Hepatic inflammatory mediators contribute to intestinal damage in necrotizing enterocolitis

2003 ◽  
Vol 284 (4) ◽  
pp. G695-G702 ◽  
Author(s):  
Melissa D. Halpern ◽  
Hana Holubec ◽  
Jessica A. Dominguez ◽  
Yolanda G. Meza ◽  
Catherine S. Williams ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Inflammatory Mediators ◽  
Gastrointestinal Disease ◽  
Neonatal Rat ◽  
Intestinal Lumen ◽  
Intestinal Damage ◽  
Tnf Α ◽  
Liver Morphology ◽  
Oxide Synthase

Necrotizing enterocolitis (NEC) is a common and devastating gastrointestinal disease of premature infants. Along with pathological effects in the ileum, severe NEC is often accompanied by mutisystem organ failure, including liver failure. The aim of this study was to determine the changes in hepatic cytokines and inflammatory mediators in experimental NEC. The well-established neonatal rat model of NEC was used in this study, and changes in liver morphology, numbers of Kupffer cells (KC), gene expression, and histological localization of IL-18, TNF-α, and inducible nitric oxide synthase were evaluated. Intestinal luminal TNF-α levels were also measured. Production of hepatic IL-18 and TNF-α and numbers of KC were increased in rats with NEC and correlated with the progression of intestinal damage during NEC development. Furthermore, increased levels of TNF-α in the intestinal lumen of rats with NEC was significantly decreased when KC were inhibited with gadolinium chloride. These results suggest an important role of the liver and the gut-liver axis in NEC pathogenesis.

scholarly journals Decreased development of necrotizing enterocolitis in IL-18-deficient mice

2008 ◽  
Vol 294 (1) ◽  
pp. G20-G26 ◽  
Author(s):  
Melissa D. Halpern ◽  
Ludmila Khailova ◽  
Dania Molla-Hosseini ◽  
Kelly Arganbright ◽  
Charity Reynolds ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Gastrointestinal Disease ◽  
Proximal Colon ◽  
Distal Ileum ◽  
Neonatal Rat ◽  
Histological Changes ◽  
Intestinal Pathology ◽  
Tnf Α ◽  
Prematurely Born Infants ◽  
Neonatal Rat Model

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease predominantly of prematurely born infants, characterized in its severest from by extensive hemorrhagic inflammatory necrosis of the distal ileum and proximal colon. Proinflammatory cytokines have been implicated in the development of NEC, and we have previously shown that IL-18 is significantly elevated in the well-established neonatal rat model of NEC. To determine whether IL-18 contributes to intestinal pathology in NEC, we subjected IL-18 knockout mice to the protocol used to develop experimental NEC in newborn rats. Newborn B6.129P2- Il18 tm1Aki/J (NEC IL-18−/−) and wild-type (NEC WT) mice were hand fed every 3 h with cow's milk-based formula and exposed to asphyxia and cold stress twice daily. After 72 h, animals were killed and distal ileum and liver were removed. Disease development was determined via histological changes in the ileum as scored by a blinded evaluator. The number of TNF-α-, IL-12-, and IL-1β-positive cells and macrophages were determined in both ileum and liver via immunohistology. IκB-α and IκB-β were determined from protein extracts from both ileum and liver using Western blot analysis. The incidence and severity of NEC was significantly reduced in NEC IL-18−/− mice compared with NEC WT. Furthermore, mean ileal macrophages and hepatic IL-1β were significantly reduced in IL-18−/− mice subjected to the NEC protocol. There were no statistically significant changes in Kupffer cells, hepatic TNF-α, ileal IL-1β, or IL-12. IκB-α and IκB-β were significantly increased in NEC IL-18−/− mice ileum and liver, respectively. These results confirm that IL-18 plays a crucial role in experimental NEC pathogenesis.

