Abstract:PURPOSE: To describe the difficulties of implementing the protocol of experimental necrotizing enterocolitis (NEC) in order to obtain a larger number of newborns affected with the disease and a lower mortality. METHODS: Term Sprague-Dawley newborns rats (22 days) were divided into four groups of 12 fetuses each (n = 48): EC - breastfed newborns; IH - breastfed newborns and subjected to a stress protocol by ischemia and hypothermia; ESB - formula-fed newborns (Esbilac®, PetAg, Hampshire, IL, USA) and NEC - form… Show more
“…Perhaps the time of drug administration was inefficient to observe significant improvement of intestinal lesions, although Cintra et al 10 also took a 12-h break between l-arginine administrations made for 3 days, or the NEC induction model was so efficient as to cause a very serious intestinal lesion that could not be prevented by a dose previously tested in other studies. The difference between our study and the experimental model by Jilling et al and further adapted by Gonçalves et al 16,17 it concerns the time of exposure to 100% nitrogen and the administration of the enteral diet. In our study, rats were kept under 100% nitrogen for 70 seconds and fed with 0.1 mL of Esbilac ® every 4h, and the experimental model by Jilling et al and further adapted by Gonçalves et al 16,17 left the rats under 60 seconds in an atmosphere of 100% nitrogen and fed with 0.1 mL of Esbilac ® every 3 h.…”
Section: Discussionmentioning
confidence: 79%
“…In our study, 0.1 mL of 10% l-arginine solution was used intraperitoneally, as in the study from Cintra et al 10 However, Cintra et al 10 described a protective effect as they show a lower degree of hystologic lesions in the intestine of rats that received l-arginine, contrary to the results found in our study. Our study method differed from the one from Cintra et al 10 , we did not promote reoxygenation (100% O2) and heating (22 °C) after episodes of hypoxia and hypothermia 16,17 . Maybe reoxygenation and rewarming potentiate the protective action of l-arginine in intestinal lesions of NEC.…”
Necrotizing enterocolitis (NEC) has a 45% mortality in neonatal intensive care units. This paper aimed to evaluate the isolated and combined effects of sildenafil and l-arginine in the prevention of necrotizing enterocolitis. Neonatal rats were fed formula milk and submitted to hypoxia under a 100% N2 atmosphere for 70 s. Then, animals were subjected to hypothermia (4 °C for 10 min), twice a day for 3 days. Forty neonatal rats were divided into five groups: negative control—not submitted to the protocol (n = 5), sildenafil group—NEC protocol (n = 9), l-arginine group—NEC protocol (n = 9), l-arginine and sildenafil group—NEC protocol (n = 9) and positive control—NEC protocol and intraperitoneal saline solution (n = 8). Jejunum and terminal ileus were removed for histopathologic and immunohistochemical Ki-67 analysis. Kruskal–Wallis test was used to analyze mortality, survival, body weight, intestinal injury score and Ki-67 proliferation index. All animals submitted to the protocol developed enterocolitis. Mortality rate was higher in group that received only l-arginine (p = 0.0293). The Ki-67 analysis showed a higher proliferative index in groups that received interventional drugs (p = 0.017). In conclusion, sildenafil and l-arginine were not effective to reduce intestinal injury.
“…Perhaps the time of drug administration was inefficient to observe significant improvement of intestinal lesions, although Cintra et al 10 also took a 12-h break between l-arginine administrations made for 3 days, or the NEC induction model was so efficient as to cause a very serious intestinal lesion that could not be prevented by a dose previously tested in other studies. The difference between our study and the experimental model by Jilling et al and further adapted by Gonçalves et al 16,17 it concerns the time of exposure to 100% nitrogen and the administration of the enteral diet. In our study, rats were kept under 100% nitrogen for 70 seconds and fed with 0.1 mL of Esbilac ® every 4h, and the experimental model by Jilling et al and further adapted by Gonçalves et al 16,17 left the rats under 60 seconds in an atmosphere of 100% nitrogen and fed with 0.1 mL of Esbilac ® every 3 h.…”
Section: Discussionmentioning
confidence: 79%
“…In our study, 0.1 mL of 10% l-arginine solution was used intraperitoneally, as in the study from Cintra et al 10 However, Cintra et al 10 described a protective effect as they show a lower degree of hystologic lesions in the intestine of rats that received l-arginine, contrary to the results found in our study. Our study method differed from the one from Cintra et al 10 , we did not promote reoxygenation (100% O2) and heating (22 °C) after episodes of hypoxia and hypothermia 16,17 . Maybe reoxygenation and rewarming potentiate the protective action of l-arginine in intestinal lesions of NEC.…”
Necrotizing enterocolitis (NEC) has a 45% mortality in neonatal intensive care units. This paper aimed to evaluate the isolated and combined effects of sildenafil and l-arginine in the prevention of necrotizing enterocolitis. Neonatal rats were fed formula milk and submitted to hypoxia under a 100% N2 atmosphere for 70 s. Then, animals were subjected to hypothermia (4 °C for 10 min), twice a day for 3 days. Forty neonatal rats were divided into five groups: negative control—not submitted to the protocol (n = 5), sildenafil group—NEC protocol (n = 9), l-arginine group—NEC protocol (n = 9), l-arginine and sildenafil group—NEC protocol (n = 9) and positive control—NEC protocol and intraperitoneal saline solution (n = 8). Jejunum and terminal ileus were removed for histopathologic and immunohistochemical Ki-67 analysis. Kruskal–Wallis test was used to analyze mortality, survival, body weight, intestinal injury score and Ki-67 proliferation index. All animals submitted to the protocol developed enterocolitis. Mortality rate was higher in group that received only l-arginine (p = 0.0293). The Ki-67 analysis showed a higher proliferative index in groups that received interventional drugs (p = 0.017). In conclusion, sildenafil and l-arginine were not effective to reduce intestinal injury.
“…Beginning within 6 h of birth, neonatal rat NEC models utilize formula feeding, LPS administration, and hypoxic stress to induce NEC (33). Previous investigations have established that intestinal damage is initiated within 24 h of NEC induction, while overall mortality limits the study window to 96 h (31)(32)(33)41). To increase intestinal insult before our treatment time point, the NEC rat pup model used in the present study included three doses of LPS within the first 30 h of NEC induction (Fig.…”
Necrotizing enterocolitis (NEC), a life-threatening intestinal disease, is becoming a larger proportionate cause of morbidity and mortality in premature infants. To date, therapeutic options remain elusive. Based on recent cell therapy studies, we investigated the effect of a human placental-derived stem cell (hPSC) therapy on intestinal damage in an experimental NEC rat pup model. NEC was induced in newborn Sprague-Dawley rat pups for 4 days via formula feeding, hypoxia, and LPS. NEC pups received intraperitoneal (IP) injections of either saline or hPSC (NEC-hPSC) at 32 and 56 hours into NEC induction. At 4 days, intestinal macroscopic and histological damage, epithelial cell composition, and inflammatory marker expression of the ileum was assessed. Breastfed (BF) littermates were used as controls. NEC pups developed significant bowel dilation and fragility in the ileum. Further, NEC induced loss of normal villi-crypt morphology, disruption of epithelial proliferation and apoptosis, and loss of critical progenitor/stem cell and Paneth cell populations in the crypt. hPSC treatment improved macroscopic intestinal health with reduced ileal dilation and fragility. Histologically, hPSC administration had a significant reparative effect on the villi-crypt morphology and epithelium. In addition to a trend of decreased inflammatory marker expression, hPSC-NEC pups had increased epithelial proliferation and decreased apoptosis when compared to NEC littermates. Further, the intestinal stem cell and crypt niche that includes Paneth cells, SOX9+ cells, and LGR5+ stem cells was restored with hPSC therapy. Together, these data demonstrate hPSC can promote epithelial healing of NEC intestinal damage.
“…The IW/BW ratio was higher in the NEC group than in the C group. This finding could be explained by the nutritional or inflammatory intestinal processes occurring as a result of NEC 10 .…”
Section: Discussionmentioning
confidence: 95%
“…Experimental NEC was induced according to the protocol described by Jilling et al and adapted by Gonçalves et al 9 , 10 . Newborn rats were fed 0.1 mL of Esbilac® artificial milk (PetAg, Hampshire, IL, USA) every 3 hours beginning at 6:00 am for 24 hours using an adapted, peripherally inserted central catheter (PICC, 1.9 Fr 26 gauge, 1 lumen, BD®, Sandy, UT, USA).…”
OBJECTIVES:Necrotizing enterocolitis is a severe multifactorial intestinal disorder that primarily affects preterm newborns, causing 20-40% mortality and morbidity. Intestinal fatty acid-binding protein has been reported to be a biomarker for the detection of intestinal injuries. Our aim was to assess intestinal tissue injury and the molecular expression of intestinal fatty acid-binding protein over time in a necrotizing enterocolitis model.METHODS:A total of 144 Newborn rats were divided into two groups: 1) Control, which received breastfeeding (n=72) and 2) Necrotizing Enterocolitis, which received formula feeding and underwent hypoxia and hypothermia (n=72). A total of six time points of ischemia (2 times a day for 3 days; 12 pups for each time point) were examined. Samples were collected for analysis of body weight, morphological and histological characteristics, intestinal weight, intestinal weight/body weight ratio, injury grade, and intestinal fatty acid-binding protein levels.RESULTS:Body and intestinal weights were lower in the Necrotizing Enterocolitis group than in the Control group (p<0.005 and p<0.0005, respectively). The intestinal weight/body weight ratio was higher in the Necrotizing Enterocolitis group than in the Control group (p<0.005) only at the sixth ischemia time point. The Necrotizing Enterocolitis group displayed higher expression of intestinal fatty acid-binding protein (p<0.0005) and showed greater tissue damage than the Control group.CONCLUSION:Intestinal fatty acid-binding protein was an efficient marker of ischemic injury to the intestine and a good correlation was demonstrated between the time of ischemic injury and the grade of intestinal injury.
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