Reduction of experimental necrotizing enterocolitis with anti-TNF-α

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00196.2001 ◽

2002 ◽

Vol 282 (1) ◽

pp. G156-G164 ◽

Cited By ~ 178

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00168.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. G20-G26 ◽

Cited By ~ 41

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.

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