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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Vascular endothelial and smooth muscle cells generate nitric oxide (NO) via different nitric oxide synthase (NOS) isozymes. Activation of the endothelial constitutive NOS (ecNOS) contributes to the maintenance of cardiovascular homeostasis, whereas expression of the endotoxin- and cytokine-inducible pathway (iNOS) within the vascular smooth muscle is thought to be responsible for the cardiovascular collapse which occurs during septic shock and antitumour therapy with cytokines. Since the cytoskeleton is involved in the activation of certain genes and in some effects of endotoxin in macrophages, we investigated the role of microtubules and microfilaments in the activation of the NO pathway in cultured vascular cells. 2. Depolymerization of microtubules by either nocodazole or colchicine prevented lipopolysaccharide (LPS)- and interleukin-1 beta-induction of NO-dependent cyclic GMP accumulation. Steady state levels of iNOS mRNA, assessed by Northern blot and RT-PCR, and iNOS protein, assessed by Western blotting, were also decreased by either colchicine or nocodazole treatment. 3. Taxol enhanced microtubule polymerization alone, and prevented microtubule depolymerization elicited by nocodazole and colchicine. Associated with its effect on microtubule assembly, taxol prevented the inhibitory effects of nocodazole and colchicine on cyclic GMP accumulation and iNOS mRNA levels. 4. Disruption of microfilaments by cytochalasins had no inhibitory effect on the activation of the inducible NO pathway. 5. In contrast to cytokine-stimulated smooth muscle cells, modulation of either microtubule or microfilament assembly did not affect the constitutive NO pathway in endothelial cells, as endothelial cell- and NO-dependent cyclic GMP accumulation in endothelial-smooth muscle co-cultures remained unchanged. 6. Our findings demonstrate that microtubules play a prominent role in the activation of the inducible NO pathway in response to inflammatory mediators in smooth muscle cells but not of the constitutive synthesis of NO in endothelial cells.
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PMID:Cytoskeleton-dependent activation of the inducible nitric oxide synthase in cultured aortic smooth muscle cells. 881 30

Tumor cells engineered to release cytokines are a valuable tool for investigating biological activities elicited by local cytokines. The parental cells of a mouse mammary adenocarcinoma (TSA-pc) were transduced with the cDNA coding for mouse interleukin-10 (IL-10). In vitro, transduced TSA cells secrete about 200 ng of IL-10/10(5) seeded cells in 48 hours (TSA-IL-10). When injected subcutaneously into syngeneic BALB/c mice, TSA-IL-10 cells gave rise to a tumor that grew progressively during the first 7-10 days and then rapidly and completely regressed. To study the events associated with this growth and disappearance, histological, immunohistochemical and ultrastructural analyses of the tumor area were performed at progressive times after challenge. A slow, but progressive and massive recruitment of leukocytes (mainly macrophages and neutrophils) into the tumor was evident. Several CD8+, CD4+ lymphocytes and a few NK cells were present. Marked inhibition of neoangiogenesis was also observed. On day 9, the microvascular network in the growth area had almost vanished, while vascular damage was present in the surrounding stromal tissue. From day 4, down-modulation of VEGF expression in the tumor area and inhibition of tumor necrosis factor-alpha (TNF-alpha) and IL-6 production by reactive leukocytes were evident. The few vessels present in the tumor area displayed poor expression of monocyte chemotactic protein-1 (MCP-1), moderate expression of VCAM-1, and strong expression of ELAM-1, three molecules that result in adhesion of inflammatory cells to the endothelium. A few tumor-infiltrating macrophages were moderately stained with anti-iNOS antibodies. These findings suggest that the collapse of established TSA-IL-10 tumors is the result of the pro- and anti-inflammatory activity of IL-10, which: a) is a signal for the local recruitment of leukocytes; b) leads to vascular damage; c) suppresses cytokine production. The coexistence of both a direct stimulatory activity on endothelial cells and an anti-angiogenic activity is evidence of the ambivalence of the local effects of IL-10.
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PMID:Local release of interleukin-10 by transfected mouse adenocarcinoma cells exhibits pro- and anti-inflammatory activity and results in a delayed tumor rejection. 961 79

Septic shock is a major cause of death following trauma and is a persistent problem in surgical patients throughout the world. It is characterised by hypotension and vascular collapse, with a failure of the major organs within the body. The role of excessive nitric oxide (NO) production, following the cytokine-dependent induction of the inducible nitric oxide synthase (iNOS), in the development of septic shock is discussed. Emphasis is placed upon the signal-transduction process by which iNOS is induced and the role of NO in cellular energy dysfunction and the abnormal function of the cardiovascular system and liver during septic shock.
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PMID:Nitric oxide in septic shock. 1032 Jun 74

1. Previous study suggested that cyclosporine A (CsA) could partially reduce ischaemia/reperfusion-induced injury in isolated heart, but the mechanism was still unclear. In this study, the possible mechanisms of cyclosporine A in regulating oxidative stress-induced cardiomyocyte apoptosis were examined. 2. Morphological (cell shrinkage, apoptotic body formation, and DNA fragmentation) and biochemical (annexin-V staining for exposed phosphatidylserine residues) evidences showed that both hydrogen peroxide (H(2)O(2)) and hypoxia/reoxygenation could induce apoptotic change in the embryonal rat heart myoblast-derived cells (H9c2). These effects were inhibited by pre-treatment with CsA at concentration of 0.01-1.0 micro M for 24 h, but were increased with 10.0 micro M CsA. 3. While examining the mechanisms of CsA in protecting cardiomyocyte apoptosis, we found that the collapse of mitochondria membrane potential (DeltaPsim) induced by oxidative stress was partially reversed by CsA (0.01-1.0 micro M). 4. Compared to the control, CSA at the concentration of 0.1 and 10.0 micro M significantly increased the level of intracellular reactive oxygen species (ROS) to 117.2+/-12.4% and 234.4+/-9.3%, respectively. Co-incubating with the antioxidant, ascorbic acid (10.0 micro M), could partially reduce the protective effect of CsA (0.01-1.0 micro M) and the toxic effect of 10.0 micro M CsA. 5. Pre-treatment with CsA at concentration of 0.01-1.0 micro M for 24 h produced up-regulation of heat shock protein 70 (Hsp 70), inducible nitric oxide synthase (iNOS) and also induced NO production, indicating that these factors might be associated with the cell protective effects of CsA. 6. These results suggest that CsA could protect the oxidative stress-induced cardiomyocyte apoptosis not only by preventing the loss of DeltaPsim in mitochondria, but also through ROS generation, Hsp70, and iNOS up-regulation.
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PMID:Cyclosporine A regulate oxidative stress-induced apoptosis in cardiomyocytes: mechanisms via ROS generation, iNOS and Hsp70. 1241 7

Accumulating evidence suggests that inflammation may play an important part in neurodegenerative diseases such as Alzheimer's disease. Inflammation itself, however, is insufficient to produce acute neurodegeneration in vivo. In this report, we determined whether inflammation increases excitotoxicity in hippocampal neurons. A proinflammagen, bacterial endotoxin lipopolysaccharide, was coinjected with ibotenate, an N-methyl-D-aspartate receptor agonist, into rat hippocampus. One week after coinjection, significant neuronal degeneration and severe tissue collapse were observed in the hippocampus. Astroglial and microglial infiltration were also detected. The neurodegeneration was suppressed by dizocilpine maleate, an N-methyl-D-aspartate receptor antagonist. We then examined whether microglial activation takes part in synergistic neuronal loss. One day after the lipopolysaccharide injection into the rat hippocampus, substantial microglial activation and induction of inducible nitric oxide synthase were observed, while neither neuronal nor astrocytic changes were detected. On the other hand, ibotenate injection at the same place 1 day after lipopolysaccharide injection in the hippocampus produced significant neuronal degeneration and gross microglial activation. These results suggest that inflammation by lipopolysaccharide might play an important role in ibotenate/lipopolysaccharide neurotoxicity.
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PMID:Acute neuroinflammation exacerbates excitotoxicity in rat hippocampus in vivo. 1242 14

We studied temporal changes in mRNA expression patterns for nitric oxide synthase (NOS), cytokines, neurotrophins and neurotrophin receptors in the dorsal root ganglion (DRG) of the rat, after application of a tourniquet to the hind limb. Collapsed myelin and degenerated axons were observed in the tourniquet segment of the sciatic nerve. Gene expression level of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) was significantly increased in ipsilateral DRG samples at 4h after application of the tourniquet but not in the contralateral or control DRG samples. Upregulation of tumor necrosis factor (TNF)-alpha, activating transcription factor (ATF)-3 and neurotrophin-3 (NT3) expressions began at 1h after application of the tourniquet in ipsilateral DRGs. It is likely that transient expression of these molecules triggers secondary events that may be beneficial to wound repair and regeneration.
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PMID:Expression of cytokines, neurotrophins, neurotrophin receptors and NOS mRNA in dorsal root ganglion of a rat tourniquet model. 1293 8

Septic shock, a severe form of sepsis, is characterized by cardiovascular collapse following microbial invasion of the body. The progressive hypotension, hyporeactivity to vasopressor agents and vascular leak leads to circulatory failure with multiple organ dysfunction and death. Many inflammatory mediators (e.g. TNF-alpha, IL-1 and IL-6) are involved in the pathogenesis of shock and, among them, nitric oxide (NO). The overproduction of NO during septic shock has been demonstrated to contribute to circulatory failure, myocardial dysfunction, organ injury and multiple organ failure. We have previously demonstrated with in vitro and in vivo studies that methylguanidine (MG), a guanidine compound deriving from protein catabolism, significantly inhibits iNOS activity, TNF-alpha release and carrageenan-induced acute inflammation in rats. The aim of the present study was to evaluate the possible anti-inflammatory activity of MG in a model of septic shock induced by lipopolysaccharide (LPS) in mice. MG was administered intraperitoneally (i.p.) at the dose of 30 mg/kg 1 h before and at 1 and 6 h after LPS-induced shock. LPS injection (10 mg/kg in 0.9% NaCl; 0.1 ml/mouse; i.p.) in mouse developed a shock syndrome with enhanced NO release and liver, kidney and pancreatic damage 18 h later. NOx levels, evaluated as nitrite/nitrate serum levels, was significantly reduced in MG-treated rats (78.6%, p < 0.0001; n = 10). Immunohistochemistry revealed, in the lung tissue of LPS-treated group, a positive staining for nitrotyrosine and poly(adenosine diphosphate [ADP] ribose) synthase, both of which were reduced in MG-treated mice. Furthermore, enzymatic evaluation revealed a significant reduction in liver, renal and pancreatic tissue damage and MG treatment also improved significantly the survival rate. This study provides evidence that MG attenuates the degree of inflammation and tissue damage associated with endotoxic shock in mice. The mechanisms of the anti-inflammatory effect of MG is, at least in part, dependent on the inhibition of NO formation.
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PMID:Effect of methylguanidine in a model of septic shock induced by LPS. 1562 90

Recent studies demonstrate that the hepatic sinusoidal endothelial cells (SEC) are a sensitive direct target for early toxicity to acetaminophen (paracetamol, APAP) and this toxicity is exacerbated following a single and multiple week-end type alcoholic binge(s). SEC become swollen and begin to lose the ability to endocytose FITC-FSA, a ligand for the scavenger receptor, as early as 30 minutes after the administration of APAP. Gaps through the SEC appear to be formed by the destruction and/or coalescence of fenestrae and are seen as early as 2 hrs after the administration of APAP which is prior to any evidence of injury to parenchymal cells. The gaps permit red blood cells to penetrate into the Space of Disse. Subsequently, the sinusoid may collapse or disintegrate reducing blood flow. The gaps are larger and more frequent in ethanol binged animals subsequently treated with APAP. Similar gaps are seen in the early stages of hepatic venoocclusive disease. Administration of a NO donor or a MMP-2 and MMP-9 inhibitor minimizes endothelial injury and red blood cell penetration into the Space of Disse. The injury is exacerbated when an inhibitor of eNOS is administered and minimized when iNOS is inhibited suggesting a protective role for constitutive NO derived from SEC. Both NO and MMPs are known to affect the cytoskeleton of SEC which in turn affects the formation and maintenance of the fenestrae.
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PMID:Sinusoidal endothelial cells as an early target for hepatic toxicants. 1654 12

Anaphylactic shock is a sudden, life-threatening allergic reaction associated with severe hypotension. Platelet-activating factor (PAF) is implicated in the cardiovascular dysfunctions occurring in various shock syndromes, including anaphylaxis. Excessive production of the vasodilator NO causes inflammatory hypotension and shock, and it is generally accepted that transcriptionally regulated inducible iNOS is responsible for this. Nevertheless, the contribution of NO to PAF-induced shock or anaphylactic shock is still ambiguous. We studied PAF and anaphylactic shock in conscious mice. Surprisingly, hyperacute PAF shock depended entirely on NO, produced not by inducible iNOS, but by constitutive eNOS, rapidly activated via the PI3K pathway. Soluble guanylate cyclase (sGC) is generally regarded as the principal vasorelaxing mediator of NO. Nevertheless, although methylene blue partially prevented PAF shock, neither 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) nor sGCalpha1 deficiency did. Also, in 2 different models of active systemic anaphylaxis, inhibition of NOS, PI3K, or Akt or eNOS deficiency provided complete protection. In contrast to the unsubstantiated paradigm that only excessive iNOS-derived NO underlies cardiovascular collapse in shock, our data strongly support the unexpected concept that eNOS-derived NO is the principal vasodilator in anaphylactic shock and define eNOS and/or PI3K or Akt as new potential targets for treating anaphylaxis.
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PMID:Anaphylactic shock depends on PI3K and eNOS-derived NO. 1688 52

Triptolide, a major active component extracted from the root of Tripterygium wilfordii Hook f, has been shown to possess potent immunosuppressive and anti-inflammatory properties. In the present report, we reported that triptolide increased the generation of reactive oxygen species (ROS) and nitric oxide (NO) and induced apoptosis of RAW 264.7 cells in a dose-dependent manner (5-25 ng/ml). The antioxidant, reduced glutathione (GSH), significantly inhibited triptolide-induced apoptosis and inhibited the degradation of Bcl-2 protein, disruption of mitochondrial membrane potential, release of cytochrome c from mitochondria into the cytosol, activation of caspase-3, and cleavage of poly-(ADP-ribose)-polymerase. The inducible nitric oxide synthase-specific inhibitor 1400w blocked triptolide-induced apoptosis, but did not alter mitochondria disruption and caspase-3 activation. These results, for the first time, implicated that the increased endogenous ROS and NO co-mediated triptolide-induced apoptosis in macrophages. ROS initiated triptolide-induced apoptosis by the mitochondria signal pathway, while the apoptotic cell death mediated by NO was not via mitochondria collapse and caspase-3 activation. In addition, combining mathematical calculation and computer simulation based on our conventional experimental results, we set and validated the apoptotic model and provided more dynamic processes of triptolide-induced apoptotic cascade in macrophages.
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PMID:The roles of endogenous reactive oxygen species and nitric oxide in triptolide-induced apoptotic cell death in macrophages. 1710 29


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