Astaxanthin Reduces the Severity of Intestinal Damage in a Neonatal Rat Model of Necrotizing Enterocolitis

2021 ◽  
Author(s):  
Hasan Akduman ◽  
Cuneyt Tayman ◽  
Veli Korkmaz ◽  
Filiz Akduman ◽  
Nurdan D. Fettah ◽  
...  
Keyword(s):  
Placebo Group ◽  
Necrotizing Enterocolitis ◽  
Caspase 3 ◽  
Neonatal Rat ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Albino Rats ◽  
Related Factor ◽  
Intestinal Damage ◽  
Tnf Α

Objective This study aimed to ascertain the effects of astaxanthin (ASX) in an experimental necrotizing enterocolitis (NEC) model using rat pups. Study Design Forty-two pups born from five Wistar albino rats were randomly divided into three groups as the control group, NEC + placebo (saline), and NEC + ASX. Pups in the NEC + ASX group were given 100 mg/kg/day oral ASX from day 1 to day 4 of the study. Saline of 2 mL/kg was given to the NEC + placebo group. Histopathological, immunohistochemical (caspase-3), and biochemical evaluations including the total antioxidant status (TAS), total oxidant status (TOS), superoxide dismutase (SOD), glutathione (GSH), lipid hydroperoxide (LPO), 8-hydroxydeoxyguanosine (8-OHdG), advanced oxidation protein products (AOPP), myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nuclear factor erythroid 2–related factor 2 (Nfr-2) activities were all performed. Results A better survival rate and weight gain were demonstrated in the NEC + ASX group (p < 0.05). In the histopathological evaluation, the severity of intestinal damage was significantly reduced in the NEC + ASX group, as well as decreased apoptosis (enzyme-linked immunosorbent assay [ELISA] for caspase-3; p = 0.001). The biochemical analyses of intestinal tissue TOS, oxidative stress index (OSI; TOS/TAS), IL-1β, LPO, 8-OHdG, AOPP, caspase-3 (p < 0.001 for all), and TNF-α and MPO (p = 0.001 for both parameters) levels were lower in the NEC + ASX group than in the NEC + placebo group. Nrf-2, TAS, GSH, and SOD levels were higher in the NEC + ASX group than in the NEC + placebo group (p = 0.001, 0.001, <0.001, and 0.01, respectively). Conclusion ASX treatment has been shown to effectively reduce the severity of intestinal damage in NEC due to its antioxidant, anti-inflammatory, and antiapoptotic properties. Key Points

Reduction of experimental necrotizing enterocolitis with anti-TNF-α

2006 ◽  
Vol 290 (4) ◽  
pp. G757-G764 ◽  
Author(s):  
Melissa D. Halpern ◽  
Jessica A. Clark ◽  
Tara A. Saunders ◽  
Sarah M. Doelle ◽  
Dania Molla Hosseini ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Rat Model ◽  
Caspase 3 ◽  
Gastrointestinal Disease ◽  
Paracellular Permeability ◽  
Neonatal Rat ◽  
Proinflammatory Mediators ◽  
Tnf Α ◽  
Ileal Disease ◽  
Neonatal Rat Model

Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants. However, despite significant morbidity and mortality, the etiology and pathogenesis of NEC are poorly understood. Evidence suggests that ileal proinflammatory mediators such as IL-18 contribute to the pathology associated with this disease. In addition, we have previously shown that upregulation of TNF-α in the liver is correlated with ileal disease severity in a neonatal rat model of NEC. With the use of a neonatal rat model of NEC, we evaluated the incidence and severity of ileal damage along with the production of both hepatic and ileal proinflammatory cytokines in animals injected with (anti-TNF-α; n = 23) or without (NEC; n = 25) a monoclonal anti-TNF-α antibody. In addition, we assessed changes in apoptosis and ileal permeability in the NEC and anti-TNF-α groups. Ileal damage was significantly decreased, and the incidence of NEC was reduced from 80% to 17% in animals receiving anti-TNF-α. Hepatic TNF-α and hepatic and ileal IL-18 were significantly decreased in pups given anti-TNF-α compared with those sham injected. In addition, ileal luminal levels of both TNF-α and IL-18 were significantly decreased in the anti-TNF-α-injected group. Ileal paracellular permeability and the proapoptotic markers Bax and cleaved caspase-3 were significantly decreased in the anti-TNF-α group. These data show that hepatic TNF-α is an important component for the development of NEC in the neonatal rat model and suggest that anti-TNF-α could be used as a potential therapy for human NEC.

scholarly journals Is Inflammation a Friend or Foe for Orthodontic Treatment?: Inflammation in Orthodontically Induced Inflammatory Root Resorption and Accelerating Tooth Movement

2021 ◽  
Vol 22 (5) ◽  
pp. 2388
Author(s):  
Masaru Yamaguchi ◽  
Shinichi Fukasawa
Keyword(s):  
Inflammatory Mediators ◽  
Orthodontic Treatment ◽  
Alveolar Bone ◽  
Tooth Movement ◽  
Root Resorption ◽  
Orthodontic Tooth Movement ◽  
Tnf Α ◽  
Orthodontic Forces ◽  
Necrosis Factor

The aim of this paper is to provide a review on the role of inflammation in orthodontically induced inflammatory root resorption (OIIRR) and accelerating orthodontic tooth movement (AOTM) in orthodontic treatment. Orthodontic tooth movement (OTM) is stimulated by remodeling of the periodontal ligament (PDL) and alveolar bone. These remodeling activities and tooth displacement are involved in the occurrence of an inflammatory process in the periodontium, in response to orthodontic forces. Inflammatory mediators such as prostaglandins (PGs), interleukins (Ils; IL-1, -6, -17), the tumor necrosis factor (TNF)-α superfamily, and receptor activator of nuclear factor (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) are increased in the PDL during OTM. OIIRR is one of the accidental symptoms, and inflammatory mediators have been detected in resorbed roots, PDL, and alveolar bone exposed to heavy orthodontic force. Therefore, these inflammatory mediators are involved with the occurrence of OIIRR during orthodontic tooth movement. On the contrary, regional accelerating phenomenon (RAP) occurs after fractures and surgery such as osteotomies or bone grafting, and bone healing is accelerated by increasing osteoclasts and osteoblasts. Recently, tooth movement after surgical procedures such as corticotomy, corticision, piezocision, and micro-osteoperforation might be accelerated by RAP, which increases the bone metabolism. Therefore, inflammation may be involved in accelerated OTM (AOTM). The knowledge of inflammation during orthodontic treatment could be used in preventing OIIRR and AOTM.

Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal rat model

2002 ◽  
Vol 282 (1) ◽  
pp. G156-G164 ◽  
Author(s):  
Bohuslav Dvorak ◽  
Melissa D. Halpern ◽  
Hana Holubec ◽  
Catherine S. Williams ◽  
Debra L. McWilliam ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Mrna Expression ◽  
Necrotizing Enterocolitis ◽  
Rat Model ◽  
Transforming Growth Factor ◽  
Gastrointestinal Disease ◽  
Neonatal Rat ◽  
Epidermal Growth ◽  
Neonatal Rat Model

Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of prematurely born infants. Maternal milk plays an important protective role against NEC development and is the major source of epidermal growth factor (EGF) for neonates. The aim of this study was to examine the effect of orally administered EGF on the incidence of NEC in a neonatal rat model. Newborn rats were artificially fed either with growth factor-free rat milk substitute (RMS) or RMS supplemented with 500 ng/ml of EGF (RMS+EGF). Experimental NEC was induced by exposure to asphyxia and cold stress. Development of NEC was evaluated by gross and histological scoring of damage in the ileum. Ileal EGF receptor (EGF-R), EGF, and transforming growth factor-α mRNA expression was assessed by RT competitive-PCR, and the EGF-R was localized by immunohistochemistry. EGF supplementation of formula reduced the incidence and severity of NEC in rats (13/16 RMS vs. 4/13 RMS+EGF). Ileal EGF-R mRNA expression was markedly increased in the RMS group compared with RMS+EGF. Enhanced EGF-R expression in the RMS group was localized predominantly in the epithelial cells of injured ileum. These data suggest a new potential therapeutic approach for the prevention and treatment of NEC.

scholarly journals Proinflammatory responses in SARS-CoV-2 infected and soluble spike glycoprotein S1 subunit activated human macrophages

2021 ◽  
Author(s):  
Kim Chiok ◽  
Kevin Hutchison ◽  
Lindsay Grace Miller ◽  
Santanu Bose ◽  
Tanya A Miura
Keyword(s):  
Virus Infection ◽  
Inflammatory Response ◽  
Virus Replication ◽  
Inflammatory Mediators ◽  
Inflammatory Responses ◽  
Activated Macrophages ◽  
Human Macrophages ◽  
Tnf Α ◽  
Proinflammatory Responses

Critically ill COVID-19 patients infected with SARS-CoV-2 display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We used SARS-CoV-2 infected and glycosylated soluble SARS-CoV-2 Spike S1 subunit (S1) treated THP-1 human-derived macrophage-like cell line to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication, virus infection resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that S1 is a key viral component inducing inflammatory response in macrophages, independently of virus replication. Thus, virus-infected or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

scholarly journals Nitric oxide-induced cardioprotection in cultured rat ventricular myocytes

2000 ◽  
Vol 278 (4) ◽  
pp. H1211-H1217 ◽  
Author(s):  
Roby D. Rakhit ◽  
Richard J. Edwards ◽  
James W. Mockridge ◽  
Anwar R. Baydoun ◽  
Amanda W. Wyatt ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ventricular Myocytes ◽  
Culture Conditions ◽  
Neonatal Rat ◽  
No Donor ◽  
Rat Ventricular Myocytes ◽  
Kinase C ◽  
Neonatal Rat Ventricular Myocytes ◽  
Oxide Synthase

The aim of this study was to investigate the role of nitric oxide (NO) in a cellular model of early preconditioning (PC) in cultured neonatal rat ventricular myocytes. Cardiomyocytes “preconditioned” with 90 min of stimulated ischemia (SI) followed by 30 min reoxygenation in normal culture conditions were protected against subsequent 6 h of SI. PC was blocked by N G-monomethyl-l-arginine monoacetate but not by dexamethasone pretreatment. Inducible nitric oxide synthase (NOS) protein expression was not detected during PC ischemia. Pretreatment (90 min) with the NO donor S-nitroso- N-acetyl-l,l-penicillamine (SNAP) mimicked PC, resulting in significant protection. SNAP-triggered protection was completely abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) but was unaffected by chelerythrine or the presence of glibenclamide and 5-hydroxydecanoate. With the use of RIA, SNAP treatment increased cGMP levels, which were blocked by ODQ. Hence, NO is implicated as a trigger in this model of early PC via activation of a constitutive NOS isoform. After exposure to SNAP, the mechanism of cardioprotection is cGMP dependent but independent of protein kinase C or ATP-sensitive K+ channels. This differs from the proposed mechanism of NO-induced cardioprotection in late PC.

scholarly journals Role of TNF-α in capillary degeneration following NMDA-induced neurotoxicity in the neonatal rat retina

2021 ◽  
Vol 94 (0) ◽  
pp. 2-O-C2-4
Author(s):  
Daiki Asano ◽  
Akane Morita ◽  
Asami Mori ◽  
Kenji Sakamoto ◽  
Toshihide Kashihara ◽  
...  
Keyword(s):  
Neonatal Rat ◽  
Rat Retina ◽  
Tnf Α ◽  
Capillary Degeneration

scholarly journals S100B Inhibition Attenuates Intestinal Damage and Diarrhea Severity During Clostridioides difficile Infection by Modulating Inflammatory Response

2021 ◽  
Vol 11 ◽  
Author(s):  
Deiziane V. S. Costa ◽  
Vivaldo Moura-Neto ◽  
David T. Bolick ◽  
Richard L. Guerrant ◽  
Jibraan A. Fawad ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Therapeutic Interventions ◽  
Intestinal Damage ◽  
Clostridioides Difficile ◽  
Tnf Α ◽  
Clostridioides Difficile Infection ◽  
Colonic Biopsies ◽  
Enteric Glial Cell ◽  
Insight Into

The involvement of the enteric nervous system, which is a source of S100B, in Clostridioides difficile (C. difficile) infection (CDI) is poorly understood although intestinal motility dysfunctions are known to occur following infection. Here, we investigated the role of S100B in CDI and examined the S100B signaling pathways activated in C. difficile toxin A (TcdA)- and B (TcdB)-induced enteric glial cell (EGC) inflammatory response. The expression of S100B was measured in colon tissues and fecal samples of patients with and without CDI, as well as in colon tissues from C. difficile-infected mice. To investigate the role of S100B signaling in IL-6 expression induced by TcdA and TcdB, rat EGCs were used. Increased S100B was found in colonic biopsies from patients with CDI and colon tissues from C. difficile-infected mice. Patients with CDI-promoted diarrhea exhibited higher levels of fecal S100B compared to non-CDI cases. Inhibition of S100B by pentamidine reduced the synthesis of IL-1β, IL-18, IL-6, GMCSF, TNF-α, IL-17, IL-23, and IL-2 and downregulated a variety of NFκB-related genes, increased the transcription (SOCS2 and Bcl-2) of protective mediators, reduced neutrophil recruitment, and ameliorated intestinal damage and diarrhea severity in mice. In EGCs, TcdA and TcdB upregulated S100B-mediated IL-6 expression via activation of RAGE/PI3K/NFκB. Thus, CDI appears to upregulate colonic S100B signaling in EGCs, which in turn augment inflammatory response. Inhibition of S100B activity attenuates the intestinal injury and diarrhea caused by C. difficile toxins. Our findings provide new insight into the role of S100B in CDI pathogenesis and opens novel avenues for therapeutic interventions.

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