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)

The paper presents the molecular biology and biological activity of IL-1 alpha, IL-1 beta and IL-1 receptor antagonist. The role of IL-1 family in pathogenesis of a various disease including myeloid leukemias and other neoplastic diseases, diabetes mellitus, inflammatory diseases, sepsis syndrome and atherosclerosis is presented. Potential therapeutic value of IL-1 and IL-1 receptor antagonist is also discussed.
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PMID:[Biological properties and clinical importance of interleukin 1]. 865 31

Cellular adhesion is mediated by distinct cell surface receptors (adhesion molecules) and plays a pivotal role in the biological processes of morphogenesis, cell migration and cell-cell communication. During the past decade many adhesion molecules have been identified and structurally analysed. This has allowed an understanding of their role in the pathophysiology of disease, including inflammation and sepsis, ischaemia and reperfusion, transplant rejection, atherosclerosis and thrombosis, angiogenesis and wound healing, as well as carcinogenesis and tumour metastasis. Understanding of the molecular mechanisms of cellular communication is not only vital for advances in surgical pathophysiology, it also has the potential to widen the spectrum of diagnosis and therapy of disease. Analysis of expression of individual surface molecules may help in the diagnosis of transplant rejection and allow a prognostic determination of tumour progression and metastasis formation. Moreover, manipulation of adhesion molecule function by monoclonal antibodies, antisense oligonucleotides or single gene products may open the door for novel therapeutic regimens to prevent transplant rejection and ischaemia-, sepsis- and shock-induced tissue injury.
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PMID:Adhesion molecules as determinants of disease: from molecular biology to surgical research. 868 99

Nitric oxide (NO) may be produced in the vascular wall by different NO synthases. One of the constitutive isoforms, the endothelial NO synthase, contributes to the regulation of vascular tone and may prevent unwanted platelet and leucocyte adhesion to the endothelial surface. The release of NO by the endothelial NO synthase is exquisitely regulated by increases of intracellular free calcium following endothelial receptors activation by shear stress, neuromediators, hormones or platelet products. The immediate and transient release of NO diffuses towards the underlying smooth muscle and contributes to the appropriate response to local changes in blood flow or composition. The endothelial release of NO depends also on the availability of NO synthase cofactors; in addition, several experimental evidences suggest a transcriptional and postranscriptional regulation of the endothelial NO synthase itself. Another isoform of NO synthase insensitive to changes in intracellular calcium may be induced following exposure to cytokines or under some pathological conditions such as sepsis, inflammation or after vessel wall injury. The massive and long-lasting release of NO caused by induction of NO synthase requires a latency period of several hours. The inducible NO synthase may compensate the dysfunction of the endothelial isoform after injury (angioplasty) or in atherosclerosis. However, uncontrolled regulation of inducible NO synthase expression may have deleterious consequences on the vascular wall.
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PMID:[Endothelial NO synthase]. 876 34

Tissue factor, a member of the cytokine-receptor superfamily and high-affinity receptor and cofactor for plasma factor VII/VIIa (ref. 1), is the primary cellular initiator of blood coagulation. It is involved in thrombosis and inflammation associated with sepsis, atherosclerosis and cancer, and can participate in other cellular processes including intracellular signalling, metastasis, tumor-associated angiogenesis, and embryogenesis. Here we report that inactivation of the tissue factor gene (TF) results in abnormal circulation from yolk sac to embryo beyond embryonic day 8.5, leading to embryo wasting and death. Vitelline vessels from null mice were deficient in smooth-muscle alpha-actin-expressing mesenchymal cells, which participate in organization of the vessel wall. This implies that tissue factor has a role in blood vessel development.
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PMID:Role of tissue factor in embryonic blood vessel development. 877 17

The plasmin/plasminogen system of enzymes may be involved in leukocyte migration through the endothelial cell layer of the vascular wall during inflammatory processes associated with vascular injury, atherosclerosis, and sepsis. Synthesis of plasminogen activator inhibitor type 1 (PAI-1) by the endothelium may protect these cells and the subendothelial cell matrix from excessive degradation and retard leukocyte migration. We report in this work for the first time the down-regulation of both basal and thrombin- or endotoxin-induced PAI-1 in cultured human endothelial cells by the activated T cell product, IFN-gamma. Down-regulation of basal and thrombin- or endotoxin-induced endothelial PAI-1 protein by IFN-gamma was found to be both time and dose dependent. Decreases of up to 71% relative to thrombin- or endotoxin-treated controls, using an optimal IFN-gamma concentration of between 20 and 200 U/ml, were found for human macrovascular and microvascular endothelial cells. However, IFN-gamma did not appear to affect IL-1 alpha- and TNF-alpha-induced levels of PAI-1 protein or mRNA in these cells. Northern blot analysis paralleled protein results, showing decreases in specific endothelial cell thrombin- or LPS-induced PAI-1 mRNA expression, respectively, after incubation with IFN-gamma for 24 h. These results suggest a means by which the migration of circulating leukocytes through endothelial cell layers during inflammation may be facilitated.
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PMID:IFN-gamma inhibits thrombin- and endotoxin-induced plasminogen activator inhibitor type 1 in human endothelial cells. 880 64

