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Paneth cell ablation in the presence of Klebsiella pneumoniae induces necrotizing enterocolitis (NEC)-like injury in the small intestine of immature mice.
Zhang C, Sherman MP, Prince LS, Bader D, Weitkamp JH, Slaughter JC, McElroy SJ
(2012) Dis Model Mech 5: 522-32
MeSH Terms: Aging, Animals, Cell Differentiation, Cytoplasmic Granules, Disease Models, Animal, Dithizone, Enteral Nutrition, Enterocolitis, Necrotizing, Humans, Infant, Newborn, Inflammation, Intestine, Small, Klebsiella pneumoniae, Mice, Paneth Cells, Zinc
Show Abstract · Added February 27, 2014
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. During NEC pathogenesis, bacteria are able to penetrate innate immune defenses and invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Normally, Paneth cells appear in the intestinal crypts during the first trimester of human pregnancy. Paneth cells constitute a major component of the innate immune system by producing multiple antimicrobial peptides and proinflammatory mediators. To better understand the possible role of Paneth cell disruption in NEC, we quantified the number of Paneth cells present in infants with NEC and found that they were significantly decreased compared with age-matched controls. We were able to model this loss in the intestine of postnatal day (P)14-P16 (immature) mice by treating them with the zinc chelator dithizone. Intestines from dithizone-treated animals retained approximately half the number of Paneth cells compared with controls. Furthermore, by combining dithizone treatment with exposure to Klebsiella pneumoniae, we were able to induce intestinal injury and inflammatory induction that resembles human NEC. Additionally, this novel Paneth cell ablation model produces NEC-like pathology that is consistent with other currently used animal models, but this technique is simpler to use, can be used in older animals that have been dam fed, and represents a novel line of investigation to study NEC pathogenesis and treatment.
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16 MeSH Terms
Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios.
Weitkamp JH, Koyama T, Rock MT, Correa H, Goettel JA, Matta P, Oswald-Richter K, Rosen MJ, Engelhardt BG, Moore DJ, Polk DB
(2013) Gut 62: 73-82
MeSH Terms: Biomarkers, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Case-Control Studies, Enterocolitis, Necrotizing, Female, Flow Cytometry, Forkhead Transcription Factors, Gene Expression Profiling, Humans, Infant, Newborn, Infant, Premature, Infant, Premature, Diseases, Intestinal Mucosa, Lymphocyte Count, Male, Prospective Studies, T-Lymphocytes, Regulatory
Show Abstract · Added February 27, 2014
BACKGROUND - Necrotising enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. Immaturity of gastrointestinal immune regulation may predispose preterm infants to NEC as FOXP3 T regulatory cells (Treg) are critical for intestinal immune homoeostasis.
OBJECTIVE - To investigate the hypothesis that abnormal developmental regulation of lamina propria Treg would define premature infants with NEC.
DESIGN - Lamina propria mononuclear cell populations from surgically resected ileum from 18 patients with NEC and 30 gestational age-matched non-NEC surgical controls were prospectively isolated. Polychromatic flow cytometry was performed to phenotype and analyse lamina propria T cell populations. The cytokine gene expression profile in NEC tissue was compared with that of non-NEC controls.
RESULTS - The total number of Treg, CD4, or CD8 T cells in each ileum section was independent of gestational age, age or postmenstrual age and similar between patients with NEC and controls. In contrast, the ratio of Treg to CD4 T cells or Treg to CD8 T cells was significantly lower in NEC ileum than in infants without NEC (medians 2.9% vs 6.6%, p=0.001 and medians 6.6% vs 25.9%, p<0.001, respectively). For any given number of CD4 or CD8 T cells, Treg were, on average, 60% lower in NEC ileum than in controls. NEC tissue cytokine gene expression profiles were characteristic of inhibited Treg development or function. Treg/CD4 and Treg/CD8 ratios recovered between initial resection for NEC and reanastomosis.
CONCLUSION - The proportion of lamina propria Treg is significantly reduced in the ileum of premature infants with NEC and may contribute to the excessive inflammatory state of this disease.
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18 MeSH Terms
Absence of gastrointestinal pathogens in ileum tissue resected for necrotizing enterocolitis.
Ullrich T, Tang YW, Correa H, Garzon SA, Maheshwari A, Hill M, Matta P, Krishnan MK, Weitkamp JH
(2012) Pediatr Infect Dis J 31: 413-4
MeSH Terms: Animals, Bacteria, Enterocolitis, Necrotizing, Female, Humans, Ileum, Infant, Infant, Newborn, Male, Multiplex Polymerase Chain Reaction, Parasites, Reverse Transcriptase Polymerase Chain Reaction, Viruses
Show Abstract · Added February 27, 2014
Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies in premature infants and has been linked with viral antigens in as much as 40% of cases in single-center cohorts. We examined 28 tissue sections from surgically resected ileum from 27 preterm infants with NEC from 2 separate institutions for 15 common bacterial, viral, and parasitic gastrointestinal pathogens using multiplex reverse transcriptase polymerase chain reaction amplification and suspension array detection methods. We did not detect infectious enteritis pathogens in any of the NEC tissues and conclude that gastrointestinal pathogens are a rare cause of NEC.
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13 MeSH Terms
Tumor necrosis factor receptor 1-dependent depletion of mucus in immature small intestine: a potential role in neonatal necrotizing enterocolitis.
McElroy SJ, Prince LS, Weitkamp JH, Reese J, Slaughter JC, Polk DB
(2011) Am J Physiol Gastrointest Liver Physiol 301: G656-66
MeSH Terms: Animals, Enterocolitis, Necrotizing, Goblet Cells, Humans, Infant, Newborn, Infant, Premature, Intestinal Mucosa, Intestine, Small, Mice, Mucin-2, Mucin-3, Mucins, Mucus, Paneth Cells, Proto-Oncogene Proteins c-ets, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Tumor Necrosis Factor-alpha
Show Abstract · Added February 27, 2014
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. NEC is believed to occur when intestinal bacteria invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Mucins are produced and secreted by epithelial goblet cells as a key component of the innate immune system and barrier function of the intestinal tract that help protect against bacterial invasion. To better understand the role of mucins in NEC, we quantified the number of mucus-containing small intestinal goblet cells present in infants with NEC and found they had significantly fewer goblet cells and Paneth cells compared with controls. To test whether inflammation has a developmentally dependent effect on intestinal goblet cells, TNF-α was injected into mice at various stages of intestinal development. TNF-α caused a loss of mucus-containing goblet cells only in immature mice and induced Muc2 and Muc3 mRNA upregulation only in mature ileum. Only minimal changes were seen in apoptosis and in expression of markers of goblet cell differentiation. TNF-α increased small intestinal mucus secretion and goblet cell hypersensitivity to prostaglandin E2 (PGE(2)), a known mucus secretagogue produced by macrophages. These TNF-α-induced changes in mucus mRNA levels required TNF receptor 2 (TNFR2), whereas TNF-α-induced loss of mucus-positive goblet cells required TNFR1. Our findings of developmentally dependent TNF-α-induced alterations on intestinal mucus may help explain why NEC is predominantly found in premature infants, and TNF-α-induced alterations of the intestinal innate immune system and barrier functions may play a role in the pathogenesis of NEC itself.
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2 Members
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18 MeSH Terms
Apical sodium-dependent bile acid transporter upregulation is associated with necrotizing enterocolitis.
Halpern MD, Weitkamp JH, Mount Patrick SK, Dobrenen HJ, Khailova L, Correa H, Dvorak B
(2010) Am J Physiol Gastrointest Liver Physiol 299: G623-31
MeSH Terms: Animals, Animals, Newborn, Cyclic N-Oxides, Enterocolitis, Necrotizing, Enterocytes, Humans, Ileum, Infant, Newborn, Infant, Premature, Mice, Mice, Knockout, Organic Anion Transporters, Sodium-Dependent, RNA, Messenger, Rats, Rats, Sprague-Dawley, Symporters, Tropanes, Up-Regulation
Show Abstract · Added February 27, 2014
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants. Previously, we showed that luminal bile acids (BAs) are increased and correlated with disease development and that the apical sodium-dependent BA transporter (ASBT), which transports BAs from the ileal lumen into enterocytes, is upregulated in rats with NEC. We hypothesized that intraenterocyte, rather than luminal, BAs are associated with NEC and that upregulation of ASBT may be a mechanism by which this occurs. Neonatal rats with or without the ASBT inhibitor SC-435, mice in which ASBT was knocked out, and mice that overproduce BAs were subjected to the NEC protocol. Disease development, ASBT, and the farnesoid X receptor protein, along with luminal and intraenterocyte BA levels, were assessed. In addition, ileal sections from premature infants with and without NEC were examined for ASBT via immunohistology and real-time PCR. When BAs were not transported into enterocytes (rats given SC-435 and ASBT knockout mice), severity and incidence of NEC were reduced. In contrast, in mice that overproduce BAs, ASBT was elevated, intraenterocyte BAs were increased, and disease development was increased. ASBT staining was more intense on the apical membrane of ileal enterocytes from premature infants with NEC than premature infants with non-NEC diagnoses. In addition, ASBT mRNA levels were significantly higher in infants with NEC. These data show that accumulation of intraenterocyte BAs contributes to disease development, elevated ASBT increases disease severity in experimental models of NEC, and ASBT is elevated in human NEC. These data confirm that BAs and upregulation of ASBT play a crucial role in NEC pathogenesis and suggest that inhibition of ASBT could be utilized as a therapeutic modality against this disease.
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18 MeSH Terms
Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice.
Wang L, Harrington L, Trebicka E, Shi HN, Kagan JC, Hong CC, Lin HY, Babitt JL, Cherayil BJ
(2009) J Clin Invest 119: 3322-8
MeSH Terms: Animals, Enterocolitis, Gene Expression Regulation, Hemochromatosis, Homeostasis, Immunity, Innate, Inflammation, Iron, Lipopolysaccharides, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88, Salmonella Infections, Signal Transduction, Toll-Like Receptor 4
Show Abstract · Added August 19, 2012
Mice deficient in the hemochromatosis gene, Hfe, have attenuated inflammatory responses to Salmonella infection associated with decreased macrophage TNF-alpha and IL-6 biosynthesis after exposure to LPS. In this study, we show that the abnormal cytokine production is related to impaired TLR4 signaling. Despite their abnormal response to LPS, Hfe KO macrophages produced amounts of TNF-alpha similar to those in WT cells after TLR2 stimulation. Consistent with this finding, LPS-induced activation of Mal/MyD88-dependent events was normal in the mutant macrophages. However, LPS-induced IFN-beta expression, a TRAM/TRIF-dependent response activated by TLR4, was reduced by Hfe deficiency. This reduction could be replicated in WT macrophages with the use of iron chelators. In contrast, TLR3-activated expression of IFN-beta, a TRIF-dependent response, was normal in Hfe KO macrophages and was unaffected by iron chelation. Our data suggest that low intracellular iron selectively impairs signaling via the TLR4/TRAM/TRIF pathway proximal to TRIF and results in reduced LPS-induced cytokine expression. Furthermore, by mimicking the altered iron metabolism associated with Hfe deficiency, we found that 3 different inhibitors of hepcidin attenuated Salmonella-induced and noninfectious enterocolitis. Thus, manipulation of iron homeostasis could represent a new therapeutic approach to controlling inflammation.
1 Communities
1 Members
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17 MeSH Terms
Ontogeny of FOXP3(+) regulatory T cells in the postnatal human small intestinal and large intestinal lamina propria.
Weitkamp JH, Rudzinski E, Koyama T, Correa H, Matta P, Alberty B, Polk DB
(2009) Pediatr Dev Pathol 12: 443-9
MeSH Terms: Enterocolitis, Necrotizing, Female, Forkhead Transcription Factors, Gestational Age, Humans, Immunity, Mucosal, Immunohistochemistry, Infant, Newborn, Intestinal Mucosa, Intestine, Large, Intestine, Small, Male, Mucous Membrane, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory
Show Abstract · Added February 27, 2014
FOXP3(+) regulatory T cells (Treg) suppress innate and adaptive immune responses and are critical for intestinal immune homeostasis. Our objective was to define the postnatal developmental regulation of Treg in relationship to other T cells in the human intestinal tract. We analyzed 41 small and 18 large intestinal paraffin-embedded tissue samples from preterm and term infants with and without necrotizing enterocolitis (NEC) for the presence of CD3(+), CD4(+), CD8(+), and FOXP3(+) cells by immunohistochemistry. We compared labeled cells against age, gestational age (GA), or (corrected) postmenstrual age (PMA). The GA ranged from 23 to 40 weeks, with a mean of 32 (standard deviation, 4.7) weeks. Independent of age, GA, or PMA, the numbers of CD4(+) cells were higher in the small intestine compared to the large intestine (P = 0.046), except in patients with NEC. FOXP3(+) cells could be detected as early as 23 weeks in GA in both large and small bowel, and similar quantities were detected at the highest GA examined (40 weeks). We saw no statistically significant effect of GA, age, or PMA on total number of FOXP3(+) cells or by comparing FOXP3(+) to CD4(+) or FOXP3(+) to CD8(+) ratios, indicating intact ontogeny of Treg in intestinal tissue early in gestation. Human infants exhibit presence of mucosal FOXP3(+) cells in the small and large intestinal mucosa at birth and as early as 23 weeks GA. The frequency of FOXP3(+) cells and the ratios of FOXP3(+) to CD4(+) or CD8(+) cells do not change with increasing intrauterine development or postnatal age.
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15 MeSH Terms
Acute right lower quadrant pain in a patient with leukemia.
de Brito D, Barton E, Spears KL, Cranmer HH, Karp SJ, Anglin D, Hutson HR
(1998) Ann Emerg Med 32: 98-101
MeSH Terms: Abdominal Pain, Acute Disease, Cecum, Diagnosis, Differential, Emergency Medical Services, Enterocolitis, Humans, Leukemia, Myeloid, Male, Middle Aged, Neutropenia, New York
Show Abstract · Added May 22, 2014
Typhlitis or neutropenic enterocolitis is a life-threatening, necrotizing process of the cecum whose incidence is increasing. It is usually encountered in patients with leukemia who have recently undergone chemotherapy. Neutropenic enterocolitis presents as fever, abdominal pain, and diarrhea in neutropenic patients. As the incidence of neutropenic enterocolitis increases, emergency physicians must be aware of this rapidly progressive and potentially fatal disease.
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12 MeSH Terms