A tungsten-supplemented diet delivered by transplacental and breast-feeding routes lowers intestinal xanthine oxidase activity and affords cytoprotection in ischemia-reperfusion injury to the small intestine

doi:10.1016/0022-3468(91)90839-L

Journal of Pediatric Surgery

Volume 26, Issue 8, August 1991, Pages 930-935

https://doi.org/10.1016/0022-3468(91)90839-L Get rights and content

Abstract

Ischemia-reperfusion injury has been implicated as playing a major role in the development of necrotizing enterocolitis, a major cause of morbidity and mortality in the newborn. A tungsten-supplemented molybdenum-free diet can reduce xanthine oxidase (XO) enzyme activity in the intestine, which in turn reduces the generation of oxygen radicals after an ischemia-reperfusion insult. This study evaluated the ability of this diet to be effective by indirect means, ie, transplacental and breast-feeding routes. XO activity of the intestine was measured in three groups of CD-1 white rats: I, weanlings fed the tungsten diet or standard chow for 1 week; II, 1-day-old rat pups whose mothers were maintained on the tungsten or standard chow for 7 to 10 days prior to term; and III, rat pups at 1 and 3 weeks after birth whose lactating mothers were maintained on the tungsten or standard chow. Some animals from group III also underwent either a 30- or 60-minute episode of occlusion of the superior mesenteric artery (SMA) to evaluate the protective effects of the diet. XO activity was significantly reduced in all groups receiving the tungsten diet (P < .0001). Blinded histopathologic studies of the entire small bowel showed significantly less villar necrosis (P < .05) and fibrosis (P < .0001) in the tungsten-treated group than in the controls. In the 60-minute occlusion study all tungsten-group animals survived, whereas 7 of 12 in the control group died of intestinal infarction within 24 hours (P < .001). These results indicate that XO activity can be lowered by a tungsten-supplemented molybdenum-free diet delivered by indirect routes. The ability to transfer the effect of the diet via the transplacental and breast-feeding routes has not been previously reported. The protective effect of the diet via breast-feeding further supports the role of ischemia-reperfusion injury as a major contributing factor to the development of necrotizing enterocolitis and loss of mucosal barrier function, and suggests areas of future research for possible prophylactic treatment of ischemia-reperfusion intestinal injuries.