Peroxynitrite is a potent oxidant formed endogenously by the near diffusion-limited reaction of nitric oxide with superoxide anion. Peroxynitrite specifically adds a nitro group to the ortho position of the phenolic ring of free and protein-associated tyrosines to form the stable product 3-nitro-L-tyrosine. Systemic administration of 3-nitro-L-tyrosine markedly inhibits the subsequent hemodynamic responses to alpha 1- and beta-adrenoceptor agonists in anesthetized rats. Angiotensin II is an important modulator of vascular tone. The vasoconstrictor effects of this hormone are known to involve the release of catecholamines from sympathetic tissues. In the present study, we examined whether 3-nitro-L-tyrosine (2.5 mumol/kg i.v.) would attenuate the hemodynamic responses produced by angiotensin II (0.1-1.0 microgram/kg i.v.). Angiotensin II produced increases in mean arterial pressure, and renal and mesenteric vascular resistances, but no changes in hindquarter vascular resistance. The pressor and renal and mesenteric vasoconstrictor responses produced by angiotensin II were significantly attenuated 30-60 min following the administration of 3-nitro-L-tyrosine. Further attenuation of these responses was evident 120-180 min following the administration of 3-nitro-L-tyrosine. The alpha 1-adrenoceptor antagonist prazosin also diminished the pressor and renal and mesenteric vasoconstrictor responses produced by angiotensin II. These results demonstrate that 3-nitro-L-tyrosine inhibits the hemodynamic responses to angiotensin II, possibly through the inhibition of alpha 1-adrenoceptor-mediated events. The effect of 3-nitro-L-tyrosine on the hemodynamic action of angiotensin II raises the possibility that 3-nitro-L-tyrosine may be involved in the pathogenesis of the hemodynamic disturbances associated with inflammatory conditions, such as atherosclerosis, ischemia-reperfusion, and sepsis, where formation of peroxynitrite is favored.
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PMID:The peroxynitrite product 3-nitro-L-tyrosine attenuates the hemodynamic responses to angiotensin II in vivo. 896 Aug 80

Leukocyte recruitment from the circulation into inflammatory tissues requires a series of soluble and cell-bound signals between the responding leukocyte and vascular endothelial barrier. Chemotactic factors are believed to be responsible for this selective adhesion and transmigration. A superfamily of small, soluble, structurally-related molecules called 'chemokines' have been identified and shown to selectively promote the rapid adhesion and chemotaxis of a variety of leukocyte subtypes both in vivo and in vitro. Chemokines are produced by almost every cell type in the body in response to a number of inflammatory signals, in particular those which activate leukocyte-endothelial cell interactions. These molecules also appear to play important roles in hematopoesis, cellular activation, and leukocyte effector functions. In addition, chemokines have been found in the tissues of a variety of disease states characterized by distinct leukocytic infiltrates, including rheumatoid arthritis, sepsis, atherosclerosis, asthma, psoriasis, ischemia/reperfusion injury, HIV replication, and a variety of pulmonary disease states. This review will primarily focus on the role of chemokines in cell adhesion and trafficking as well as their role as effector molecules.
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PMID:Chemokine-leukocyte interactions. The voodoo that they do so well. 902 58

VEGF has been proposed to participate in normal and pathological vessel formation. Surprisingly, lack of only a single VEGF allele resulted in embryonic lethality due to abnormal formation of intra- and extra-embryonic vessels. Homozygous VEGF-deficient embryos, generated by tetraploid aggregation, revealed an even more severe defect in vessel formation. These results (1) suggest a tight regulation of early vessel development by VEGF and, indirectly, the presence of other VEGF-like molecules; (2) reveal an unprecedented lethal phenotype associated with heterozygous deficiency of an autosomal gene, and (3) demonstrate that tetraploid aggregation was a valid and the only method to study the phenotype of the homozyogous VEGF-deficient embryos. The dominant and strict dose-dependent role of VEGF in vivo renders this molecule a desirable therapeutic target for promoting or preventing angiogenesis. Tissue factor (TF) is the principal cellular initiator of coagulation and its deregulated expression has been related to thrombogenesis in sepsis, cancer, and inflammation. However, TF appears to be also involved in a variety of non-hemostatic functions including inflammation, cancer, brain function, immune response, and tumor-associated angiogenesis. Surprisingly, TF deficiency resulted in embryonic lethality due to abnormal extra-embryonic vessel development and defective vitelloembryonic circulation. The abnormal yolk sac vasculature is reminiscent of that observed in embryos lacking VEGF, possibly suggesting that both gene functions are interconnected. These targeting studies extend the recently documented role of TF in tumor-associated angiogenesis and warrant further study of its role in angiogenesis during other pathological disorders. The plasminogen system, via its triggers, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), has been implicated in thrombosis, arterial neointima formation, and atherosclerosis. Studies in mice with targeted gene inactivation of t-PA, u-PA, PAI-1, the urokinase receptor (u-PAR), and plasminogen (Plg) revealed (1) that deficiency of t-PA or u-PA increase the susceptibility to thrombosis associated with inflammation and that combined deficiency of t-PA:u-PA or deficiency of Plg induces severe spontaneous thrombosis; (2) that vascular injury-induced neointima formation is reduced in mice lacking u-PA-mediated plasmin proteolysis, unaltered in t-PA- or u-PAR-deficient mice and accelerated in PAI-1-deficient mice, but that it can be reverted by adenoviral PAI-1 gene transfer; and (3) that atherosclerosis in mice doubly deficient in apolipoprotein E (apoE) and PAI-1 is reduced after 10 weeks of cholesterol-rich diet. Thus, the plasminogen system significantly affects thrombosis, restenosis, and atherosclerosis.
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PMID:Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system. 918 98

Twelve patients with rupture of the perivisceral abdominal aorta were admitted to the UCLA Medical Center between 1984 and 1996. Six patients had atherosclerotic thoracoabdominal aneurysms (TAA) which ruptured in the visceral segment of the aorta. The remaining 6 patients proved to have ruptured mycotic aneurysm (MA). Clinical presentation was different in the two groups. Whereas all 6 patients with TAA and < 24 hr history of abdominal, chest, or back pain, patients with MA had these symptoms for 2-5 weeks (mean 3.4 weeks). History of sepsis was present in 4/6 MA and in 0/6 TAA patients. No difference in risk factors for atherosclerosis were seen between these two groups. Clinical outcomes were also different. Operation consisted of in situ vascular grafting in all patients. Operative mortality for TAA was 33% (2/6), whereas all patients with MA survived repair with no operative mortality. Two patients had cardiac arrest prior to surgery. One of these had a TAA and died 5 days after surgery, whereas the other survived repair of an MA. Follow-up ranges from 1-84 months (mean 48 months). Four survivors in the TAA group are alive at 6, 8, 14, and 84 months, with the latter having a pseudoaneurysm of the visceral patch-graft anastomosis. All 6 patients with MA are alive at 1-73 months (mean 39 months) without evidence of graft sepsis or recurrent aneurysm. We conclude that rupture of the visceral portion of the aorta is often associated with a mycotic process, with important differences noted in clinical presentation when compared to atherosclerotic TAA. Surgical intervention is effective in both MA and TAA. Operative mortality, however, is significantly higher in patients with ruptured TAA. In situ prosthetic replacement for ruptured MA is associated with low mortality and excellent long-term results.
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PMID:Rupture of the perivisceral aorta: atherosclerotic versus mycotic aneurysm. 923 87

Nitric oxide (NO) is a mediator that modulates vessel wall tone and hemostatic-thrombotic balance. Platelet function is regulated by NO generated from platelets, endothelial cells and leukocytes. Nitric oxide has been shown to inhibit platelet adhesion, aggregation, and stimulate disaggregation of preformed platelet aggregates. Many of the effects of NO are mediated by its stimulation of guanylate cyclase and the formation of cyclic GMP and its subsequent transduction mechanism. In vivo, NO is likely to interact with prostacyclin, metabolites of ecto-nucleotidase, and lipoxygenase to modulate platelet function in a synergistic manner. An imbalance of NO production (deficiency or overproduction) has been implicated in the pathogenesis of various vascular disorders including thrombosis, atherosclerosis, septicemia, and ischemia-reperfusion injury. It is likely that some of detrimental effects of NO are mediated through its reaction with superoxide anion to form the potent oxidant, peroxynitrite. Nitric oxide gas and NO donors are used for the pharmacological treatment of various vascular disorders. Because inhaled NO has been documented to improve systemic oxygenation and reduce the need for extracorporeal membrane oxygenation, it has been widely used in neonates with severe hypoxemia. An inhibition of platelet function, resulting in a prolonged bleeding time, has been shown in adults receiving inhaled NO. Because bleeding complications may occur in high-risk infants, it is important to evaluate the effect of inhaled NO on platelet function and its correlation with clinical consequences such as intracranial hemorrhage. For these reasons, hemostasis should be carefully monitored during the administration of inhaled NO to critically ill neonates.
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PMID:Nitric oxide and platelet function: implications for neonatology. 935 13


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