Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Sepsis is the clinical syndrome that results from a host's inflammatory response to infection via activation of the innate immune system. This response involves a complex network of inflammatory mediators that is self-reinforcing. When this immune response progresses uncontrollably, it can ultimately result in cardiovascular collapse and death. This complex inflammatory response is comprised of multiple mediators including cytokines such as TNF-alpha and IL-1beta, that are synthesized and secreted in response to signaling by receptors of the Toll-like receptor (TLR) family of pattern recognition receptors (PRR) that bind to pathogen associated molecules. A central downstream element of TLR-dependent signaling is the pleiotropic transcription factor NF-kappaB. NF-kappaB has been implicated in the regulation of multiple biological phenomena and disease states, including apoptosis, cell growth, stress response, innate immunity and septic shock. NF-kappaB-dependent genes are numerous and several have been implicated in the pathogenesis of sepsis and associated with cardiac dysfunction in sepsis. NF-kappaB activation occurs in multiple organs and cell types, and may be primarily protective in one tissue but injurious in another. Thus, a detailed understanding of the molecular basis of the pathophysiology of sepsis is needed in order to specifically block pro-inflammatory and pro-apoptotic signaling in the heart, while avoiding adverse effects in other organs.
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PMID:NF-kappaB action in sepsis: the innate immune system and the heart. 1497 37

Various proapoptotic stimuli increase the production of superoxide and H(2)O(2) by mitochondria. Whereas superoxide impairs mitochondrial function and is removed by Mn(2+)-dependent superoxide dismutase, the role and metabolism of mitochondrial H(2)O(2) during apoptosis have remained unclear. The effects on apoptotic signaling of depletion of peroxiredoxin (Prx) III, a mitochondrion-specific H(2)O(2)-scavenging enzyme, have now been investigated by RNA interference in HeLa cells. Depletion of Prx III resulted in increased intracellular levels of H(2)O(2) and sensitized cells to induction of apoptosis by staurosporine or TNF-alpha. The rates of mitochondrial membrane potential collapse, cytochrome c release, and caspase activation were increased in Prx III-depleted cells, and these effects were reversed by ectopic expression of Prx III or mitochondrion-targeted catalase. Depletion of Prx III also exacerbated damage to mitochondrial macromolecules induced by the proapoptotic stimuli. Our results suggest that Prx III is a critical regulator of the abundance of mitochondrial H(2)O(2), which itself promotes apoptosis in cooperation with other mediators of apoptotic signaling.
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PMID:Peroxiredoxin III, a mitochondrion-specific peroxidase, regulates apoptotic signaling by mitochondria. 1528 Mar 82

Anesthetized rams envenomed s.c. with 40 microg/kg Tityus discrepans scorpion venom developed fasciculation, hypothermia, polyuria, pulmonary wet rales, tachypnea, respiratory distress and arrhythmia. Rams developed a cascade of inflammation reactions, characterized by activation of macrophages, fibroblasts and neutrophils, neutrophil infiltration and aggregation, vasculitis, arteritis and abundant fibrin deposition. At the inoculation site, venom was detected by immunohistochemistry in the extra cellular matrix, lymphatic vessels' and venules' lumen, inside macrophages and surrounding nerves. Extra cellular matrix was degraded at the inoculation site perhaps by activated neutrophils. Envenoming produced hepatocytes with Mallory body-like vacuoles which may be due to the increased plasmatic levels of TNF-alpha and IL6. Venom produced degranulation and vacuolization of acinary cells as well as interstitial swelling and necrosis. Necrosis of the Langerhan's islets occurred occasionally. Lungs showed the most deleterious effects developing wall collapse and necrosis, diffuse injury of the alveolar capillary barrier, interstitial and alveolar fibrin deposits with strong neutrophil infiltration. Massive infiltration of lymphocytes and macrophage occurred in the intestinal submucose, to the point that it modified villi and intestinal folding morphology. Envenomation developed a marked leukocyte aggregation surrounding nerves at the inoculation site. This study reveals that beyond its neurotoxicity, Tityus venom produces a severe and widespread inflammatory syndrome, expressed as histopathological changes at the site of inoculation, as well as in remote organs such as pancreas, lungs, intestine and liver. Our results suggest that not all remote targets are directly affected by the venom but that, as proposed earlier, are modified by inflammation by products produced elsewhere.
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PMID:Histopathological changes and inflammatory response induced by Tityus discrepans scorpion venom in rams. 1553 Sep 67

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

Bacteria stimulate macrophages as part of normal host defense. However, when this response is not limited, vascular smooth muscle may also be activated to express "vasoactive" genes (e.g., cyclooxygenase), leading to vascular collapse and septic shock. In macrophages, Toll-like receptors (TLRs) 4 and 2 transduce responses to Gram-negative and Gram-positive bacteria, respectively. However, the role of these TLRs in sensing bacteria in vascular smooth muscle is unclear. To address this question, we have cultured vascular smooth muscle cells from mice deficient in TLR4 (TLR4(-/-) mice), mice deficient in TLR2 (TLR2(-/-) mice), or control mice. Cells cultured from control or TLR2(-/-) mice, but not from TLR4(-/-) mice, expressed cyclooxygenase-2 and released increasing levels of prostaglandin E(2) after stimulation with whole Escherichia coli bacteria; the combination of IL-1beta plus TNF-alpha induced cyclooxygenase-2 in cells cultured from all three groups of animals. By contrast, Staphylococcus aureus affected cyclooxygenase-2 expression in two distinct ways. First, S. aureus induced a transient inhibition of cyclooxygenase-2 expression, which was overcome with time, and increased protein expression was noted. The effects of S. aureus on cyclooxygenase-2 expression were TLR2- and not TLR4-dependent. Thus, we show that Gram-positive and Gram-negative bacteria induce cyclooxygenase-2 in vascular smooth muscle with differing temporal profiles but with appropriate TLR2-versus-TLR4 signaling. These data have important implications for our understanding of the innate immune response in vascular cells and how it may impact vascular disease.
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PMID:Role of Toll-like receptors 2 and 4 in the induction of cyclooxygenase-2 in vascular smooth muscle. 1575 14

The authors believe that with fascioscapulohumeral muscular dystrophy (FSHD), like Duchenne muscular dystrophy, there is Ca2+ dysregulation in the muscle cells. The dysregulated Ca2+ can cause cell death in various ways. One mechanism may be Ca2+ triggering abnormal levels of tumor necrosis factor (TNF-alpha). Another mechanism may involve excessive Ca2+ levels within the mitochondria which would cause this organelle's membrane to collapse ultimately inducing apoptosis and/or necrosis. With this in mind, it has been reported that in FSHD there is over expression of adenine nucleotide translocator-1 (ANT-1). This Ca2+ dependent protein, which is a component of the mitochondrial permeability transition pore, could be an important culprit in mitochondrial membrane collapse. Therefore, dysregulated Ca2+ as well as TNF-alpha, in addition to over-expression of ANT-1, may result in cell disruption ultimately causing the characteristic dystrophic muscle wasting. The present investigators have noted that some individuals with FSHD benefit from a regimen of diltiazem, a Ca2+ channel blocker. Initial results using diltiazem may represent the first beneficial treatment for a form of muscular dystrophy. Even if there is only a slowing of progression, this would be a positive first step. A combination of several different Ca2+ regulating agents and TNF-alpha inhibitors may be necessary to truly alter and/or reverse the deleterious effects of this form of muscular dystrophy.
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PMID:Fascioscapulohumeral muscular dystrophy: a progressive degenerative disease that responds to diltiazem. 1596 57

The chemotherapeutic drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) inhibits intratumoural blood flow, causing hypoxia, haemorrhagic necrosis, vascular collapse and tumour cell death. Production of TNF-alpha and IFN is also induced, causing local inflammation and activation of immune cells including CD8+ T cells. We used the tumour cell line LL-LCMV, which expresses the gp33 epitope of lymphocytic choriomeningitis virus in a non-immunogenic form, to investigate whether tumour cell death caused by treatment with DMXAA may improve the success of tumour immunotherapy mediated by CD8+ T cells. Treatment with DMXAA was effective at reducing the size of LL-LCMV tumours. However, compared to normal mice, tumour reduction was no more marked or sustained in mice carrying high numbers of naive, tumour-specific CD8+ T cells. The antitumour effect of activated CD8+ T cells was also not affected by DMXAA treatment. Tumour-specific CD8+ T cells activated in vivo by immunization with dendritic cells and specific tumour peptide antigen, or generated in vitro and adoptively transferred into tumour-bearing mice by i.v. injection, did not improve or sustain the reduction in tumour size induced by DMXAA treatment. We conclude that the presence of high numbers of naive CD8+ T cells, or immunotherapies leading to CD8+ T-cell activation, do not synergize with the tumour cell death and local inflammation induced by DMXAA treatment. It is possible that this lack of synergism may result from both treatments inducing activation of CD8+ T cells and that treatments that activate different populations of immune cells may achieve better success.
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PMID:5,6-Dimethylxanthenone-4-acetic acid treatment of a non-immunogenic tumour does not synergize with active or passive CD8+ T-cell immunotherapy. 1683 73

CD137 is expressed on activated T cells and ligands to this costimulatory molecule have clinical potential for amplifying CD8 T cell immunity to tumors and viruses, while suppressing CD4 autoimmune T cell responses. To understand the basis for this dichotomy in T cell function, CD4 and CD8 antiviral immunity was measured in lymphocytic choriomeningitis virus (LCMV) Armstrong- or A/PR8/34 influenza-infected mice injected with anti-CD137 mAbs. We found that the timing of administration of anti-CD137 mAbs profoundly altered the nature of the antiviral immune response during acute infection. Antiviral immunity progressed normally for the first 72 hours when the mAb was administered early in infection before undergoing complete collapse by day 8 postinfection. Anti-CD137-injected LCMV-infected mice became tolerant to, and persistently infected with, LCMV Armstrong. Elevated levels of IL-10 early in the response was key to the loss of CD4(+) T cells, whereas CD8(+) T cell deletion was dependent on a prolonged TNF-alpha response, IL-10, and upregulation of Fas. Blocking IL-10 function rescued CD4 antiviral immunity but not CD8(+) T cell deletion. Anti-CD137 treatment given beyond 72 hours after infection significantly enhanced antiviral immunity. Mice treated with anti-CD137 mAb 1 day before infection with A/PR8/34 virus experienced 80% mortality compared with 40% mortality of controls. When treatment was delayed until day 1 postinfection, 100% of the infected mice survived. These data show that anti-CD137 mAbs can induce T cell activation-induced cell death or enhance antiviral immunity depending on the timing of treatment, which may be important for vaccine development.
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PMID:Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time dependent. 1785 40

Although the concept that dendritic cells (DCs) recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of Trypanosoma cruzi through the triggering of G-protein-coupled bradykinin B2 receptors (B2R). Here we report that C57BL/6.B2R-/- mice infected intraperitoneally with T. cruzi display higher parasitemia and mortality rates as compared to B2R+/+ mice. qRT-PCR revealed a 5-fold increase in T. cruzi DNA (14 d post-infection [p.i.]) in B2R-/- heart, while spleen parasitism was negligible in both mice strains. Analysis of recall responses (14 d p.i.) showed high and comparable frequencies of IFN-gamma-producing CD4+ and CD8+ T cells in the spleen of B2R-/- and wild-type mice. However, production of IFN-gamma by effector T cells isolated from B2R-/- heart was significantly reduced as compared with wild-type mice. As the infection continued, wild-type mice presented IFN-gamma-producing (CD4+CD44+ and CD8+CD44+) T cells both in the spleen and heart while B2R-/- mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B2R-/- mice was linked to upregulated secretion of IL-17 and TNF-alpha by antigen-responsive CD4+ T cells. In vitro analysis of tissue culture trypomastigote interaction with splenic CD11c+ DCs indicated that DC maturation (IL-12, CD40, and CD86) is controlled by the kinin/B2R pathway. Further, systemic injection of trypomastigotes induced IL-12 production by CD11c+ DCs isolated from B2R+/+ spleen, but not by DCs from B2R-/- mice. Notably, adoptive transfer of B2R+/+ CD11c+ DCs (intravenously) into B2R-/- mice rendered them resistant to acute challenge, rescued development of type-1 immunity, and repressed TH17 responses. Collectively, our results demonstrate that activation of B2R, a DC sensor of endogenous maturation signals, is critically required for development of acquired resistance to T. cruzi infection.
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PMID:Bradykinin B2 Receptors of dendritic cells, acting as sensors of kinins proteolytically released by Trypanosoma cruzi, are critical for the development of protective type-1 responses. 1805 32

The upper airway of obstructive sleep apnoea patients is subjected to recurrent negative pressure swings promoting its collapse and reopening. The aim of the present study was to ascertain whether this mechanical stress induces upper airway inflammation in a rat model. The upper airway of Sprague-Dawley rats was subjected to a periodic pattern of recurrent negative (-40 cmH2O, 1 s) and positive (4 cmH2O, 2 s) pressures inducing collapse and reopening for 5 h. Rats that were instrumented but not subjected to negative pressure swings were used as controls. The gene expression of the pro-inflammatory biomarkers macrophage inflammatory protein (MIP)-2, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and P-selectin in the soft palate and larynx tissues was assessed by real-time PCR. A marked overexpression of MIP-2, TNF-alpha, IL-1beta and P-selectin (approximately 40-, 24-, 47- and 7-fold greater than controls, respectively) was observed in the larynx tissue; similar results were found in the soft palate tissue (approximately 14-, 7-, 35- and 11-fold greater than controls, respectively). Recurrent upper airway collapse and reopening mimicking those experienced by obstructive sleep apnoea patients triggered an early local inflammatory process. These results could explain the inflammation observed in the upper airway of obstructive sleep apnoea patients.
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PMID:Upper airway collapse and reopening induce inflammation in a sleep apnoea model. 1866 83


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