The Platelet-Activating Factor Receptor Antagonist WEB 2170 Prevents Neonatal Necrotizing Enterocolitis in Rats

Caplan, Michael S.; Hedlund, Erik; Adler, Luba; Lickerman, Matthew; Hsueh, Wei

doi:10.1097/00005176-199703000-00012

Cited by 93 publications

(43 citation statements)

References 27 publications

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“…Altered PAF metabolism has been associated with NEC in human studies and animal experiments (3,4). For example, using the same NEC animal model we used in the present study, pups treated with the PAFR antagonist WEB 2170 and PAF-degrading enzyme PAF-AH had a lower incidence of NEC.…”

Section: Discussionmentioning

confidence: 60%

“…One of the key inflammatory mediators associated with NEC is PAF. Studies have shown that PAFR blockade or enhanced intestinal PAF degradation via PAF acetylhydrolase (PAF-AH) supplementation reduces the incidence of NEC in a neonatal rat model, and this experimental model resembles the clinical and pathologic features quite similar to human neonatal NEC (3,4).…”

mentioning

confidence: 99%

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Polyunsaturated Fatty Acid Supplementation Alters Proinflammatory Gene Expression and Reduces the Incidence of Necrotizing Enterocolitis in a Neonatal Rat Model

et al. 2007

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Although supplementation of preterm formula with polyunsaturated fatty acids (PUFA) has been shown to reduce the incidence of necrotizing enterocolitis (NEC) in animal models and clinical trials, the mechanisms remain elusive. We hypothesized that the protective effect of PUFA on NEC may be due to the ability of PUFA to suppress Toll-like receptor (TLR) 4 and platelet-activating factor receptor (PAFR) gene expression (molecules that are important in the pathogenesis of NEC) in epithelial cells. To investigate the efficacy of different PUFA preparations on NEC in a neonatal rat model, we compared the incidence of NEC among the four PUFA supplemented groups-A: arachidonic acid and docosahexaenoic acid (AAϩDHA), B: egg phospholipids (EP), C: DHA, and D: control without PUFA. PUFA supplementation reduced the incidence of NEC and inhibited intestinal PAFR and TLR4 gene expression compared with the controls. To validate the in vivo observations, IEC-6 cells were exposed to PAF after pretreatment with AA or DHA. Both AA and DHA supplementation blocked PAF-induced TLR4 and PAFR mRNA expression in these enterocytes. These results suggest that PUFA modulates gene expression of key factors involved in experimental NEC pathogenesis. These effects might in part explain the protective effect of PUFA on neonatal NEC. neonates. Risk factors of prematurity, enteral feeding, hypoxia and/or intestinal ischemia, and bacterial colonization have been associated with the development of neonatal NEC (1,2). One of the key inflammatory mediators associated with NEC is PAF. Studies have shown that PAFR blockade or enhanced intestinal PAF degradation via PAF acetylhydrolase (PAF-AH) supplementation reduces the incidence of NEC in a neonatal rat model, and this experimental model resembles the clinical and pathologic features quite similar to human neonatal NEC (3,4).Supplementation of preterm formula with PUFA has generated significant interest in recent years and now appears to be the standard of care. A previous randomized, controlled clinical trial showed that PUFA supplementation for preterm infants reduced the incidence of NEC (5). Nonetheless, subsequent trials have not substantiated this important reduction of NEC incidence with PUFA supplementation (6). Despite the inconsistency, the mechanism by which PUFA might alter the incidence of NEC in these clinical studies remains elusive. We previously reported that PUFA supplementation reduced the incidence of NEC in an experimental neonatal rat model of NEC, and that AA and DHA supplementation in the formula may have beneficial effects on epithelial cell integrity by reducing bacterial or endotoxin translocation and/or reducing mucosal PAF synthesis and receptor activation (7). In vivo studies have demonstrated that n-3 fatty acids protected mice from hypoxia-induced bowel necrosis by directly inhibiting endogenous PAF production and leukotriene B4 production (8). In addition, dietary supplementation of eicosatrienoic acid and DHA suppressed PAF generation in mouse peritoneal ...

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Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

Polyunsaturated Fatty Acid Supplementation Alters Proinflammatory Gene Expression and Reduces the Incidence of Necrotizing Enterocolitis in a Neonatal Rat Model

et al. 2007

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“…These include anti-TNF-α [82] , PAF receptor antag onists [203] , heparin-binding EGF-like g rowth factor [204] , anti-inflammator y cytokines (IL-10) [205] , pentoxifylline [206] , intestinal trefoil factor 3 [207] , and glucagon-like peptide 2. Recent research has identified that complex glycosphingolipids in the form of gangliosides act as bioactive factors down-regulating many acute proinflammatory signals in the intestinal mucosa.…”

Section: Resultsmentioning

confidence: 99%

Necrotizing enterocolitis: A multifactorial disease with no cure

Schnabl

Aerde²,

Thomson³

et al. 2008

WJG

161

120

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INTRODUCTIONNecrotizing enterocolitis (NEC) is an inflammatory bowel disease of neonates and remains one of the most common gastrointestinal emergencies in newborn infants [1] . Onset of NEC is often within the first three months of life and neonates who are of extremely low birth weight (< 1000 g) and under 28 wk gestation are the most susceptible [2] . Full term neonates account for 10% of all NEC cases while premature infants account for 90% [3] . With an incidence rate of 1%-5% for all newborns admitted to the NICU [1] , a prevalence of 7%-14% of very low birth weight infants (VLBW, 500-1500 g) [4] and a mortality rate approaching 20%-50% [5] , NEC continues to represent a significant clinical problem. In Canada, the incidence rate is 1.8 per 100 live births with a prevalence of 7% of VLBW infants [1] . Advances in obstetric and neonatal care have improved survival rates for smaller, more immature infants, and as more VLBW preterm infants survive the neonatal period, the population at risk for NEC increases [1] .No consistent association between sex, race, and rates of NEC has been identified. However, male VLBW infants and black infants are at greater risk of death [6] . Due to inadequate treatments and no effective preventative strategy, an estimated 20%-40% of babies with NEC require surgery [1] and 10%-30% experience significant morbidity including neurodevelopmental impairment, vision and hearing impairment, failure to thrive, feeding abnormalities, diarrhea, bowel obstruction, and short bowel syndrome [1,2,7] . The case fatality rate with surgical intervention is as high as 50% [1] . NEC is also a financial burden to the health care system with yearly hospital charges reported to be as high as $6.5 million in the US [8] . Thus, NEC continues to be an important health issue for preterm neonates. DIAGNOSIS Clinical signs and symptomsThe onset of NEC can occur suddenly within a few AbstractNecrotizing enterocolitis is an inflammatory bowel disease of neonates with significant morbidity and mortality in preterm infants. Due to the multifactorial nature of the disease and limitations in disease models, early diagnosis remains challenging and the pathogenesis elusive. Although preterm birth, hypoxic-ischemic events, formula feeding, and abnormal bacteria colonization are established risk factors, the role of genetics and vasoactive/inflammatory mediators is unclear. Consequently, treatments do not target the specific underlying disease processes and are symptomatic and surgically invasive. Breast-feeding is the most effective preventative measure. Recent advances in the prevention of necrotizing enterocolitis have focused on bioactive nutrients and trophic factors in human milk. Development of new disease models including the aspect of prematurity that consistently predisposes neonates to the disease with multiple risk factors will improve our understanding of the pathogenesis and lead to discovery of innovative therapeutics.

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“…Additional experiments have evaluated the importance of PAF in neonatal rats using the typical risk factors of NEC, including asphyxia and formula feeding [16]. In this model, we have shown that PAF receptor blockade reduces the incidence of NEC, and that the PAF-degrading enzyme PAF-AH given with enteral feeding interferes with the initiation of NEC [17,18]. Breast milk, which is thought to reduce the risk for NEC, contains significant quantities of this enzyme.…”

Section: The Role Of Platelet Activating Factor Homeostasismentioning

confidence: 99%

Intestinal Epithelial Cell Apoptosis, Immunoregulatory Molecules, and Necrotizing Enterocolitisb

Jilling¹

2012

J Clin Cell Immunol

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Necrotizing enterocolitis is one of the most severe, life-threatening consequences of premature birth, affecting 5-15% of premature neonates with birth weights <1,500 grams. Many lines of evidence suggest a role for the dysregulation of enterocyte apoptosis in NEC pathogenesis. In addition to apoptosis, the roles of several inflammatory mediators such as platelet-activating factor, IL-8, TNFα and endotoxin have been shown to be pathogenic. Receptors for these ligands and downstream cellular signaling pathways, such as mitochondrial injury-induced caspase activation and NFĸB-mediated transcriptional regulation are thought to be involved in the mechanisms of mucosal injury in NEC. In this review, we attempt to summarize the role of enterocyte apoptosis in NEC along with an analysis of the connection between inflammatory signaling and apoptosis in this disease.

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The Platelet-Activating Factor Receptor Antagonist WEB 2170 Prevents Neonatal Necrotizing Enterocolitis in Rats

Abstract: The data support the role of PAF in the final common pathway of neonatal NEC.

Cited by 93 publications

References 27 publications

Polyunsaturated Fatty Acid Supplementation Alters Proinflammatory Gene Expression and Reduces the Incidence of Necrotizing Enterocolitis in a Neonatal Rat Model

Polyunsaturated Fatty Acid Supplementation Alters Proinflammatory Gene Expression and Reduces the Incidence of Necrotizing Enterocolitis in a Neonatal Rat Model

Necrotizing enterocolitis: A multifactorial disease with no cure

Intestinal Epithelial Cell Apoptosis, Immunoregulatory Molecules, and Necrotizing Enterocolitisb

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