title: Mechanisms underlying reduced apoptosis in neonatal neutrophils.
abstract: Apoptosis, which leads to phagocytosis by mononuclear cells, represents the primary mechanism for removing neutrophils from inflamed tissues and minimizing injury. The present studies show that membrane phosphatidylserine turnover and permeability, as well as DNA fragmentation, were reduced in neutrophils from neonates when compared with adults. The activity of caspase 3 and expression of the proapoptotic proteins Bax, Bad, and Bak were also decreased in neonatal relative to adult neutrophils. These findings are consistent with impaired apoptosis in neonatal cells, which may contribute to prolonged inflammation in infants after oxidative stress or infection. Neutrophil apoptosis is induced by endogenous ligands such as Fas (FasL), which engage death receptors of the tumor necrosis factor/nerve growth factor superfamily, including Fas receptor (FasR). We found that expression of FasR was decreased in neonatal when compared with adult cells. Moreover, neonatal neutrophils did not undergo apoptosis in response to anti-FasR antibody and exhibited impaired chemotaxis to soluble FasL. However, in both adult and neonatal cells, p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase inhibitors blocked Fas-induced activity. These data suggest that prolonged survival of neonatal neutrophils at injured sites is due, in part, to reduced responsiveness to FasL. This may be related to decreased expression of both FasR and Bcl-2-family proteins that mediate neutrophil apoptosis.
authors.affiliation: Department of Pediatrics, UMDNJ-Robert Wood Johnson Medical School, 1 Robert Wood Johnson Place, New Brunswick, NJ 08903, USA.
authors.forename: Nazeeh
authors.initials: N
authors.lastname: Hanna
authors.forename: Pedro
authors.initials: P
authors.lastname: Vasquez
authors.forename: Petra
authors.initials: P
authors.lastname: Pham
authors.forename: Diane E
authors.initials: DE
authors.lastname: Heck
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
authors.forename: Barry
authors.initials: B
authors.lastname: Weinberger
mesh_terms: D000328:Adult; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002633:Chemotaxis; D053938:DNA Fragmentation; D053222:Fas Ligand Protein; D005312:Fetal Blood / Q000166:cytology; D005434:Flow Cytometry; D006801:Humans; D007231:Infant, Newborn; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D010539:Permeability; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein
chemical_list: C494819:BAD protein, human; C494772:BAK1 protein, human; C494826:BAX protein, human; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010718:Phosphatidylserines; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases