title: Acute endotoxemia prolongs the survival of rat lung neutrophils in response to 12-O-tetradecanoyl-phorbol 13-acetate.
abstract: Acute endotoxemia is associated with prolonged survival of adherent neutrophils in the lung vasculature. In the present studies, the effects of inflammatory mediators on signaling pathways regulating neutrophil survival were examined. We found that the protein kinase C activator, 12-O-tetradecanoyl-phorbol 13-acetate (TPA), but not interferon-gamma (IFN-gamma), prolonged the survival of adherent vasculature lung neutrophils from endotoxemic rats, a response that was correlated with reduced apoptosis. Although endotoxin administration to rats induced the expression of the anti-apoptotic protein Mcl-1 in lung neutrophils, TPA had no effect on this response. Endotoxin administration also induced expression of total p38 and p44/42 mitogen activated protein kinases (MAPK) in neutrophils, as well as phosphatidyl inositol 3 kinase (PI3K) and its downstream target protein kinase B (PKB). Treatment of the cells with TPA increased p38 MAPK expression in cells from both control and endotoxin treated animals. Cells from endotoxin treated, but not control animals, were found to exhibit constitutive binding activity of nuclear factor kappa B (NF-kappaB) which was blocked by TPA. In contrast, constitutive CCAAT/enhancer binding protein (C/EBP) nuclear binding activity evident in neutrophils from control animals was reduced following endotoxin administration. Moreover, this response was independent of TPA. These data suggest that NF-kappaB plays a role in TPA-induced signaling leading to prolonged survival of adherent vascular neutrophils in the lung during acute endotoxemia.
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Vasanthi R
authors.initials: VR
authors.lastname: Sunil
authors.forename: Agnieszka J
authors.initials: AJ
authors.lastname: Connor
authors.forename: Natasha
authors.initials: N
authors.lastname: Lavnikova
authors.forename: Carol R
authors.initials: CR
authors.lastname: Gardner
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019446:Endotoxemia / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011652:Pulmonary Circulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013755:Tetradecanoylphorbol Acetate