allopurinol and Enterocolitis--Pseudomembranous

Evidence is presented that supports a role of oxygen free radicals in the pathogenesis of various disorders of the digestive system. In the intestine, there is evidence that oxygen radicals play an important role in the endothelial and epithelial damage associated with certain models of ischemia. The mechanism for superoxide production in this condition differs from that described for other pathologic states (i.e., oxygen toxicity and neutrophil-mediated inflammation). This mechanism involves the reaction of xanthine oxidase, hypoxanthine, and molecular oxygen to produce a burst of oxygen radicals with reperfusion of the ischemic bowel. Evidence implicating oxygen radicals in inflammatory disorders of the digestive tract (i.e., pancreatitis), radiation injury, and hepatic cirrhosis is also presented. The available data suggest that oxygen radicals appear to be a fundamental mechanism of tissue injury in the pathogenesis of various disorders of the digestive system.

Topics: Allopurinol; Animals; Capillary Permeability; Cats; Digestive System Diseases; Dimethyl Sulfoxide; Enterocolitis, Pseudomembranous; Free Radicals; Humans; Inflammation; Intestinal Mucosa; Intestine, Small; Ischemia; Liver Diseases; Oxygen; Pancreatitis; Rats; Stomach Diseases; Superoxide Dismutase; Trypsin Inhibitors; Vascular Resistance; Xanthine Oxidase

Topics: Adult; Allopurinol; Azathioprine; Clostridioides difficile; Colitis, Ulcerative; Crohn Disease; Drug Interactions; Drug Therapy, Combination; Enterocolitis, Pseudomembranous; Female; Gout; Gout Suppressants; Histoplasmosis; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Psoas Abscess; Tumor Necrosis Factor-alpha

Gut ischemia has been implicated in the pathogenesis of necrotizing enterocolitis. Cyclosporine A (CSA), a potent immunosuppressant, attenuates immune/inflammatory cellular reactions. CSA also might be useful for inhibiting cellular immune responses involved in tissue ischemia/reperfusion injury. The authors hypothesized that CSA would attenuate inflammatory cellular changes associated with gut ischemic injury and that these effects could be quantified by computerized morphometry.. Twenty Sprague-Dawley rats underwent 60 minutes of gut ischemia by vascular occlusion of the superior mesenteric vessels. After 1 hour of reperfusion, the ischemic small bowel was harvested for histopathological examination and computerized morphometry, as well as xanthine oxidase (XO, U/mg protein) and maltase (MALT, mmol/L substrate degraded/min/mg protein) assays. CSA (5 mg/kg/d subcutaneously) was given to experimental animals (CSA, n = 10) for 5 days before ischemia, and vehicle was given to controls (CON, n = 10). The computer morphometric parameters studied were: surface index (SI, mucosal surface length per linear unit of intestine), average villous thickness (AVT), and average villous height (AVH).. Results are provided in Table 1.. The results of this study show that CSA may play a role in attenuating ischemia/reperfusion injury in the gut. Enzymatic analysis showed a beneficial role in the preservation of mucosal cell function after gut ischemia/reperfusion injury, as demonstrated by an elevated maltose level. Computerized morphometry demonstrated significant differences in all parameters in the experimental group, showing that CSA does confer gut mucosal protection during ischemia.

Topics: alpha-Glucosidases; Animals; Cyclosporine; Disease Models, Animal; Enterocolitis, Pseudomembranous; Image Interpretation, Computer-Assisted; Immunosuppressive Agents; Intestinal Mucosa; Intestine, Small; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Xanthine Oxidase

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 (i.v.) 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 anesthetized and the superior mesenteric vessels occluded for 15 to 20 minutes, followed by i.v. 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.

Topics: Allopurinol; Animals; Ductus Arteriosus, Patent; Enterocolitis, Pseudomembranous; Gastric Lavage; Indomethacin; Intestines; Mice; Premedication; Reperfusion Injury

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.

Topics: Animals; Animals, Newborn; Enterocolitis, Pseudomembranous; Fasting; Intestine, Small; Ischemia; Peroxidase; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

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 less than .0001). Blinded histopathologic studies of the entire small bowel showed significantly less villar necrosis (P less than .05) and fibrosis (P less than .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 less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Breast Feeding; Enterocolitis, Pseudomembranous; Female; Free Radicals; Intestine, Small; Placenta; Pregnancy; Rats; Reperfusion Injury; Tungsten; Xanthine Oxidase

In the feline intestine studies have implicated superoxide (O.-) and other oxygen derived free radicals as initiators of injury as measured by increased capillary permeability during the reperfusion period. Biochemical mechanisms of this free radical generation include: xanthine oxidase dependent O.- production, hydrogen peroxide (H2O2) formation by superoxide dismutase (SOD), hydroxyl radical (OH-) production via the Haber-Weiss reaction, and lipid radical formation from membrane peroxidation. Pathological consequences of these events include inflammatory neutrophil infiltration, damage to the collagen and mucosal basement membrane, increased capillary permeability, edema, cell degeneration and necrosis. Animal models of neonatal necrotizing enterocolitis (NNEC) indicate that intestinal injury occurs after the etiologic factors (hypothermia, hypoxia) are removed. In order to determine the role of active oxygen species in the pathogenesis of NNEC, weanling hamsters and neonatal piglets were cold stressed and activities of pro/antioxidant enzymes were determined, and histopathologic and ultrastructural studies were performed. Cold stressed weanling hamsters showed a 55.7% (P less than 0.05) decrease in xanthine dehydrogenase/xanthine oxidase activity ratio. Light microscopy revealed scattered colonic mucosal erosions and submucosal edema in 50% of cold stressed animals. Transmission electron microscopy demonstrated degeneration of colonic mucosal epithelial cells, enlarged intracellular spaces, cytoplasmic vacuolization, and nuclear membrane swelling. The colonic serosa was also edematous and infiltrated with bacteria. Large intestinal tissue from cold stressed neonatal piglets showed a significant increase (P less than 0.05) in Mn and Cu, Zn, SOD, CAT, GSH-Red, total GSH, and Glc6-PD at 0 and 12 hrs. post stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Cricetinae; Enterocolitis, Pseudomembranous; Free Radicals; Intestines; Oxygen; Reperfusion Injury; Xanthine Oxidase

The mechanism of tissue and cell injury in ischaemic bowel necrosis is unclear. The present study investigated the role of oxygen derived free radicals in the development of bowel necrosis using injections of platelet activating factor (PAF) into the mesenteric vasculature. Animals were pretreated with allopurinol or superoxide dismutase together with catalase, before administration of PAF. Superoxide dismutase/catalase markedly improved the PAF-induced lesions, indicating that most of the intestinal damage after PAF injection is because of the release of oxygen radicals. The major source of oxygen radicals is xanthine oxidase, as allopurinol ameliorated small bowel lesions. Pretreatment with allopurinol produced a significant (p less than 0.01) preventive effect on PAF induced hypotension. In contrast, superoxide dismutase/catalase did not alter PAF induced hypotension. Superoxide dismutase/catalase pretreatment improved PAF induced haemoconcentration and leucopenia, while allopurinol showed no effect.

Topics: Allopurinol; Animals; Catalase; Enterocolitis, Pseudomembranous; Free Radicals; Hypotension; Intestinal Mucosa; Intestines; Male; Mesenteric Arteries; Oxygen; Platelet Activating Factor; Rats; Rats, Inbred Strains; Superoxide Dismutase; Vasoconstriction

Oxygen-derived free radicals, particularly superoxide anion, are considered important mediators of intestinal injury induced by ischemia/reperfusion based on the protective effects of superoxide dismutase and allopurinol. A role for free radicals was investigated in a model of necrotizing enterocolitis (NEC) which was initiated by a luminal, as opposed to a vascular, insult. Intestinal loops of weanling rabbits received either saline (control loops) or a solution of 10 mg/ml casein and 50 mg/ml calcium gluconate acidified to pH 4 with proprionic acid (treated loops). When the animals were sacrificed 3 hours later, severe damage was noted in the treated loops, which included blunting of villi and edema, with all animals surviving. At 16 hours only 5 of 8 rabbits survived, and 3 had hemorrhagic necrosis. Control loops were normal in each case. Intravenous infusion of superoxide dismutase (4 mg/kg/hr), commencing 15 minutes after NEC induction, totally prevented intestinal injury. On the other hand, pretreatment with allopurinol, an inhibitor of xanthine oxidase, for 2 days (30 and 60 mg/kg by mouth) was not protective against intestinal damage. A cellular infiltration in treated loops was not histologically evident in the majority of animals at 3 hours after treatment, a finding confirmed by the minimal accumulation of 111In-labeled leukocytes in damaged and intact intestinal tissue. These results suggest that superoxide generated locally from sources other than xanthine oxidase play a critical and early role in experimental NEC and that superoxide dismutase may prove to be an effective therapy in this devastating neonatal disease.

Topics: Allopurinol; Animals; Animals, Newborn; Calcium Gluconate; Enterocolitis, Pseudomembranous; Free Radicals; Indium; Intestines; Oxygen; Rabbits; Superoxide Dismutase; Xanthine Oxidase

We report in detail the ontogeny and the response of antioxidant enzymes to glucocorticoids in the rat small intestine. Pregnant rats in the treatment group received four injections of dexamethasone starting on days 18, 19, or 20 of gestation; fetuses were killed 2 days later. Control rats were injected with 0.9% saline solution. Postnatal rats reaching 14, 19, and 104 days of age received four injections of hydrocortisone and were killed 2 days later. Age-matched controls were injected with 0.9% saline solution. The activities of xanthine oxidase, superoxide dismutase, and catalase were measured in small intestines from fetal (20 and 21 days gestation), newborn, and older (aged 16, 21, and 106 days) rats. Xanthine oxidase rose with maturation; the major increase occurred on postnatal day 21. Catalase and superoxide dismutase rose minimally during intrauterine life. On day 16 postpartum, catalase and superoxide dismutase values were 160% and 60%, respectively, higher than at birth. Glucocorticoid administration stimulated maltase and sucrase activities, but had no effect on the antioxidant enzymes or xanthine oxidase.

Topics: Animals; Catalase; Dexamethasone; Enterocolitis, Pseudomembranous; Female; Hydrocortisone; Intestine, Small; Pregnancy; Pregnancy, Animal; Rats; Rats, Inbred Strains; Risk; Superoxide Dismutase; Xanthine Oxidase