Necrotizing enterocolitis (NEC) is an intestinal inflammatory and necrotic disease seen in premature infants, and remains the leading cause of death resulted from gastrointestinal diseases in premature infants. The specific pathogenesis of NEC is still unclear. In recent years, a lot of studies have reported that Toll-like receptor 4 (TLR4) plays a key role in the pathogenesis of NEC. TLR4, which is abundantly expressed in intestinal epithelial cells of premature infants, binds to bacterial lipopolysaccharide (LPS) to activate downstream signaling pathways, leading to disruption of intestinal epithelial integrity and bacterial translocation, resulting in intestinal ischemic necrosis and inflammatory responses, which may rapidly progress to severe sepsis, multiple organ dysfunction, and death. This paper reviews the mechanism of TLR4-related signaling pathways in intestinal epithelial injury and inflammatory responses in newborns with NEC, providing a reference to study new therapeutic targets for NEC.
Enterocolitis, Necrotizing/pathology* ; Toll-Like Receptor 4/metabolism* ; Humans ; Infant, Newborn ; Signal Transduction ; Inflammation/metabolism* ; Animals ; Intestines/immunology* ; Intestinal Mucosa/pathology* ; Infant, Premature

OBJECTIVETo improve the understanding of recognizing and diagnosis of neonatal necrotizing enterocolitis (NEC), imaging assessment of neonates with NEC was analyzed retrospectively.

METHODData of 211 cases of NEC were retrospectively collected from the Department of Neonatology, Children's Hospital of Chongqing Medical University between Jan.1(st) 2006-Dec.31(st) 2011.

RESULTAnalysis of abdominal X-ray of 211 cases showed that there were 40 cases (19.0%) who had no changes on each X-ray, 47 cases (22.3%) had improvement and 23 cases (10.9%) became worse. In the group of no changes, positive rate with good prognosis was 97.5% and with poor prognosis, it was 2.5%. In the group of improvement, positive rate with good prognosis was 97.9%, and the contrary was 2.1%. Positive rate with good prognosis was 56.5%, and the contrary was 43.5% in worse group. Chi-square analysis of the three groups showed χ(2) = 31.742, P < 0.01. Comparison of detection rate of pneumoperitoneum on abdominal X-ray (16.0%, 12/75) and Doppler US (1.3%, 1/75), χ(2) = 10.191, P < 0.05, portal pneumatosis on abdominal X-ray(1.3%, 1/75) versus Doppler US (12.0%,9/75), χ(2) = 6.857, P < 0.05. Surgical timing mostly corresponded to pneumoperitoneum (OR = 19.543) and intestinal obstruction (OR = 19.527) of abdominal X-ray. The logistic regression equation is y = -2.915-1.588x1+2.972x4+2.973x7 + 1.711x9 (χ(2) = 101.705, P < 0.01).

CONCLUSIONAbdominal X-ray is the most important method of diagnosis of NEC, the group of deterioration of abdominal X-ray has obvious bad prognosis differ from no change group and better group. Comparison with abdominal X-ray and Doppler US, the former in pneumoperitoneum positive rate was higher than the latter, at the same time, portal pneumatosis on Doppler US is more sensitive to abdominal X-ray, the value of two imaging assessments both supplement each other. Surgical timing mostly corresponds to pneumoperitoneum and intestinal obstruction.

Abdomen ; diagnostic imaging ; surgery ; Birth Weight ; Enterocolitis, Necrotizing ; diagnosis ; pathology ; surgery ; Female ; Humans ; Infant, Newborn ; Infant, Newborn, Diseases ; diagnosis ; pathology ; surgery ; Infant, Premature ; Intestinal Perforation ; diagnostic imaging ; surgery ; Logistic Models ; Male ; Pneumoperitoneum ; diagnosis ; diagnostic imaging ; Portal Vein ; diagnostic imaging ; pathology ; Predictive Value of Tests ; Prognosis ; Radiography, Abdominal ; Retrospective Studies ; Severity of Illness Index ; Ultrasonography, Doppler, Color

OBJECTIVEBased on the observation that coagulation necrosis occurs in the majority of neonatal necrotizing enterocolitis (NEC) patients, it is clear that intestinal ischemia is a contributing factor to the pathogenesis of NEC. However, the published studies regarding the role of intestinal ischemia in NEC are controversial. The aim of this paper is to review the current studies regarding intestinal microcirculatory dysfunction and NEC, and try to elucidate the exact role of intestinal microcirculatory dysfunction in NEC.

DATA SOURCESThe studies cited in this review were mainly obtained from articles listed in Medline and PubMed. The search terms used were "intestinal microcirculatory dysfunction" and "neonatal necrotizing enterocolitis".

STUDY SELECTIONMainly original milestone articles and critical reviews written by major pioneer investigators in the field were selected.

RESULTSImmature regulatory control of mesentery circulation makes the neonatal intestinal microvasculature vulnerable. When neonates are subjected to stress, endothelial cell dysfunction occurs and results in vasoconstriction of arterioles, inflammatory cell infiltration and activation in venules, and endothelial barrier disruption in capillaries. The compromised vasculature increases circulation resistance and therefore decreases intestinal perfusion, and may eventually progress to intestinal necrosis.

CONCLUSIONIntestinal ischemia plays an important role through the whole course of NEC. New therapeutic agents targeting intestinal ischemia, like HB-EGF, are promising therapeutic agents for the treatment of NEC.

Endothelin-1 ; physiology ; Endothelium, Vascular ; physiopathology ; Enterocolitis, Necrotizing ; drug therapy ; etiology ; pathology ; Heparin-binding EGF-like Growth Factor ; Humans ; Infant, Newborn ; Intercellular Signaling Peptides and Proteins ; therapeutic use ; Intestines ; blood supply ; Ischemia ; complications ; Microcirculation ; physiology ; Nitric Oxide ; physiology ; Splanchnic Circulation

OBJECTIVETo establish an appropriate neonatal rat model of necrotizing enterocolitis (NEC) and to investigate the protective effects of glycomacropeptide (GMP) on the gut from injury in neonatal rats with NEC.

METHODA total of 36 neonatal SD rats were randomly divided into 3 groups: NEC model group (Group M), NEC + GMP group (Group G) and normal control group (Group N), each group had 12 rats. All the neonatal rats were fed with breast milk in the first 3 days after birth. During the second 3 days after birth, the rats of Group N were still maternal breast-fed, but the rats of Group M and Group G were separated from their mothers and lived in incubator and began to be formula fed, and were subjected to cold exposure shortly after hypoxic-reoxygenation treatment. After being fed in such means for 6 days, all the neonatal rats were placed into the incubator and fasted for 24 hours. Then all the rats were sacrificed by cervical dislocation. Intestinal tissue located at the boundary of ileum and cecum was obtained for: (1) histological examination after HE staining, (2) TUNEL detection, (3) electron microscopic observation; and the tissue homogenate was obtained for checking TNF-α and IL-1β levels by ELISA and platelet activating factor (PAF) mRNA expression by quantitative fluorescence (QF)-PCR.

RESULT(1) The pathological scores of the 3 groups were 2.17 ± 0.83 (Group M), 0.92 ± 0.79 (Group G) and 0.17 ± 0.39 (Group N) separately. There was significant difference between Group M and Group G (H = 8.819, P = 0.003). (2) TNF-α levels of 3 groups were (41.94 ± 13.51) pg/ml (Group M), (31.69 ± 11.68) pg/ml (Group G) and (17.42 ± 7.18) pg/ml (Group N) separately, and TNF-α level in Group G was significantly lower than that of Group M (F = 3.959, P = 0.030). (3) IL-1β levels of 3 groups were (150.33 ± 36.41) pg/ml (Group M), (118.36 ± 33.00) pg/ml (Group G) and (28.44 ± 15.04) pg/ml (Group N) separately, and IL-1β level in Group G was lower than that of Group M (F = 5.080, P = 0.013). (4) Expression levels of intestinal PAF mRNA (2(-ΔΔCt) value): 3.01 ± 0.96 (Group M), 1.56 ± 0.29 (Group G), 1.01 ± 0.13 (Group N), the level of Group G was significantly lower than that of Group M (F = 25.251, P = 0.000). (5)Electron microscopy: Group N showed that its cell volume was mostly occupied by the nucleus, the structure was clear, nuclear membrane existed, suggesting the normal phase of cell; Group M showed that apoptotic body existed, suggesting that the advanced stage phase of apoptosis; Group G showed that condensed chromatin marginated around the nuclear envelope, nuclear pores expanded, suggesting the early phase of apoptosis. (6) The apoptosis rate of intestinal epithelial cells by TUNEL detection: 38.79 ± 9.79 (Group M), 29.54 ± 7.30 (Group G), 6.37 ± 1.96 (Group N); the apoptosis rate of intestinal epithelial cells of Group G was significantly lower than that of Group M (F = 6.888, P = 0.003).

CONCLUSIONGMP has protective effects on guts of neonatal rats with NEC, which may probably work by reducing TNF-α, IL-1β and PAF expression, inhibiting the apoptosis of intestinal epithelial cells and reducing intestinal tissue injury.

Animals ; Animals, Newborn ; Apoptosis ; Caseins ; pharmacology ; Cold Temperature ; Enterocolitis, Necrotizing ; drug therapy ; metabolism ; pathology ; Epithelial Cells ; drug effects ; metabolism ; pathology ; Female ; Hypoxia ; complications ; Interleukin-1beta ; metabolism ; Intestinal Mucosa ; metabolism ; pathology ; Intestines ; metabolism ; pathology ; Male ; Peptide Fragments ; pharmacology ; Platelet Activating Factor ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVETo study the expression of Toll-like receptor 4 (TLR-4) and caspase-3 in the intestine of neonatal rats with necrotizing enterocolitis (NEC), and explore the protective effects and possible regulatory mechanisms of glutamine (Gln) in NEC.

METHODSSixty premature rats were randomly divided into three groups (n=20 each): control, NEC model and Gln intervention group. NEC model was prepared by formula feeding, hypoxia and cold stress. The Gln intervention group was also subjected to hypoxia and cold stress but was fed with formula containing Gln (0.3 g/kg). Two days later, the rats were sacrificed and the intestine tissues were obtained. The histological changes of ileal tissues were observed by hemetoxylin and eosin staining. The expression of caspase-3 and TLR-4 protein in the jejunum, ileum and colon were detected by inmunohistochemistry. The expression of TLR-4 mRNA in the jejunum, ileum and colon were detected by RT-PCR.

RESULTSCompared with the control group, the histological score of ileal tissues, and the expression of caspase-3, TLR-4 protein and TLR-4 mRNA in the NEC model group increased significantly (P<0.01). Gln intervention decreased significantly the histological score of ileal tissues, and the expression of caspase-3, TLR-4 protein and TLR-4 mRNA compared with the NEC model group (P<0.05).

CONCLUSIONSTLR-4 might be involved in the pathogenesis of NEC. Gln may provide protective effects on intestine possibly through reducing the TLR-4 expression and then decreasing the apoptosis of intestinal epithelial cells.

Animals ; Animals, Newborn ; Caspase 3 ; analysis ; Enterocolitis, Necrotizing ; metabolism ; pathology ; Female ; Glutamine ; pharmacology ; Immunohistochemistry ; Pregnancy ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Toll-Like Receptor 4 ; analysis ; genetics

Enterocolitis, Necrotizing ; metabolism ; pathology ; Female ; Humans ; Immunohistochemistry ; Infant, Newborn ; Intestinal Mucosa ; metabolism ; pathology ; Male ; Platelet Activating Factor ; metabolism

OBJECTIVEThis study examined the effects of curcumin on intestinal histopathological changes, cyclooxygenase-2 (COX-2) expression, and tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) concentrations in neonatal rats with necrotizing enterocolitis (NEC), in order to investigate the effects of curcumin against NEC.

METHODSForty neonatal rats were randomly divided into four groups (n=10 each): normal control, solvent control, NEC model, and curcumin intervention. The general situations of rats were observed for 3 consecutive days, and the rats were then sacrificed on the 4th day. Intestinal tissues were obtained for examining the histopathological changes, COX-2 expression, and TNF-alpha and IL-10 concentrations.

RESULTSCurcumin treatment ameliorated the general situations and histopathological signs in rats with NEC. TNF-alpha and IL-10 concentrations in the NEC model and the curcumin intervention groups increased significantly compared with those in the normal and solvent control groups (p<0.05). The concentration of TNF-alpha decreased (p<0.05), while the concentration of IL-10 increased significantly in the curcumin intervention group in comparison with the NEC model group (p<0.05). Immunohistochemistry results indicated that the positive expression of COX-2 in the curcumin intervention group was significantly lower than that in the NEC model group.

CONCLUSIONSCurcumin has protective effects against NEC in neonatal rats, possibly through inhibiting COX-2 expression, reducing TNF-alpha content, and increasing IL-10 content.

Animals ; Animals, Newborn ; Body Weight ; Curcumin ; therapeutic use ; Cyclooxygenase 2 ; analysis ; physiology ; Disease Models, Animal ; Enterocolitis, Necrotizing ; drug therapy ; pathology ; Female ; Interleukin-10 ; analysis ; Intestines ; pathology ; Male ; NF-kappa B ; physiology ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; analysis

PURPOSE: Although early treatment of neonatal necrotizing enterocolitis (NEC) is very important, there exists no definite way of diagnosing NEC at an early stage. Previous reports argue that gases in portal veins and liver parenchyme are detected by liver ultrasonography (USG) even when no symptoms corresponding to NEC are provoked. This study demonstrates the importance of liver USG for early diagnosis of NEC. METHODS: Abdominal USG was performed on 1381 newborn infants who were admitted to the neonatal intensive care unit of Soonchunhyang University Cheonan Hospital between February 2003 and September 2005. Twelve infants were diagnosed with NEC by liver USG and their individual pathologies were compared. RESULTS: All of the patients described here were full-term and the most frequent symptom observed was watery diarrhea; four had no symptoms at all. Severe metabolic acidosis was seen in two patients, a rise of C-reactive protein (CRP) in five patients and rotavirus antigen positivity in five patients. One of the patients showed portal vein gas, pneumatosis intestinalis and ileus in a simple abdominal radiography and another patient showed ileus only. However, all of the other 10 patients presented with no abnormal symptoms, according to simple abdominal radiography. CONCLUSION: NEC should be considered in neonates with gases present in portal veins, intestinal walls and liver parenchyme, as detected by liver USG even when no symptoms corresponding to NEC are provoked.
Acidosis ; C-Reactive Protein ; Chungcheongnam-do ; Diarrhea ; Early Diagnosis ; Enterocolitis, Necrotizing* ; Gases* ; Humans ; Ileus ; Infant ; Infant, Newborn* ; Intensive Care, Neonatal ; Liver* ; Pathology ; Portal Vein* ; Radiography, Abdominal ; Rotavirus ; Ultrasonography*