Fetal asphyctic preconditioning modulates the acute cytokine response thereby protecting against perinatal asphyxia in neonatal rats.
BACKGROUND
Perinatal asphyxia (PA) is a major cause of brain damage and neurodevelopmental impairment in infants. Recent investigations have shown that experimental sublethal fetal asphyxia (FA preconditioning) protects against a subsequent more severe asphyctic insult at birth. The molecular mechanisms of this protection have, however, not been elucidated. Evidence implicates that inflammatory cytokines play a protective role in the induction of ischemic tolerance in the adult brain. Accordingly, we hypothesize that FA preconditioning leads to changes in the fetal cytokine response, thereby protecting the newborn against a subsequent asphyctic insult.


METHODS
In rats, FA preconditioning was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global PA was induced by placing the uterine horns, containing the pups, in a saline bath for 19 min. We assessed, at different time points after FA and PA, mRNA and protein expression of several cytokines and related receptor mRNA levels in total hemispheres of fetal and neonatal brains. Additionally, we measured pSTAT3/STAT3 levels to investigate cellular responses to these cytokines.


RESULTS
Prenatally, FA induced acute downregulation in IL-1β, TNF-α and IL-10 mRNA levels. At 96 h post FA, IL-6 mRNA and IL-10 protein expression were increased in FA brains compared with controls. Two hours after birth, all proinflammatory cytokines and pSTAT3/STAT3 levels decreased in pups that experienced FA and/or PA. Interestingly, IL-10 and IL-6 mRNA levels increased after PA. When pups were FA preconditioned, however, IL-10 and IL-6 mRNA levels were comparable to those in controls.


CONCLUSIONS
FA leads to prenatal changes in the neuroinflammatory response. This modulation of the cytokine response probably results in the protective inflammatory phenotype seen when combining FA and PA and may have significant implications for preventing post-asphyctic perinatal encephalopathy.
Department of Pediatrics Division of Neonatology, Maastricht University Medical Center, School for Oncology and Developmental Biology Maastricht (GROW), Maastricht, AZ, 6202, The Netherlands. danilo.gavilanes@mumc.nl
Evi
E
Vlassaks
Eveline
E
Strackx
Johan Sh
JSh
Vles
Maria
M
Nikiforou
Pilar
P
Martinez-Martinez
Boris W
BW
Kramer
Antonio Wd
AW
Gavilanes
D000818:Animals; D000831:Animals, Newborn; D001237:Asphyxia / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines