The central role of PAF in necrotizing enterocolitis development.
We have addressed two critical questions concerning NEC development. 1) Why is the neonatal intestine particularly susceptible to necrosis? and 2) Does PAF play a critical role in NEC development? We have found that intestinal tissue of the newborn has the highest specific activity for the acetyltransferase of the de novo pathway. It is suggested that the high capacity of this tissue to synthesize PAF may contribute to the fact that the necrosis of the newborn is more prevalent in this tissue. We have previously reported that dexamethasone lowers the activity of acetyl-CoA:lyso-PAF acetyltransferase in liver and spleen. This hormone also cause an increase in plasma PAF-acetylhydrolase activity and an increased secretion of PAF-acetylhydrolase by various macrophages. It would, therefore, appear that the beneficial effects of glucocorticoids on the prevention of NEC may be due to both increased inactivation of PAF as caused by the increase in PAF-acetylhydrolase as well as a decrease in PAF synthesis. We are presently investigating the effect of glucocorticoids on acetyl-CoA: alkyl-lyso-sn-glycero-3-phosphate acetyltransferase. The reported studies in which NEC was prevented by intravenous infusion of recombinant PAF-acetylhydrolase provides further documentation as to the importance of PAF in the development of NEC. The specific activity of PAF-acetylhydrolase required for protection by dexamethasone was similar. This finding would be suggestive of the fact that the mechanisms by which dexamethasone causes a complete protection against NEC may be mediated by increasing the plasma activity. Other mechanisms have been proposed such as facilitating the maturation of the small bowel. As discussed, other factors such as hypoxia, endotoxins, TNF alpha, and enternal feeding have been suggested to be contributing agents of NEC development. Many of these factors and procedures are known to increase in PAF. We have suggested a mechanism to explain the increase in PAF formation as caused LPS, TNF alpha, and interleukins being the inhibition of the secretion of PAF-AH by macrophages. Our previous reports on the mechanisms involve in the prevention of NEC by glucocorticoids and the reported findings that human recombinant PAF-acetylhydrolase can prevent NEC provide further support for a central role for PAF in NEC development. Furthermore, the presence of a high PAF biosynthetic activity in the neonatal intestine affords an explanation as to why this tissue is highly susceptible to this disease.
Muguruma
K
K
Department of Biochemistry, Cecil H. & Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center at Dallas 75235-9051, USA.
Gray
P W
PW
Tjoelker
L W
LW
Johnston
J M
JM
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004198:Disease Susceptibility; D004761:Enterocolitis, Pseudomembranous / Q000503:physiopathology* / Q000517:prevention & control; D005326:Fetal Proteins / Q000378:metabolism; D006801:Humans; D007269:Injections, Intra-Arterial; D007421:Intestine, Small / Q000196:embryology / Q000201:enzymology / Q000254:growth & development; D007668:Kidney / Q000196:embryology / Q000201:enzymology / Q000254:growth & development; D008099:Liver / Q000196:embryology / Q000201:enzymology / Q000254:growth & development; D008861:Microsomes / Q000201:enzymology; D008892:Milk / Q000201:enzymology; D009928:Organ Specificity; D010741:Phospholipases A / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D010972:Platelet Activating Factor / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
D005326:Fetal Proteins; D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D003907:Dexamethasone; D000123:Acetyltransferases; C046035:1-alkylglycerophosphocholine acetyltransferase; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase