Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of human neutrophils by LPS is central to the pathogenesis of sepsis and the adult respiratory distress syndrome. The intracellular signaling pathway that results in cellular responses following LPS stimulation in neutrophils is unknown. We report that exposure of neutrophils to LPS results in the phosphorylation and activation of a p38 mitogen-activated protein (MAP) kinase, occurring in a concentration-dependent manner, with maximum response at 20 to 25 min. Partial purification of a p38 MAP kinase by ion exchange chromatography established it as distinct from the p42/p44 (extracellular signal-regulated kinases (ERK-1 and ERK-2) MAP kinases). Activation of the p38 MAP kinase by LPS in human neutrophils occurs via CD14, a proposed LPS receptor, and requires the presence of plasma containing the LPS-binding protein. This intracellular signaling pathway is independent of protein kinase C and does not involve Raf, MAP/ERK kinase kinase-1, MAP/ERK kinase-1, or MAP/ERK kinase-2 and does not result in the activation of the p42/p44 ERK MAP kinases or the c-jun N-terminal kinases.
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PMID:Activation of a p38 mitogen-activated protein kinase in human neutrophils by lipopolysaccharide. 864 36

Hypertonic saline (HS) resuscitation has recently gained attention from trauma physicians because it may benefit the immune system of trauma patients. We have found that HS augments in vitro and in vivo immune function of healthy T-cells. In addition, HS restored the function of suppressed T-cells in vitro and in vivo and reduced immunosuppression after hemorrhage, protecting mice from subsequent sepsis. These effects of HS are based on its direct influence on cellular signaling events through specific signaling pathway(s) that include protein tyrosine kinase and mitogen-activated protein kinase p38 activation. HS provides a costimulatory signal that enhances the proliferation of activated T-cells. HS may be able to substitute signals lost through blockage as a result of trauma induced suppressive factors, thereby restoring the function of suppressed T-cells. Although further work is needed to determine the optimal conditions and possible risks of HS resuscitation, the data presented in this short review of our recent work shed a favorable light on HS as a simple but effective tool to modulate cellular immune function after trauma.
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PMID:Hypertonic saline resuscitation: a tool to modulate immune function in trauma patients? 932 23

Cell wall compounds of gram-positive bacteria are capable of inducing the biosynthesis of proinflammatory cytokines in CNS cells in a similar way as lipopolysaccharide (LPS) of gram-negative bacteria does. Astrocytes, which lack the CD14 LPS receptor, have also been shown to respond to LPS-stimulation by increased cytokine synthesis. However, almost nothing is known about signaling steps involved in this process. We have therefore examined signaling events in primary cultures of rat astrocytes and the human astrocytoma cell line U373MG, brought about by LPS and pneumococcal cell walls (PCW). Of particular interest to us was the tyrosine phosphorylation patterns and activation states of three members of the mitogen activated protein kinase (MAPK) family, i.e., extracellular signal-regulated protein kinase (erk)-1, erk-2, and the recently identified p38. We show that LPS and PCW initiate tyrosine phosphorylation and activation of erk-1, erk-2, and p38 in a dose-dependent fashion. Inhibitors of tyrosine phosphorylation were able to alleviate this effect and also blocked cytokine production of astrocytes. Both, LPS- and PCW-induced responses of astrocytic cells required the presence of soluble CD14 (sCD14) present in serum. Unraveling the signaling steps induced by bacterial compounds in cells of the CNS may potentially help to elucidate the pathomechanisms of meningitis and central nervous complications of sepsis and may offer options for novel treatment strategies.
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PMID:Lipopolysaccharide and pneumococcal cell wall components activate the mitogen activated protein kinases (MAPK) erk-1, erk-2, and p38 in astrocytes. 948 15

Tyrosine kinase blockers from the AG 126/AG-556 tyrphostin family are shown to inhibit the lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNFalpha), nitric oxide (NO), and prostaglandin E2 (PGE2) in primary rat astrocytes cultures. The tyrphostin AG-556 which was previously shown to be effective against sepsis in mice and dogs also show excellent efficacy in inhibiting experimental autoimmune encephalomyelitis (EAE) in mice. AG-556 does not block the activation of JNK/SAPK and of p38/HOG and therefore seems to act at a target down stream to these kinases which is activated in stress or at a target on an obligatory parallel pathway. These findings together with previous results showing inhibition of sepsis in mice and dogs suggest that protein tyrosine kinase (PTK) blockers of the AG-556 family may be considered in the management of human autoimmune disorders such as multiple sclerosis (MS).
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PMID:Suppression of experimental autoimmune encephalomyelitis by tyrphostin AG-556. 987 84

Altered endotoxin (LPS) signal transduction in macrophages (Mphi) may mediate development of organ dysfunction in sepsis. C3H/HeJ Mphi have a specific genetic defect that renders them "tolerant" to in vitro LPS activation. LPS tolerance can be induced in normal C3H/HeN Mphi following in vitro LPS pretreatment. In these experiments, in vitro LPS-stimulated activation of Mphi mitogen-activated protein (MAP) kinases were compared in C3H/HeJ and C3H/HeN mice. C3H/HeJ and C3H/HeN Mphi were cultured+/-10 ng/mL LPS pretreatment for 24 h, then stimulated with 0-1,000 ng/mL LPS for 6 h. Western blots were performed on lysates with monoclonal antibody to active ERK1,2 (p42/44), stress-activated protein kinase (SAPK, p54/46), and p38 kinase. Supernatant TNF or IL-1 was determined by bioassay. High dose LPS stimulation activated ERK, SAPK, and p38 kinases in both C3H/HeN and C3H/HeJ Mphi. ERK activation, p46 SAPK, and p38 activation were inhibited in C3H/HeN Mphi after LPS pretreatment, whereas they were unchanged or increased in HeJ Mphi. TNF secretion was significantly decreased in C3H/HeN Mphi following LPS pretreatment, but absent in C3H/HeJ Mphi at all times. Mphi from normal C3H/HeN mice rendered endotoxin tolerant by in vitro, low dose LPS pretreatment have specific signal transduction defects that are not present in genetically LPS hyporesponsive C3H/HeJ mice.
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PMID:In vitro macrophage endotoxin tolerance: defective in vitro macrophage map kinase signal transduction after LPS pretreatment is not present in macrophages from C3H/HeJ endotoxin resistant mice. 992 18

A critical feature of sepsis-induced acute lung injury is the release of cytokines from endotoxin (LPS)- stimulated alveolar macrophages (AM). LPS is also known to activate various members of the mitogen- activated protein kinase (MAPK) family in other types of cells. In this study, we evaluated whether multiple members of the MAPK family regulate cytokine gene expression in LPS-stimulated AM. We found that LPS activates both the extracellular signal-regulated kinase (Erk) and p38 kinases, and that this activation is augmented when the cells are cultured in serum. Inhibition of either the Erk (with PD98059) or p38 (with SB203580) kinase pathway resulted in only a partial reduction in cytokine (interleukin-6 and tumor necrosis factor) messenger RNA accumulation and cytokine release, whereas inhibition of both pathways simultaneously resulted in a decrease in cytokine gene expression to near-control levels. Nuclear run-on assays showed that the effect of these MAPK pathways on LPS-induced expression of the cytokine genes was attributable, at least in part, to regulation of gene transcription. These findings suggest that activation of both the Erk and p38 kinase pathways is necessary for optimal cytokine gene expression in LPS-stimulated human AM, and that the MAPK pathways play a critical role in the inflammatory response that occurs in sepsis-induced acute lung injury.
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PMID:Both Erk and p38 kinases are necessary for cytokine gene transcription. 1010 Oct 8

