesions by VEGFR-2 inhibition. The cecum of 37 mice were abraded to promote adhesion formation and a silicone patch was sutured to the abdominal wall. The mice were randomized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. After 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then repeated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib. All 19 control mice developed intra-abdominal adhesions. Six of the 18 (33.3%) mice in the treatment group were adhesion-free. Collectively, the sunitinib-treated mice had a lower adhesion score [2.0 (IQR 0.0-5.0; range 0-8.0)] than the control group [5.0 (IQR 3.0-8.0; range 2.0-10.0) (P = 0.002)]. Long-term results were consistent with this finding [sunitinib 0.0 (IQR 0.0-3.0; range 0-7) and control 6.0 (IQR 3.0-7.0; range 0-12) (P = 0.049)]. Adhesion formation is angiogenesis-dependent and is in part mediated through VEGFR-2. Sunitinib, a VEGFR-2 antagonist, significantly reduces adhesion formation in a murine model. Antiangiogenic therapy may be an efficacious strategy to prevent or treat adhesions after intra-abdominal procedures.
    Journal of Surgical Research 12/2007; 149(1):115-9. · 2.02 Impact Factor
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    ABSTRACT: We hypothesize that compensatory lung growth after unilateral pneumonectomy in a murine model is, in part, angiogenesis dependent and can be altered using angiogenic agents, possibly through regulation of endothelial cell proliferation and apoptosis. Left pneumonectomy was performed in mice. Mice were then treated with proangiogenic factors [vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF)], VEGF receptor antibodies (MF-1, DC101), and VEGF receptor small molecule chemical inhibitors. Lung volume and mass were measured. The lungs were analyzed using immunohistochemistry by CD31 staining, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, type II pneumocytes staining, and proliferating cell nuclear antigen. Compensatory lung growth was complete by postoperative day 10 and was associated with diffuse apoptosis of endothelial cells and pneumocytes. This process was accelerated by VEGF, such that growth was complete by postoperative day 4 with similar associated apoptosis. bFGF had no effect on lung growth. MF-1 and DC101 had no effect. The VEGF receptor small molecule chemical inhibitors also had no effect. VEGF, but not bFGF, accelerates growth. VEGF receptor inhibitors do not block growth, suggesting that other proangiogenic factors play a role or can compensate for VEGF receptor blockade. Diffuse apoptosis, endothelial cell and pneumocyte, occurs at cessation of both normal compensatory and VEGF-accelerated growth. Angiogenesis modulators may control growth via regulation of endothelial cell proliferation and apoptosis, although the exact relationship between endothelial cells and pneumocytes has yet to be determined. The fact that bFGF did not accelerate growth in our model when it did accelerate regeneration in the liver model suggests that angiogenesis during organ regeneration is regulated in an organ-specific manner.
    AJP Lung Cellular and Molecular Physiology 04/2007; 292(3):L742-7. · 3.52 Impact Factor
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    ABSTRACT: Steatosis is a prominent feature of nonalcoholic fatty liver disease and a potential promoter of inflammation. Injury leading to cirrhosis is partly mediated by dysregulation of matrix protein turnover. Matrix metalloproteinase (MMP) inhibitors protect mice from lethal TNF-alpha induced liver injury. We hypothesized that Marimastat, a broad-spectrum MMP and TNF-alpha converting enzyme (TACE) inhibitor, might modulate this injury through interruption of inflammatory pathways. Triglyceride and phospholipid levels (liver, serum) and fatty acid profiles were used to assess essential fatty acid status and de novo lipogenesis as mechanisms for hepatic steatosis. Mice receiving a fat-free, high-carbohydrate diet (HCD) for 19 days developed severe fatty liver infiltration, demonstrated by histology, magnetic resonance spectroscopy, and elevated liver function tests. Animals receiving HCD plus Marimastat (HCD+MAR) were comparable to control animals. Increased tissue levels of peroxisome proliferator activated receptor-alpha (PPAR-alpha), higher levels of serum IL-6, and decreased levels of serum TNF-alpha receptor II were also seen in the HCD+MAR group compared with HCD-only. In addition, there was increased phosphorylation, and likely activation, of PPAR-alpha in the HCD+MAR group. PPAR-alpha is a transcription factor involved in beta-oxidation of fatty acids, and IL-6 is a hepatoprotective cytokine. Liver triglyceride levels were higher and serum triglyceride and phospholipid levels lower with HCD-only but improved with Marimastat treatment. HCD-only and HCD+MAR groups were essential fatty acid deficient and had elevated rates of de novo lipogenesis. We therefore conclude that Marimastat reduces liver triglyceride accumulation by increasing fat oxidation and/or liver clearance of triglycerides. This may be related to increased expression and activation of PPAR-alpha or IL-6, respectively.
    AJP Gastrointestinal and Liver Physiology 01/2007; 291(6):G1011-9. · 3.65 Impact Factor
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    ABSTRACT: Recent years have brought a resurgence of research interest in fatty acids, with studied fields running the gamut of human disease. This movement has run in parallel with an increased interest in using nutrition modalities as therapeutic measures, as opposed to their conventional role as energy sources. The aim of this manuscript is to provide a basic review of current clinical applications of omega-6 and omega-3 fatty acids, with a particular focus on the latter. A selective review of the voluminous literature, including randomized controlled trials, meta-analyses, population studies, and case reports, was used to compile data and identify trends in pertinent clinical applications of fatty acid therapy. There are a myriad of disorders and maladies that seem to benefit from fatty acid supplementation, specifically omega-3 fatty acids. It has clearly been shown that omega-3 fatty acid supplementation provides a protective benefit in heart disease, and in particular sudden cardiac death. Rheumatoid arthritis (RA) is another disease entity that has been proven to benefit from this nutrition intervention, with improvement in symptoms and diminished nonsteroidal antiinflammatory drug (NSAID) usage. In addition, many psychiatric disorders, particularly schizophrenia and major depressive disorder (MDD), have shown positive results when supplementation has been used as an adjunct to standard pharmacotherapy. The remainder of clinical applications for omega-3 fatty acids requires further investigation. Specifically, according to preliminary clinical evidence, parenteral administration of fatty acids warrants further study.
    Nutrition in Clinical Practice 09/2006; 21(4):323-41. · 1.58 Impact Factor
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Publication Stats

548 Citations
64.23 Total Impact Points

Institutions

  • 2006–2011
    • Boston Children's Hospital
      • Department of Pharmacy
      Boston, Massachusetts, United States
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 2009
    • Neural Stem Cell Institute
      Rensselaer, New York, United States
  • 2008
    • Harvard Medical School
      • Department of Surgery
      Boston, MA, United States
  • 2007
    • Erasmus MC
      • Department of Surgery
      Rotterdam, South Holland, Netherlands