Article

Poly(ADP-Ribose) Polymerase-1: A Novel Therapeutic Target in Necrotizing Enterocolitis

Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
Pediatric Research (Impact Factor: 2.84). 03/2011; 70(1):67-71. DOI: 10.1203/PDR.0b013e31821928ff
Source: PubMed

ABSTRACT Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of infancy, afflicting 11% of infants born 22-28 wk GA. Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production, protein oxidation, and DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide (NAD+) as a substrate. However, in the presence of severe oxidative stress and DNA damage, PARP-1 overactivation may ensue, depleting cells of NAD+ and ATP, killing them by metabolic catastrophe. Here, we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked PARP-1 expression and that administration of a PARP-1 inhibitor (nicotinamide) attenuates intestinal injury in a newborn rat model of NEC. In this model, 56% of control pups developed NEC (any stage) versus 14% of pups receiving nicotinamide. Forty-four percent of control pups developed high-grade NEC (grades 3-4), whereas only 7% of pups receiving nicotinamide developed high-grade NEC. Nicotinamide treatment protects pups against intestinal injury incurred in the newborn rat NEC model. We speculate that PARP-1 overactivation in NEC may drive mucosal cell death in this disease and that PARP-1 may be a novel therapeutic target in NEC.

0 Followers
 · 
143 Views
 · 
0 Downloads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intestinal epithelial restitution is the first part in the process of mucosal repair after injury in the intestine. Integrity of the intestinal mucosal barrier is important as a first line of defense against bacteria and endotoxin. Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in extremely-low-birth-weight infants, but its mechanisms are not well defined. Abnormal bacterial colonization, immature barrier function, innate immunity activation, and inflammation likely play a role. Lipopolysaccharide (LPS)-binding protein (LBP) is secreted by enterocytes in response to inflammatory stimuli and has concentration-dependent effects. At basal concentrations, LBP stimulates the inflammatory response by presenting LPS to its receptor; however, at high concentrations, LBP is able to neutralize LPS and prevent an exaggerated inflammatory response. We sought to determine how LBP would affect wound healing in an in vitro model of intestinal cell restitution and protect against intestinal injury in a rodent model of NEC. Immature intestinal epithelial cells (IEC-6) were seeded in poly-L-lysine-coated 8-chamber slides and grown to confluence. A 500-μm wound was created using a cell scraper mounted on the microscope to achieve uniform wounding. Media was replaced with media containing LPS ± LBP. Slide wells were imaged after 0, 8, and 24 hours and then fixed. Cellular restitution was evaluated via digital images captured on an inverted microscope and wound closure was determined by automated analysis. Toll-like receptor 4 (TLR4) was determined by reverse transcriptase-polymerase chain reaction after RNA isolation from wounded cells 24 hours after treatment. LPS alone attenuated wound healing in immature intestinal epithelium. This attenuation is reversed by 24 hours with increasing concentrations of LBP so that wound healing is equivalent to control (P < 0.001). TLR4 was increased with LPS alone but levels returned to that of control after addition of LBP in the higher concentrations. LBP had no effect on the development of intestinal injury when given during our rodent model of NEC. Abnormal bacterial colonization and activation of innate immunity by LPS are likely involved in the pathogenesis of NEC.The attenuation of wound healing was reversed when LBP was added to LPS but only in the higher concentrations. At these same concentrations of LBP, TLR4 was decreased to that of control. These results indicate that LBP may be a novel therapeutic strategy to facilitate wound healing after the acute phase of NEC and other forms of intestinal injury.
    Journal of pediatric gastroenterology and nutrition 10/2011; 54(5):639-44. DOI:10.1097/MPG.0b013e31823a895a · 2.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Necrotizing enterocolitis is the leading cause of morbidity and mortality from gastrointestinal disease in premature infants, and is characterized by initial feeding intolerance and abdominal distention followed by the rapid progression to coagulation necrosis of the intestine and death in many cases. While the risk factors for NEC development remain well accepted - namely premature birth and formula feeding- the underlying mechanisms remain incompletely understood. Current thinking indicates that NEC develops in response to an abnormal interaction between the mucosal immune system of the premature host and an abnormal indigenous microflora, leading to an exaggerated mucosal inflammatory response and impaired mesenteric perfusion. In seeking to understand the molecular and cellular events leading to NEC, various animal models have been developed. However, the large number and variability between the available animal models and the unique characteristics of each has raised important questions regarding the validity of particular models for NEC research. In an attempt to provide some guidance to the growing community of NEC researchers, we now seek to review the key features of the major NEC models that have been developed in mammalian and non mammalian species, and to assess the advantages, disadvantage, challenges and major scientific discoveries yielded by each. A strategy for model validation is proposed, the principal models are compared, and future directions and challenges within the field of NEC research are explored.
    AJP Gastrointestinal and Liver Physiology 04/2014; 306(11). DOI:10.1152/ajpgi.00422.2013 · 3.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The anti-inflammatory activity of 3-aminobenzamide (3-AB) has been shown via histopathology and immunohistochemistry in various colitis models. We aimed to study the effects of 3-AB on tissue mechanical endurance and, associatively, preventing perforation in colitis. Thirty male Wistar albino rats were randomly divided into three groups. Rectal saline was administered to Group 1 (sham + saline). Rectal trinitrobenzensulphonic acid was applied to induce colitis in Group 2 (colitis + saline) and Group 3 (colitis + 3-AB). Groups 1 and 2 were treated intraperitoneally with saline (1 ml every 12 hours) and Group 3 was treated with 3-AB (10 mg/kg every 12 hours). After seven days, rats were sacrificed and colon lipid peroxidation levels, the serum tumor necrosis factor alpha (TNF-α) level, bowel bursting pressures, and bowel wall tensions were measured. Bowel bursting pressure in Group 2 was significantly lower than in Groups 1 and 3 (p<0.001 for both groups). Bowel wall tension in Group 2 was significantly lower than in Groups 1 and 3 (p<0.001 for both groups). There were no significant differences between groups for serum TNF-α levels. For lipid peroxidation, malondialdehyde (MDA) levels were increased in Groups 2 and 3 compared to Group 1. 3-AB may aid prevention of perforations that develop in inflammatory bowel disease, requiring surgical treatment.
    The Turkish journal of gastroenterology: the official journal of Turkish Society of Gastroenterology 12/2014; 25(Suppl 1):S86-S91. DOI:10.5152/tjg.2014.4288 · 0.47 Impact Factor

Preview (2 Sources)

Download
0 Downloads
Available from