During gram-negative sepsis, human monocytes are triggered to produce large quantities of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) in response to endotoxin (lipopolysaccharide [LPS]). Several studies have identified signal transduction pathways that are activated by LPS, including activation of nuclear factor-kappaB (NF-kappaB) and activation of mitogen-activated protein kinases (MAPKs), including ERK1 and ERK2, c-Jun N-terminal kinase, and p38. In this study, the relevance of ERK1 and ERK2 activation for LPS-induced TNF-alpha production by primary human monocytes has been addressed with PD-098059, which specifically blocks activation of MAPK kinase (MEK) by Raf-1. TNF-alpha levels in the monocyte culture supernatant, induced by 10 ng of LPS/ml, were reduced by PD-098059 (50 microM). In addition, PD-098059 also reduced TNF-alpha mRNA expression when cells were stimulated for 1 h with LPS. On the other hand, LPS-induced interleukin-10 (IL-10) levels in the monocyte supernatant were only slightly inhibited by PD-098059. Ro 09-2210, a recently identified MEK inhibitor, completely abrogated TNF-alpha levels at nanomolar concentrations. IL-10 levels also were strongly reduced. To show the efficacy of PD-098059 and Ro 09-2210, ERK1 and -2 activation was monitored by Western blotting with an antiserum that recognizes the phosphorylated (i.e., activated) forms of ERK1 and ERK2. Addition of LPS to human monocytes resulted in activation of both ERK1 and ERK2 in a time- and concentration (50% effective concentration between 1 and 10 ng of LPS/ml)-dependent manner. Activation of ERK2 was blocked by PD-098059 (50 microM), whereas ERK1 seemed to be less affected. Ro 09-2210 completely prevented LPS-induced ERK1 and ERK2 activation. LPS-induced p38 activation also was prevented by Ro 09-2210. These data further support the view that the ERK signal transduction pathway is causally involved in the synthesis of TNF-alpha by human monocytes stimulated with LPS.
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PMID:Lipopolysaccharide-induced tumor necrosis factor alpha production by human monocytes involves the raf-1/MEK1-MEK2/ERK1-ERK2 pathway. 1041 44

The central nervous dysfunctions of lethargy, fever and anorexia are manifestations of sepsis that seem to be mediated by increased cytokine production. Here we demonstrate that tumor necrosis factor (TNF)-alpha, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent degradation of RGS7, a regulator of G-protein signaling. The stabilization of RGS7 by TNF-alpha requires activation of the stress-activated protein kinase p38 and the presence of candidate mitogen-activated protein kinase phosphorylation sites. In vivo, RGS7 is rapidly upregulated in mouse brain after exposure to either endotoxin or TNF-alpha, a response that is nearly abrogated in mice lacking TNF receptor 1. Our findings indicate that TNF-mediated upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function.
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PMID:Upregulation of RGS7 may contribute to tumor necrosis factor-induced changes in central nervous function. 1042 8

Adult respiratory distress syndrome (ARDS) characterized by permeability edema is observed in severe insults such as bacteremia sepsis. Interleukin (IL)-8, which chemoattracts and activates neutrophils, has been suggested to play an important role in the production of ARDS. Therefore, the inhibition of IL-8 production is an important strategy for the treatment of ARDS. Recent studies have revealed the role of p38 mitogen-activated protein (MAP) kinase in cytokine expression and the inhibition by a selective inhibitor of p38 MAP kinase activity of cytokine expression in a variety of cell types. However, little is known about the role of p38 MAP kinase in lipopolysaccharide (LPS)-induced IL-8 expression in pulmonary vascular endothelial cells and the effect of a selective p38 MAP kinase inhibitor on it. In the present study, we therefore attempted to clarify these issues. The results showed that LPS induced p38 MAP kinase phosphorylation and activity, and SB 203580 as a selective inhibitor of p38 MAP kinase activity inhibited p38 MAP kinase activity and IL-8 expression in LPS-stimulated pulmonary vascular endothelial cells. These results indicate that p38 MAP kinase regulates LPS-induced IL-8 expression in pulmonary vascular endothelial cells. Although it is currently not known whether SB 203580 is capable of producing beneficial effects on ARDS, a strategy of inhibiting p38 MAP kinase activity by a selective p38 MAP kinase inhibitor may apply to the therapy for ARDS.
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PMID:Selective inhibitor of p38 mitogen-activated protein kinase inhibits lipopolysaccharide-induced interleukin-8 expression in human pulmonary vascular endothelial cells. 1077 4

A stress-activated serine/threonine protein kinase, p38 mitogen-activated protein kinase (p38 MAPK), belongs to the MAP kinase superfamily. Diverse extracellular stimuli, including ultraviolet light, irradiation, heat shock, high osmotic stress, proinflammatory cytokines and certain mitogens, trigger a stress-regulated protein kinase cascade culminating in activation of p38 MAPK through phosphorylation on a TGY motif within the kinase activation loop. p38 MAPK appears to play a major role in apoptosis, cytokine production, transcriptional regulation, and cytoskeletal reorganization, and has been causally implicated in sepsis, ischemic heart disease, arthritis, human immunodeficiency virus infection, and Alzheimer's disease. The availability of specific inhibitors helps to clarify the role that p38 MAPK plays in these processes, and may ultimately offer therapeutic benefit for certain critically ill patients.
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PMID:MAP kinase pathways activated by stress: the p38 MAPK pathway. 1080 18


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