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)

Members of the Toll-like receptor (TLR) family are key regulators of both innate and adaptive immune responses. The function of TLRs in various human diseases has been investigated by comparison of the incidence of disease among people having different polymorphisms in genes that participate in TLR signaling. These studies have shown that TLR function affects several diseases, including sepsis, immunodeficiencies, atherosclerosis and asthma. As this body of data grows, it will provide new insights into disease pathogenesis as well as valuable information on the merits of various therapeutic options.
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PMID:Toll-like receptors in the pathogenesis of human disease. 1545 20

The discovery of the physico-chemical host defence is closely connected with the endotoxin research. It is well known that the toxic effects of endotoxins under experimental conditions can be induced only when they are administered parenterally. However, in naturally occurring entero-endotoxemic diseases (e.g. septic and various shocks, etc.), the endotoxin is absorbed from the intestinal tract. The cause and mode of translocation have been unknown. The generally used experimental shock models differ from natural diseases only in the mode by which endotoxin enters the blood circulation. If the common bile duct of rats was chronically canulated (bile-deprived animals) orally administered endotoxin was absorbed from the intestinal tract into blood circulation and provoked endotoxin shock. This translocation of endotoxins and the consequent shock can be prevented by sodium deoxycholate or natural biles. The bile acids split the endotoxin macromolecule into atoxic fragments. A similar detoxifying detergent action plays a significant role in host defence against infectious agents with outer lipoprotein structure (e.g. so-called 'big' viruses). This defence mechanism of macroorganisms based on the detergent activity of bile acids (end-products of the cholesterol metabolism) is called as physico-chemical defence system. Therefore, bile deficiency and the consequent endotoxemia are important components in the pathogenesis of certain diseases (e.g. sepsis, intestinal syndrome of radiation disease, hepato-renal syndrome, parvovirus infection, herpes, psoriasis, atherosclerosis, etc.). Bile acids may be used for the prevention and/or therapy of the above mentioned clinical conditions.
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PMID:Bile acids in physico-chemical host defence. 1556 10

Plasminogen activator inhibitor-1 (PAI-1), a 45-kDa serine proteinase inhibitor with reactive site peptide bond Arg345-Met346, is the main physiological plasminogen activator inhibitor. It occurs in human plasma at an antigen concentration of about 20 ng mL(-1). Besides the active inhibitory form of PAI-1 that spontaneously converts to a latent form, also a substrate form exists that is cleaved at the P1-P1' site by its target enzymes, but does not form stable complexes. Besides its role in regulating hemostasis, PAI-1 plays a role in several biological processes dependent on plasminogen activator or plasmin activity. Studies with transgenic mice have revealed a functional role for PAI-1 in wound healing, atherosclerosis, metabolic disturbances such as obesity and insulin resistance, tumor angiogenesis, chronic stress, bone remodeling, asthma, rheumatoid arthritis, fibrosis, glomerulonephritis and sepsis. It is not always clear if these functions depend on the antiproteolytic activity of PAI-1, on its binding to vitronectin or on its intereference with cellular migration or matrix binding.
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PMID:Pleiotropic functions of plasminogen activator inhibitor-1. 1563 64

Although frequently asymptomatic, homozygous C2 deficiency (C2D) is known to be associated with severe infections and rheumatic disease. We describe the clinical findings in 40 persons with C2D from 33 families identified in Sweden over 25 years. Medical records covering 96% of the accumulated person-years were reviewed, giving a mean observation time of 39 years (range, 1-77 yr). Severe infection was the predominant clinical manifestation in the cohort: 23 patients had a past history of invasive infections, mainly septicemia or meningitis caused by Streptococcus pneumoniae, and 12 patients had repeated infections of this kind. Nineteen patients had at least 1 episode of pneumonia, and recurrent pneumonia was documented in 10 patients. Repeated infections occurred mainly during infancy and childhood. Systemic lupus erythematosus was found in 10 patients. Another 7 patients had undifferentiated connective tissue disease (n = 4) or vasculitis (n = 3). We found no correlation between susceptibility to invasive infection and rheumatologic disease. Cardiovascular disease occurred at a high rate, with a total of 10 acute myocardial infarctions and 5 cerebrovascular episodes in 6 patients. Causes of death among the C2D patients were infection (n = 5), acute myocardial infarction (n = 3), and cancer (n = 1). We suggest that severe infection may be the principal clinical manifestation of C2D. We also provide novel evidence for a possible role of C2D in the development of atherosclerosis consistent with findings in mannan-binding deficiency and experimental C3 deficiency. In addition, we confirm the well-known association between C2D and systemic lupus erythematosus.
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PMID:Hereditary C2 deficiency in Sweden: frequent occurrence of invasive infection, atherosclerosis, and rheumatic disease. 1564 97

For many years the vascular endothelium was believed simply to provide a passive lining between circulating blood and extravascular tissue. It is now clear, however, that this monolayer of cells on the luminal surface of all blood vessels, provides a selective barrier that responds dynamically to various stimuli, and controls a complex series of cellular reactions and interactions. The current presentation describes the use of computer enhanced video recording to study interactions between endothelial cells and circulating blood cells, especially leucocytes. Subsequently, modern assays for soluble cell adhesion molecules and other cell receptors were assessed for potential use in routine clinical practice. The results demonstrated that adhesive mechanisms involving leucocytes and endothelial cells involve a range of interrelationships that cut across conventional views of haemostasis and leucocyte function. The findings also suggest that interplay between the vascular lumen and circulating blood cells might be vitally important in clinically demanding pathologies, such as life-threatening sepsis, ischaemic heart disease, atherosclerosis and cancer. The concepts provide challenging strategies for further investigation.
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PMID:Soluble adhesion molecules in inflammatory and vascular diseases. 1578 16

The nucleoside adenosine accumulates in many tissues following the onset of ischaemia and inflammation. This initiates a series of protective mechanisms in target cells upon binding and activation of a family of four G-protein-coupled cell surface adenosine receptor (AR) proteins. The magnitude and duration of adenosine's effects are dictated by the identity and expression levels of each receptor subtype on individual cell types within the hypoxic microenvironment. Given the key role of endothelial cells (ECs) in the development of inflammatory diseases, such as sepsis, rheumatoid arthritis (RA) and atherosclerosis, ARs represent attractive targets for therapeutic intervention in these conditions. In this review, we examine several critical aspects of endothelial function in vivo, assess the role of individual AR subtypes in these events and, where known, discuss the molecular mechanisms by which specific ARs exert their effects.
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PMID:Adenosine receptors and the control of endothelial cell function in inflammatory disease. 1587 24

Redox signaling is evolving as a new field of biochemical and pharmacological research. Unlike oxidative stress which is characterized by a macroscopic shift in cellular redox potentials and usually accompanied by oxygen radical induced damage, redox regulation involves subtle and more chemically defined oxidations of short duration. Most important is the reductive component as a necessary part of a reversible regulatory process. Examples of redox regulation occur during early stages of the immune response, in hypoxia or in endothelial dysfunction. Persistent oxidative events together with a decline in the cellular reduction potential lead to oxidative stress as is seen in the pathophysiology of sepsis, reperfusion damage, atherosclerosis and diabetes. Oxidative signals involve superoxide and nitric oxide as the main players which form a system of oxidizing, nitrating or nitrosating species leading to posttranslational modifications of proteins. Modern techniques of immunohistochemistry and mass spectrometry allow a correlation of protein modification, e.g., disulfide, S-oxide, S-nitroso or nitrotyrosine formation, with enzyme activities and cellular responses. In this commentary, examples of the control of prostanoid synthesis by the NO/O2- system are described. Redox regulation represents an interesting challenge for the development of drugs that modulate the oxidative trigger mechanisms or enforce the reductive pathways.
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PMID:Redox regulation: a new challenge for pharmacology. 1589 73

Significant advances have been made in defining the spectrum of clinical manifestations and the prognosis of systemic lupus erythematosus (SLE). With the use of corticosteroids and other immunosuppressive agents as well as better management of complications such as infection, there has been a dramatic improvement in the short-term prognosis of patients who have SLE from less than 50% survival at 5 years to 93% at 5 years and 85% and 10 years. However, many patients who survive early complications of organ failure and sepsis later develop premature coronary artery disease (CAD). In this evidence-based review, the magnitude of the problem of premature atherosclerosis in SLE is defined and evaluation of the strength of association of risk factors determined to date. The authors focus on the emerging role of new modalities for noninvasive assessment of vascular health in patients who have SLE and offer a strategy for screening and management of those at risk of CAD. The article concludes with a discussion on the important questions that remain to be answered and future directions for research.
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PMID:Premature atherosclerosis in systemic lupus erythematosus. 1592 49

Infection of the aorta usually results from septic embolization to the vasa vasorum, hematogenous seeding of an existing aneurysm, or extension from a contiguous site of infection. The diagnosis should be considered in patients, often men over the age of 50 years with atherosclerosis, who present with fever, abdominal pain, palpable abdominal mass, and leukocytosis, with or without positive blood cultures. In the pre-antibiotic area, infectious aortitis was largely a complication of infective endocarditis, and was usually caused by group A streptococci, Streptococcus pneumoniae, or Haemophilus influenzae. Now a diverse array of bacteria and fungi has been associated, most commonly Salmonella species, which comprise nearly one third of the abdominal aortic infections and Staphylococcus aureus. Computed tomography is the most useful imaging modality. Medical treatment alone carries a high mortality, whereas the mortality with surgery combined with antimicrobial treatment is lower. Empiric antibiotics effective against S. aureus and gram-negative rods, such as Salmonella, should be initiated in cases identified before microbiologic diagnosis. Surgical debridement and revascularization should be completed early because delay may lead to aneurysm rupture, which increases mortality. The intent of surgery is to 1) control hemorrhage, if the aneurysm has ruptured; 2) confirm the diagnosis; 3) control sepsis; and 4) reconstruct the arterial vasculature. The patient should remain on parenteral or oral antibiotics for at least 6 weeks, perhaps longer, to assure full eradication of the pathogen and prevent recurrent infection. Close medical follow-up is indicated and includes serial blood cultures and computed tomography scans.
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PMID:Infectious Aortitis. 1593 17

The recently-discovered class of toll-like receptors (TLRs) play an essential role in the complex defence system against microorganisms. TLRs are the first to detect potential pathogens, initiate immune responses and form the crucial link between the innate and acquired immune systems. TLRs also play an important role in the pathophysiology of infectious diseases, inflammatory diseases such as Crohn's disease and atherosclerosis, and possibly play a role in autoimmune diseases. Common polymorphisms in TLR genes are associated with predisposition to severe infections. Drugs that target the TLRs offer new opportunities for the development of therapeutics against a wide variety of diseases such as sepsis syndrome, asthma, inflammatory-bowel diseases and cancer. The first drug that works by modulating the TLR response has already been registered.
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PMID:[Toll-like receptors and the significance for clinical medicine]. 1594 Sep 18


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