Growth factor modulation of hepatic inflammation: a novel approach to the management of total parenteral nutrition-associated liver disease
ABSTRACT Dependence on total parenteral nutrition in intestinal failure or short bowel syndrome patients can lead to many complications. The most significant complication is progressive liver injury leading to liver failure. This study assesses the potential of hepatocyte growth factor (HGF) in modulating the hepatic response in a rat cholestatic liver injury model.
Female Sprague-Dawley rats were divided into 3 groups: control (n = 5), chronic liver injury (alpha-naphtylisocyocyanate [ANIT] every 3.5 days at 75 mg/kg; n = 5), and chronic liver injury plus HGF (ANIT + HGF at 250 microg kg(-1) d(-1); n = 5). The rats initially underwent massive (80%) small bowel resections. Seven days later, they were given intraperitoneal injections of saline (control) or ANIT and implantation of an osmotic minipump for continuous intravenous saline or HGF. Intraperitoneal saline or ANIT injections were subsequently administered every 3.5 days to create a chronic cholestatic model. After 14 days, the animals were euthanized, and liver biopsies were obtained. The liver biopsies were evaluated by histology, immunofluorescence staining for interleukin-6 and tumor necrosis factor alpha, and assessment of apoptosis by terminal dUTP-transferase-mediated nick end labeling (TUNEL) technique.
In this chronic liver injury model, HGF did not effect the grade of inflammation. However, HGF did induce retention of the ductal structures and avoided ductal proliferation, damage, and evidence of primary sclerosing cholangitis (P < .05). Hepatocyte growth factor induced less interleukin-6 (P < .011) and tumor necrosis factor alpha (P < .01) expression. Apoptotic activity was also significantly less in the HGF group (P < .01).
Hepatocyte growth factor preserved the hepatic ductal system, modulated the hepatic inflammatory response, and reduced the apoptotic index in this chronic cholestatic liver injury model. It may diminish or prevent liver damage in patients with total parenteral nutrition-induced liver injury.
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ABSTRACT: Abstract Total parenteral nutrition (TPN) represents a therapeutic modality that could save the life of a patient with inflammatory bowel disease (IBD) facing severe nutritional problems, by restoring the patient's impaired nutritional status. TPN does not compete with enteral nutrition (EN), the latter being the first choice for all patients having anatomically intact and functionally normal digestive tract. TPN allows bowel rest while supplying adequate calorific intake and essential nutrients, and removes antigenic mucosal stimuli. The value of TPN in malnourished patients with intestinal failure due to CD is beyond doubt. However, it is difficult to suggest TPN as a sole treatment for active CD. An increased rate of remission could not be expected by applying TPN. The utility of TPN is restricted to certain cases involving efforts to close enterocutaneous or other complicated fistulas in patients with fistulizing CD, the treatment of short bowel syndrome following extensive resections for CD, or when EN is impractical for other reasons. There are no advantages of TPN therapy over EN therapy regarding fistula healing. TPN has no influence on the surgical intervention rate and little benefit by bypassing the intestinal passage could be expected. Also TPN shows no advantage if the disease is chronically active. However, an optimal supply of nutrients improves bowel motility, intestinal permeability and nutritional status, and reduces inflammatory reactions. TPN might be associated with an increased risk of adverse events, although TPN undertaken by experienced teams does not cause more complications than does EN.Scandinavian Journal of Gastroenterology 01/2014; 49(1):3-14. DOI:10.3109/00365521.2013.860557 · 2.33 Impact Factor
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ABSTRACT: Hepatocyte growth factor (HGF) decreases intestinal inflammation and cytokine levels in an animal model of inflammatory bowel disease (IBD). Luminal omega-3 (OM-3) is anti-angiogenic, reduces inflammation, and may decrease symptoms in patients with Crohn's disease. This study evaluates the synergism of HGF and OM-3. Twenty adult female transgenic HLA-B27 rats were divided into 4 groups: group 1: regular feeds, IV saline; group 2: OM-3-enriched feeds, IV saline; group 3: regular feeds, IV HGF (150 µg/kg per day); and group 4: OM-3-enriched feeds, IV HGF(150 µg/kg per day). Rats were killed at 14 days after pump placement. Small and large bowel mucosa was harvested, and DNA and protein were extracted and quantified. Statistical analysis was done by analysis of variance with post-hoc Tukey's HSD test. Content of protein and DNA in the ileum were significantly increased by supplementation of HGF (P < .001, P < .01, respectively) alone. OM-3 significantly increased protein content but not DNA (P = .02, P = 0.3, respectively). Combined, they had a synergistic effect greater than either supplement alone (P = .0001, P = .002, respectively). In the colon, HGF and OM-3 did not significantly increase protein or DNA content individually or together. This is the first demonstration of the synergistic effect of a growth factor (HGF) and a dietary supplement (OM-3) in an immunologic model of IBD.Journal of Pediatric Surgery 01/2012; 47(1):194-8. DOI:10.1016/j.jpedsurg.2011.10.043 · 1.31 Impact Factor
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ABSTRACT: The etiology of parenteral nutrition—associated liver disease (PNALD) is complex and multifactorial. Recent evidence suggests that the composition of the intravenous lipid emulsion, which is typically administered as part of parenteral nutrition to provide dense calories and prevent essential fatty acid deficiency, can significantly contribute to PNALD. Since September 2004, Children’s Hospital Boston has been treating patients with PNALD by stopping the conventional soy oil—based emulsions and using one that is composed solely of fish oils. Despite favorable outcomes, concerns about the use of fish oil as monotherapy continue to be raised because of the perceived risks of increased bleeding and essential fatty acid deficiency. This review discusses the published evidence to date describing the efficacy of this novel therapy in the treatment of an often fatal complication of parenteral nutrition use.ICAN Infant Child & Adolescent Nutrition 08/2010; 2(4):251-257. DOI:10.1177/1941406410376239