Mechanisms mediating reduced responsiveness of neonatal neutrophils to lipoxin A4.
Lipoxin A4 is an eicosanoid that plays a key role in the resolution of neutrophilic inflammation. In these studies, we investigated the hypothesis that responses to lipoxin A4 are impaired in neonates, relative to adults. Lipoxin A4 was found to inhibit chemotaxis and respiratory burst in adult neutrophils. In contrast, it had no effect on these activities in neonatal neutrophils. In addition, while lipoxin A4 augmented apoptosis in LPS-treated adult neutrophils, apoptosis in neonatal cells was not affected by lipoxin A4 alone or in combination with LPS. The biologic actions of anti-inflammatory eicosanoids are mediated, in part, via the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Expression of PPAR-gamma mRNA and its target gene, neutrophil gelatinase-associated lipocalin (NGAL), were significantly reduced in neonatal cells when compared with adult cells. Moreover, whereas treatment of adult neutrophils with lipoxin A4 increased PPAR-gamma expression, no effects were observed in neonatal cells. 5- and 15-lipoxygenase, enzymes required for the synthesis of lipoxin A4, were also reduced in neonatal neutrophils. These findings suggest that the anti-inflammatory activity of lipoxin A4 is impaired in neonatal neutrophils and that this is due, in part, to reduced PPAR-gamma signaling. This may contribute to diseases associated with chronic inflammation in neonates.
Weinberger
Barry
B
Department of Pediatrics, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA. weinbebi@umdnj.edu
Quizon
Cecile
C
Vetrano
Anna M
AM
Archer
Faith
F
Laskin
Jeffrey D
JD
Laskin
Debra L
DL
D000328:Adult; D000367:Age Factors; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D002633:Chemotaxis / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007231:Infant, Newborn; D044045:Lipoxins / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects*; D047495:PPAR gamma / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
D044045:Lipoxins; D047495:PPAR gamma; C040527:lipoxin A4; D006861:Hydrogen Peroxide