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Background/Purpose: Hypothermia (HT) remains a significant stress to the newborn and has been implicated in the pathogenesis of necrotizing enterocolitis (NEC). The authors assessed the effect of transient HT (32°C) on regional organ blood flow in anesthetized piglets at age 7 to 10 days preterm (PREM), 1 to 2 days (NB), and 1 to 2 weeks (NEO).
Methods: Radiolabeled microspheres were used to determine organ blood flows (mL/min/g) at baseline, 15, and 60 minutes after HT and 60 minutes after rewarming to baseline core temperature.
Results: Heart rate and cardiac output decreased significantly in all groups. Cardiac flow decreased significantly in the NEO group, and central nervous system (CNS) flow decreased significantly in the NB and NEO groups. Both returned to baseline levels after rewarming. The PREM group experienced decreased cardiac, CNS, and intestinal blood flows but not to significant levels. NB and NEO intestinal blood flow showed significant decreases, which remained so after rewarming (a response not seen in hypoxia or hypovolemia). Cardiac output did not return to baseline levels in any group.
Conclusions: HT causes derangements in organ blood flows that differ from other deleterious stimuli such as hypoxia and hypovolemia. The prolonged intestinal ischemia supports HT as a factor in the development of NEC. This delay may offer opportunity to intervene in an attempt to lessen ischemiareperfusion injury.
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Research into the pathogenesis of neonatal necrotizing enterocolitis has been a diverse mixture of clinical case reviews, searches for a single cause, analysis of subjective observations and some designed experimental studies. The experimental research has been hampered by the lack of reproducible and clinically appropriate animal models in which to test hypotheses of pathogenic pathways. Reviewing the models which have been evaluated reveals many design inconsistencies and little in depth assessment of the appropriateness of many of these experimental systems. Many species have been studied as potential, clinically adequate models but often without relevant attention to the physiological differences and the effect of age. The piglet seems to present the most extrapolatable data from an appropriate model system for the study of neonatal necrotizing enterocolitis.
Hypoxia-induced necrotizing enterocolitis in the immature rat: The role of lipid peroxidation and management by vitamin E
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The authors developed an experimental model of necrotizing enterocolitis (NEC) by hypoxia-reoxygenation, and determined the content of malondialdehyde levels as an index of lipid peroxidation, related with a free-radical reaction in the gastrointestinal tract of newborn rats. They also investigated the role of vitamin E, an antioxidant, in this free-radical injury. The study was performed on 1-day-old rats. The 30 rat pups were divided into three groups. Hypoxia was induced by placing the pups in a 100% carbon dioxide chamber for 5 minutes. The pups were reoxygenated with 100% oxygen for 5 minutes. Group 1 (n = 10) was subjected to hypoxia-reoxygenation and killed 3 days after hypoxia. Group 2 (n = 10) was subjected to hypoxia-reoxygenation and treated with vitamin E (30 IU/kg/d intraperitoneally) for the next 3 days, and killed. Group 3 (n = 10) rats served as controls. The histopathology of the intestinal lesions in group 1 animals was characteristic of ischemic injury and ranged from superficial epithelial damage with villous shortening to transmural necrosis. In the vitamin E-treated animals these lesions were milder. The malondialdehyde levels of group 1 were significantly higher than those of the other two groups (P < .001). This study shows that oxidant-mediated lipid peroxidation injury plays a central role in mediating hypoxia-induced intestinal necrosis and suggests that vitamin E may play a therapeutic role in NEC.
Vanadate, molybdate and tungstate for orthomolecular medicine
1994, Medical Hypotheses
Recent studies indicate that oxyanions, such as vanadate (V) or vanadyl (IV), cause insulin-like effects on rats by stimulating the insulin receptor tyrosine kinase. Tungstate (VI) and molybdate (VI) show the same effects on rat adipocytes and hepatocytes. Results of uncontrolled trials on volunteers accumulated in Japan also suggest that tungstate effectively regulates diabetes mellitus without detectable side effects. Since these oxyanions naturally exist in organisms, oxyanion therapy, the oral administration of vanadate, vanadyl, molybdate, or tungstate, can be considered to be orthomolecular medicine. Therefore, these oxyanions may provide a viable alternative to chemotherapy. Many diseases in addition to diabetes mellitus might also be treated since the implication of these results is that tyrosine kinases are involved in a variety of diseases.
Allopurinol protects the bowel from necrosis caused by indomethacin and temporary intestinal ischemia in mice
1993, Journal of Pediatric Surgery
The present study was undertaken to evaluate if allopurinol administration protects mice from bowel necrosis caused by temporary intestinal ischemia followed by indomethacin (INDO). We have previously reported that ischemia (15-minute occlusion of superior mesenteric vessels) followed by intravenous (IV) INDO caused significant bowel necrosis in CD-1 mice. Ischemia or INDO alone did not cause necrosis. To investigate protective measures against necrosis, we used CD-1 mice, 25 to 30 g. Forty-four animals were gavage fed 1 mL of water for 7 days and 32 animals were gavage fed 10 mg/kg allopurinol for 7 days. On the seventh day all animals were anesthatized and the superior mesenteric vessels occluded for 15 to 20 minutes, followed by IV INDO (0.5 mg/kg) once daily for 3 days. Animals who died were examined for bowel necrosis and all animals were killed 7 days after surgery and necropsied. Of the 44 saline-fed animals, 12 developed bowel necrosis (27%). Of the 32 allopurinol-fed animals, 1 developed necrosis (3%). The result of Fisher's exact two-tailed test was P = .006. Pretreatment with oral allopurinol significantly protects the mice from developing bowel necrosis when the mesenteric vessels are temporarily occluded and INDO is administered. Allopurinol may prevent reperfusion injury by inhibiting formation of xanthine oxidase generated, oxygen-derived free radicals and may be valuable in pretreating premature infants with patent ductus arteriosus who have had an ischemic episode in whom INDO use is contemplated.
Inflammatory enzyme composition of the neonatal rat intestine: Implications for susceptibility to ischemia
1993, Journal of Pediatric Surgery
Recent evidence has suggested that the immaturity of the neonatal intestine may play a key role in the development of ischemic injury. However, relatively little data exist on the susceptibility of the neonatal intestine to ischemic injury at various ages especially in the fed versus fasted states. In this study, the levels of xanthine oxidase ([XO] an enzyme which is a known, major source of free radicals in postischemic tissue) and myeloperoxidase ([MPO] an index of tissue neutrophil infiltration) were measured in 1-, 5-, 10-, 15-, and 20-day-old Sprague-Dawley rats. Rats were divided into fed (n = 8/day) and fasted (n = 8/day) groups 4 hours prior to sacrifice. The entire small intestine was removed and divided into five segments: the duodenum, proximal jejunum, distal jejunum, proximal ileum, and distal ileum. The specimens were homogenized and assayed for XO and MPO levels. A significant increase in XO was observed in the fasted animals compared to the fed animals on all days. Peak levels in XO were observed in both groups from day 5 to 10. MPO levels were significantly higher in the fasted versus fed animals on day 1. MPO levels decreased as the animals aged. These data demonstrate dramatic differences in the levels of inflammatory enzymes of the newborn rat in the fed versus fasted states. Also, marked variations with age are seen in both XO and MPO. Whether the XO and MPO levels present at the time of ischemic insult affect severity of injury remains to be seen.

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Supported in part by a Southern Medical Association (Birmingham, AL) Research Fund Grant.

Presented at the 42nd Annual Meeting of the Surgical Section of the American Academy of Pediatrics, Boston, Massachusetts, October 6–7, 1990.

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A tungsten-supplemented diet delivered by transplacental and breast-feeding routes lowers intestinal xanthine oxidase activity and affords cytoprotection in ischemia-reperfusion injury to the small intestine☆

Abstract

J Pediatr Surg

Gastroenterology

Gastroenterology

J Biol Chem

J Surg Res

J Surg Res

Gastroenterology

Gastroenterology

Arch Biochem Biophys

Clin Perinatol

Curr Probl Pediatr

J Pediatr Surg

J Pediatr Surg

Surgery of necrotizing enterocolitis

World J Surg

Necrotizing enterocolitis