Activation of extracellular signal-regulated kinases, NF-kappa B, and cyclic adenosine 5'-monophosphate response element-binding protein in lung neutrophils occurs by differing mechanisms after hemorrhage or endotoxemia.
Acute lung injury is frequently associated with sepsis or blood loss and is characterized by a proinflammatory response and infiltration of activated neutrophils into the lungs. Hemorrhage or endotoxemia result in activation of cAMP response element-binding protein (CREB) and NF-kappa B in lung neutrophils as well as increased expression of proinflammatory cytokines, such as TNF-alpha and macrophage-inflammatory peptide-2, by these cells. Activation of the extracellular regulated kinase (ERK) pathway occurs in stress responses and is involved in CREB activation. In the present experiments, hemorrhage or endotoxemia produced increased activation of mitogen-activated protein kinase kinase (MEK)1/2 and ERK2 (p42), but not of ERK1 (p44), in lung neutrophils. ERK1, ERK2, and MEK1/2 were not activated in peripheral blood neutrophils after hemorrhage or endotoxemia. Inhibition of xanthine oxidase led to further increase in the activation of MEK1/2 and ERK2 in lung neutrophils after hemorrhage, but not after endotoxemia. Alpha-adrenergic blockade before hemorrhage resulted in increased activation in lung neutrophils of MEK1/2, ERK1, ERK2, and CREB, but decreased activation of NF-kappa B. In contrast, alpha-adrenergic blockade before endotoxemia was associated with decreased activation of MEK1/2, ERK2, and CREB, but increased activation of NF-kappa B. Beta-adrenergic blockade before hemorrhage did not alter MEK1/2 or ERK1 activation in lung neutrophils, but decreased activation of ERK2 and CREB, while increasing activation of NF-kappa B. Beta-adrenergic inhibition before endotoxemia did not affect activation of MEK1/2, ERK1, ERK2, CREB, or NF-kappa B. These data indicate that the pathways leading to lung neutrophil activation after hemorrhage are different from those induced by endotoxemia.
Abraham
E
E
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Science Center, Denver, CO 80262, USA. Edward.Abraham@UCHSC.edu
Arcaroli
J
J
Shenkar
R
R
D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage; D000821:Animal Feed; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019446:Endotoxemia / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D006470:Hemorrhage / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D007274:Injections, Intraperitoneal; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018375:Neutrophil Activation / Q000187:drug effects; D010646:Phentolamine / Q000008:administration & dosage; D011433:Propranolol / Q000008:administration & dosage; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014414:Tungsten / Q000008:administration & dosage; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D011433:Propranolol; D014969:Xanthine Oxidase; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D014414:Tungsten; D010646:Phentolamine