Dual roles of endogenous platelet-activating factor acetylhydrolase in a murine model of necrotizing enterocolitis.
Human preterm infants with necrotizing enterocolitis (NEC) have increased circulating and luminal levels of platelet-activating factor (PAF) and decreased serum PAF-acetylhydrolase (PAF-AH), the enzyme that inactivates PAF. Formula supplemented with recombinant PAF-AH decreases NEC in a neonatal rat model. We hypothesized that endogenous PAF-AH contributes to neonatal intestinal homeostasis and therefore developed PAF-AH mice using standard approaches to study the role of this enzyme in the neonatal NEC model. After exposure to a well-established NEC model, intestinal tissues were evaluated for histology, proinflammatory cytokine mRNA synthesis, and death using standard techniques. We found that mortality rates were significantly lower in PAF-AH pups compared with wild-type controls before 24 h of life but surviving PAF-AH animals were more susceptible to NEC development compared with wild-type controls. Increased NEC incidence was associated with prominent inflammation characterized by elevated intestinal mRNA expression of sPLA2, inducible NOS, and CXCL1. In conclusion, the data support a protective role for endogenous PAF-AH in the development of NEC, and because preterm neonates have endogenous PAF-AH deficiency, this may place them at increased risk for disease.
Department of Pediatrics, Pritzker School of Medicine, University of Chicago, Evanston, IL 60201, USA.
Jing
J
Lu
Marissa
M
Pierce
Andrew
A
Franklin
Tamas
T
Jilling
Diana M
DM
Stafforini
Michael
M
Caplan
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D054360:Chemokine CXCL1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D020345:Enterocolitis, Necrotizing / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D054497:Phospholipases A2, Secretory / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D054360:Chemokine CXCL1; D016207:Cytokines; D010972:Platelet Activating Factor; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; D054497:Phospholipases A2, Secretory; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase