Platelet activating factor-induced ischemic bowel necrosis: The effect of PAF antagonists

Hsueh, Wei; González-Crussí, F.; Arroyave, Josefa L.; Anderson, Robert C.; Lee, Mark L.; Houlihan, William J.

doi:10.1016/0014-2999(86)90690-4

Cited by 60 publications

(24 citation statements)

References 5 publications

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“…the PAF degrading enzyme) in premature neonates suggests a role for this molecule in NEC pathogenesis. Initial studies in adult rats using an acute model have shown that exogenous PAF given intravenously results in ischemic bowel necrosis (11) and endotoxin, hypoxia, or tumor necrosis factor (TNF)-induced intestinal injury can be prevented by PAF receptor (PAFR) antagonists (12,13 …”

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confidence: 99%

Intestinal Epithelial Apoptosis Initiates Gross Bowel Necrosis in an Experimental Rat Model of Neonatal Necrotizing Enterocolitis

et al. 2004

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The histopathology of necrotizing enterocolitis (NEC) is characterized by destruction of the mucosal layer in initial stages and by transmural necrosis of the intestinal wall in advanced stages of the disease. To test the hypothesis that enhanced epithelial apoptosis is an initial event underlying the gross histologic changes, we analyzed epithelial apoptosis and tissue morphology in an animal model of NEC and evaluated the effect of caspase inhibition on the incidence of experimental NEC in this model. Apoptosis was analyzed with terminal deoxynucleotidyltransferase-mediated dUTP-FITC nick end labeling (TUNEL) staining in intestinal sections and by measuring caspase 3 activity from intestinal lysates of neonatal rats subjected to formula feeding and cold/asphyxia stress (FFCAS) and from mother-fed (MF) controls. Morphologic evaluation was based on hematoxylin and eosin staining of intestinal sections. FFCAS resulted in histologic changes consistent with NEC, which were absent from MF animals. FFCAS was also associated with a significantly increased rate of nuclear DNA fragmentation in the small intestinal epithelium compared with MF. Elevated tissue caspase 3 activity confirmed the presence of apoptosis in samples with increased DNA fragmentation. Analysis of the coincidence of morphologic damage and apoptosis in corresponding tissue sections indicated that apoptosis precedes gross morphologic changes in this model. Furthermore, supplementation of formula with 8 boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, significantly reduced the incidences of apoptosis and experimental NEC. These findings indicate that in neonatal rats FFCAS induces epithelial apoptosis that serves as an underlying cause for subsequent gross tissue necrosis. NEC occurs in 5-15% of premature infants born weighing Ͻ1500 g and remains one of the leading causes of death in these patients (1-3). Nonetheless, the etiology of NEC remains elusive, and no specific treatment or preventive approaches have been successful. Several lines of evidence suggest that neonatal risk factors of prematurity, asphyxia, intestinal ischemia, and formula feeding are all contributing to the occurrence of the disease (4 -6). The immaturity of mucosal host defense, inappropriate bacterial colonization profile, and an imbalance of endothelin-dependent vasoconstriction and nitric oxide-dependent vasodilatation have also been implicated in the disease (7-10). Among the many inflammatory mediators that have been identified as possible culprits in the pathogenesis of NEC, PAF has been shown to play a central role. Elevated serum PAF levels in NEC patients and decreased serum PAF acetylhydrolase (i.e. the PAF degrading enzyme) in premature neonates suggests a role for this molecule in NEC pathogenesis. Initial studies in adult rats using an acute model have shown that exogenous PAF given intravenously results in ischemic bowel necrosis (11) and endotoxin, hypoxia, or tumor necrosis factor (TNF)-induced intestinal injury can be prevented by PAF receptor (PAFR...

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confidence: 99%

Intestinal Epithelial Apoptosis Initiates Gross Bowel Necrosis in an Experimental Rat Model of Neonatal Necrotizing Enterocolitis

et al. 2004

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“…The intravenous administration of PAF into the descending aorta of adult rats results in lesions limited to the intestine that are morphologically identical to the lesions of ischemic necrosis seen in human NEC [8]. The injurious effect of PAF on the intestine is enhanced by the addition of endotoxin, and high-dose endotoxin alone results in intestinal injury that can be prevented with PAF receptor antagonists [16]. This endotoxin-induced intestinal injury has been shown to be associated with increased endogenous PAF production in intestinal homogenate [6].…”

Section: Discussionmentioning

confidence: 97%

Platelet-Activating Factor Concentration in the Stool of Human Newborns: Effects of Enteral Feeding and Neonatal Necrotizing Enterocolitis

Amer¹,

Hedlund²,

Rochester³

et al. 2004

Neonatology

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Epidemiologic studies have identified enteral feedings as a risk factor for necrotizing enterocolitis (NEC). Enteral feedings provide the substrate for colonization of the newborn gut with gram-negative bacteria with endotoxin production, which may trigger the production of endogenous inflammatory mediators, including platelet-activating factor (PAF). In this prospective study, we examined the effect of enteral feeding on PAF concentration in the stool of preterm and full-term human newborns. The concentration of PAF levels in stool was measured at the following times: at passage of first meconium, within 24 h prior to the onset of feedings, at the 3rd and 14th day of feeding and at any time confirmed NEC developed. Stool samples also were analyzed for levels of acetylhydrolase, the PAF breakdown enzyme. Stool PAF concentration rose significantly following the start of enteral feedings. The mean PAF concentration for day 14 samples was significantly higher than the mean concentration of meconium samples (4.90 ± 1.03 vs. 1.81 ± 0.38 ng/g, p < 0.05) and day 0 samples (4.90 ± 1.03 vs. 1.79 ± 0.39 ng/g, p < 0.05). For the 7 patients diagnosed with definite NEC, the mean stool PAF concentration was 12.42 ± 0.77 ng/g, significantly elevated compared to the mean PAF levels in stool from healthy infants at all sampling times (p < 0.01). There was no significant change in acetylhydrolase activity at any of the sampling times. Stool PAF concentration increases with the provision of enteral feedings and rises further with the development of NEC. Since stool acetylhydrolase activity remained unchanged, we speculate the increase of PAF in stool likely represents increased PAF production at the local level following the provision of enteral feedings or the development of neonatal necrotizing enterocolitis.

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“…For example, ONO-6240 is significantly less potent as an antagonist of PAF binding to human platelets than to human neutrophils [1], and at 0.3 mg/kg ONO-6240 attenuated PAF-induced intestinal damage, but did not prevent PAF-induced neutrophilia [2]. Similarly, BN-52021 inhibited eicosanoid release in the perfused, isolated rat stomach, while producing only slight changes in the perfusion rate [3].…”

Section: Introductionmentioning

confidence: 96%

Differential antagonism of platelet activating factor-induced neutrophilia and gastric hemorrhage in the rat

et al. 1993

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Intravenous injection of platelet activating factor (PAF) in rats produced hypotension, neutrophilia, gastric congestion, and sloughing of the gastric epithelium. The congestion was quantified by measuring hemoglobin in the gastric mucosa. Other lesions were quantified by scores of gross pathology and histopathology. PAF-induced changes in neutrophil levels were prevented by pretreatment with the PAF-antagonist Ro24-4736, but not by the PAF-antagonist CV-3988. Both PAF antagonists reduced the hypotension, the amount of hemoglobin in the gastric mucosa, and the PAF-induced gastric pathology. These results suggest that PAF receptors involved in PAF-induced neutrophil mobilization respond differently from PAF receptors in the gastrointestinal and cardiovascular systems.

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Platelet activating factor-induced ischemic bowel necrosis: The effect of PAF antagonists

Cited by 60 publications

References 5 publications

Intestinal Epithelial Apoptosis Initiates Gross Bowel Necrosis in an Experimental Rat Model of Neonatal Necrotizing Enterocolitis

Intestinal Epithelial Apoptosis Initiates Gross Bowel Necrosis in an Experimental Rat Model of Neonatal Necrotizing Enterocolitis

Platelet-Activating Factor Concentration in the Stool of Human Newborns: Effects of Enteral Feeding and Neonatal Necrotizing Enterocolitis

Differential antagonism of platelet activating factor-induced neutrophilia and gastric hemorrhage in the rat

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