Glucocorticoid responsiveness in developing human intestine: possible role in prevention of necrotizing enterocolitis

2005 ◽  
Vol 288 (1) ◽  
pp. G85-G92 ◽  
Author(s):  
N. Nanda Nanthakumar ◽  
Cheryl Young ◽  
Jae Sung Ko ◽  
Di Meng ◽  
Ji Chen ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Nuclear Translocation ◽  
Preventive Therapy ◽  
Human Intestine ◽  
Lactase Activity ◽  
Functional Development ◽  
Chemotactic Protein ◽  
Finite Period ◽  
Steroid Responsiveness ◽  
In Utero Development

Necrotizing enterocolitis (NEC) is a major inflammatory disease of the premature human intestine that can be prevented by glucocorticoids if given prenatally before the 34th wk of gestation. This observation suggests that a finite period of steroid responsiveness exists as has been demonstrated in animal models. Human intestinal xenografts were used to determine whether a glucocorticoid responsive period exists in the developing human intestine. Developmental responsiveness was measured by lactase activity and inflammatory responsiveness by IL-8, IL-6, and monocyte chemotactic protein-1 (MCP-1) induction after an endogenous (IL-1β) or exogenous (LPS) proinflammatory stimulus, respectively. Functional development of ileal xenografts were monitored for 30 wk posttransplantation, and the lactase activity recapitulated that predicted by in utero development. Cortisone acetate accelerated the ontogeny of lactase at 20 wk (immature) but the effect was lost by 30 wk (mature) posttransplant. Concomitant with accelerated maturation, the IL-8 response to both IL-1β and LPS was significantly dampened (from 6- to 3-fold) by glucocorticoid pretreatment in the immature but not mature xenografts. The induction of IL-8 was reflected at the level of IL-8 mRNA, suggesting transcriptional regulation. The excessive activation of IL-8 in the immature gut was mediated by a prolonged activation of ERK and p38 kinases and nuclear translocation of NF-κB due to low levels of IκB. Steroid pretreatment in immature intestine dampens activation of all three signaling pathways in response to proinflammatory stimuli. Therefore, accelerating intestinal maturation by glucocorticoids within the responsive period by accelerating functional and inflammatory maturation may provide an effective preventive therapy for NEC.

Normal and glucocorticoid-induced development of the human small intestinal xenograft

2003 ◽  
Vol 285 (1) ◽  
pp. R162-R170 ◽  
Author(s):  
N. Nanda Nanthakumar ◽  
Corrie E. Klopcic ◽  
Isabel Fernandez ◽  
W. Allan Walker
Keyword(s):  
In Utero ◽  
Human Intestine ◽  
Lactase Activity ◽  
Developmental Potential ◽  
Protein Levels ◽  
Small Intestinal ◽  
Immunocompromised Mice ◽  
Proximal Intestine ◽  
In Utero Development ◽  
Fetal Intestine

The aim of this study was to determine whether intestinal xenografts could recapitulate human in utero development by using disaccharidases as markers. Twenty-week-old fetal intestine was transplanted into immunocompromised mice and was followed. At 20-wk of gestation, the fetal human intestine was morphologically developed with high sucrase and trehalase but had low lactase activities. By 9-wk posttransplantation, jejunal xenografts were morphologically and functionally developed and were then monitored for ≤6 mo. Both sucrase and trehalase activities remained unchanged, but lactase activity increased in a manner similar to that described in in utero development. Changes in sucrase and lactase activities were paralleled by protein levels. Cortisone acetate treatment at 20-wk posttransplantation accelerated the ontogeny of lactase but did not alter sucrase and trehalase activities. Biopsies from 1- and 2-yr-old infant intestine showed that all activities, except trehalase in the proximal intestine, corresponded to the levels found in jejunal xenografts at 24 wk posttransplantation. These studies suggest that 20-wk-old fetal intestine has the extrauterine developmental potential to follow normal intrauterine ontogeny as a xenograft.

Endothelial Nitric Oxide Synthase in Human Intestine Resected for Necrotizing Enterocolitis

2007 ◽  
Vol 150 (1) ◽  
pp. 40-45 ◽  
Author(s):  
Philip T. Nowicki ◽  
Donna A. Caniano ◽  
Sue Hammond ◽  
Peter J. Giannone ◽  
Gail E. Besner ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Necrotizing Enterocolitis ◽  
Endothelial Nitric Oxide Synthase ◽  
Human Intestine ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

scholarly journals Fecal filtrate transplantation protects against necrotizing enterocolitis

2021 ◽  
Author(s):  
Anders Brunse ◽  
Ling Deng ◽  
Xiaoyu Pan ◽  
Yan Hui ◽  
Josué L. Castro-Mejía ◽  
...  
Keyword(s):  
Preterm Infants ◽  
Necrotizing Enterocolitis ◽  
Fecal Microbiota Transplantation ◽  
Gastrointestinal Disorder ◽  
Preventive Therapy ◽  
Fecal Microbiota ◽  
Rrna Gene ◽  
Ileal Mucosa ◽  
Relevant Animal Model ◽  
Life Threatening

AbstractNecrotizing enterocolitis (NEC) is a life-threatening gastrointestinal disorder afflicting preterm infants, which is currently unpreventable. Fecal microbiota transplantation (FMT) is a promising preventive therapy, but the transfer of pathogenic microbes or toxic compounds raise concern. Removal of bacteria from donor feces by micropore filtering may reduce this risk of bacterial infection, while residual bacteriophages could maintain the NEC-preventive effects. We aimed to assess preclinical efficacy and safety of fecal filtrate transplantation (FFT). Using fecal material from healthy suckling piglets, we compared rectal FMT administration (FMT, n = 16) with cognate FFT by either rectal (FFTr, n = 14) or oro-gastric administration (FFTo, n = 13) and saline (CON, n = 16) in preterm, cesarean-delivered piglets as models for preterm infants. We assessed gut pathology and analyzed mucosal and luminal bacterial and viral composition using 16S rRNA gene amplicon and meta-virome sequencing. Finally, we used isolated ileal mucosa, coupled with RNA-Seq, to gauge the host response to the different treatments. Oro-gastric FFT completely prevented NEC, which was confirmed by microscopy, whereas FMT did not perform better than control. Oro-gastric FFT increased viral diversity and reduced Proteobacteria relative abundance in the ileal mucosa relative to control. An induction of mucosal immunity was observed in response to FMT but not FFT. As preterm infants are extremely vulnerable to infections, rational NEC-preventive strategies need incontestable safety profiles. We show in a clinically relevant animal model that FFT, as opposed to FMT, efficiently prevents NEC without any recognizable side effects.

scholarly journals Angiogenin Reduces Immune Inflammation via Inhibition of TANK-Binding Kinase 1 Expression in Human Corneal Fibroblast Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Seung Hoon Lee ◽  
Kyoung Woo Kim ◽  
Kyong-Mi Min ◽  
Kyu-Wan Kim ◽  
Soo-Ik Chang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Mrna Expression ◽  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Immune Mediated ◽  
Chemotactic Protein ◽  
Anti Inflammatory

Angiogenin (ANG) is reportedly multifunctional, with roles in angiogenesis and autoimmune diseases. This protein is involved in the innate immune system and has been implicated in several inflammatory diseases. Although ANG may be involved in the anti-inflammatory response, there is no evidence that it has direct anti-inflammatory effects. In this study we sought to determine whether ANG has an anti-inflammatory effect in human corneal fibroblasts (HCFs) exposed to media containing tumor necrosis factor-alpha (TNF-α). We found that ANG reduced the mRNA expression of interleukin-1 beta (IL-1β), -6, -8 and TNF-αreceptors (TNFR) 1 and 2. In contrast, ANG increased the mRNA expression of IL-4 and -10. Protein levels of TANK-binding kinase 1 (TBK1) were reduced by ANG in HCFs treated with TNF-α. Moreover, ANG diminished the expression of IL-6 and -8 and monocyte chemotactic protein- (MCP-) 1. The protein expression of nuclear factor-κB (NF-κB) was downregulated by ANG treatment. These findings suggest that ANG suppressed the TNF-α-induced inflammatory response in HCFs through inhibition of TBK1-mediated NF-κB nuclear translocation. These novel results are likely to play a significant role in the selection of immune-mediated inflammatory therapeutic targets and may shed light on the pathogenesis of immune-mediated inflammatory diseases.

scholarly journals Requirement for NF-κB in Transcriptional Activation of Monocyte Chemotactic Protein 1 by Chlamydia pneumoniae in Human Endothelial Cells

2000 ◽  
Vol 68 (7) ◽  
pp. 4282-4288 ◽  
Author(s):  
Robert E. Molestina ◽  
Richard D. Miller ◽  
Alex B. Lentsch ◽  
Julio A. Ramirez ◽  
James T. Summersgill
Keyword(s):  
Endothelial Cells ◽  
Mrna Expression ◽  
Transcriptional Activation ◽  
Chlamydia Pneumoniae ◽  
Nuclear Translocation ◽  
Umbilical Vein ◽  
Specific Inhibitor ◽  
Human Endothelial Cells ◽  
Monocyte Chemotactic Protein ◽  
Chemotactic Protein

ABSTRACT Infection with Chlamydia pneumoniae, a causative agent of acute and chronic respiratory diseases, has recently been implicated as a potential risk factor in atherosclerosis. Atherosclerotic lesions are characterized by monocyte infiltration, which may be regulated by the chemokine monocyte chemotactic protein 1 (MCP-1). We have previously shown that C. pneumoniae infection stimulates MCP-1 production in human endothelial cells, an event which may be specific to this species of Chlamydia, sinceChlamydia trachomatis infection fails to induce this response. To examine the underlying mechanisms by which C. pneumoniae infection induces MCP-1 production in endothelial cells, the present study investigated the role of transcription factor NF-κB in MCP-1 mRNA expression. Human umbilical vein endothelial cells (HUVEC) were infected with the coronary isolate C. pneumoniae A-03 or with C. trachomatis L2, and MCP-1 mRNA expression was assessed after different periods of infection by reverse transcription-PCR. Expression of MCP-1 mRNA in C. pneumoniae-infected HUVEC was significantly elevated as early as 1 h postinfection and increased dramatically by 12 and 24 h compared to baseline controls. Nuclear translocation of NF-κB occurred by 30 min of infection, as determined by electrophoretic mobility shift assays and immunofluorescence staining. Treatment ofC. pneumoniae-infected HUVEC with parthenolide, a specific inhibitor of NF-κB activation, suppressed MCP-1 mRNA expression. In contrast, infection with C. trachomatis L2 did not induce MCP-1 mRNA in infected HUVEC and failed to activate NF-κB. Results from this study demonstrate a requirement for NF-κB activation in stimulation of MCP-1 gene expression by C. pneumoniae in human endothelial cells. Furthermore, the data suggest that, within the genus Chlamydia, functionally distinct signaling pathways leading to NF-κB activation are utilized by C. pneumoniaein endothelial cells during infection.

Increased glucocorticoid receptor β expression leads to reduced nuclear translocation of glucocorticoid receptor α and impaired steroid responsiveness

2002 ◽  
Vol 109 (1) ◽  
pp. S261-S261
Author(s):  
Pia J Hauk ◽  
Ian Strickland ◽  
Alessandro Vottero ◽  
George P Chrousos ◽  
Kevin O Kisich ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Nuclear Translocation ◽  
Steroid Responsiveness

scholarly journals Functional Role of VCAM-1 Targeted Flavonoid-Loaded Lipid Nanoemulsions in Reducing Endothelium Inflammation

Pharmaceutics ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 391 ◽  
Author(s):  
Elena Fuior ◽  
Mariana Deleanu ◽  
Cristina Constantinescu ◽  
Daniela Rebleanu ◽  
Geanina Voicu ◽  
...  
Keyword(s):  
Water Solubility ◽  
Nuclear Translocation ◽  
Dependent Manner ◽  
Protective Effects ◽  
Necrosis Factor Alpha ◽  
Chemotactic Protein ◽  
Citrus Flavonoids ◽  
Tnf Α ◽  
Cell Adhesion Molecule 1

Citrus flavonoids have well-documented protective effects on cardiovascular system, but the poor water solubility and reduced bioavailability restrict their therapeutic use. We aimed to overcome these limitations and encapsulated naringenin and hesperetin into lipid nanoemulsions (LNs), targeted to vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated endothelial cells (ECs). LNs were characterized by a hydrodynamic size of ~200 nm, negative zeta potential, an encapsulation efficiency of flavonoids higher than 80%, good in vitro stability and steady release of the cargo. The LNs were neither cytotoxic to human ECs line EA.hy926, nor provoked in vitro lysis of murine erithrocytes. Then, we tested whether these nanoformulations reduce tumor necrosis factor-alpha (TNF-α) induced EC-activation. We found that flavonoid-loaded LNs, either non-targeted or targeted to the endothelium, were taken up by the EA.hy926 cells in a dose-dependent manner, but dependent on TNF-α only in the case of endothelium-targeted LNs. Moreover, these nanoparticles inhibited both the adhesion and transmigration of THP-1 monocytes on/through activated ECs, by mechanisms involving a reduced expression of the pro-inflammatory chemokine monocyte chemotactic protein 1 (MCP-1) and diminished nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).

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