Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 beta-converting enzyme (ICE) is a cysteine protease responsible for proteolytic activation of the biologically inactive interleukin-1 beta precursor to the proinflammatory cytokine. ICE and homologous proteases also appear to mediate intracellular protein degradation during programmed cell death. Inhibition of ICE is a new antiinflammatory strategy being explored by the design of both reversible inhibitors and irreversible inactivators of the enzyme. Such compounds are capable of blocking release of interleukin-1 beta from human monocytes. ICE inhibitors that cross react against multiple ICE homologs can also block apoptosis in diverse cell types. ICE inhibitors impart protection in vivo from endotoxin-induced sepsis and collagen-induced polyarthritis in rodent models. Further optimization of the current generation of peptidyl ICE inhibitors will be required to produce agents suitable for administration in chronic inflammatory and neurodegenerative diseases.
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PMID:In vitro and in vivo studies of ICE inhibitors. 901 50

Healing in the GI tract is rapid when free of complications: Unlike cutaneous healing, in which progress can be observed on a daily basis and intervention instituted early if necessary, healing of the intestinal anastomosis is anatomically obscured from inspection, allowing the surgeon only the patient's parameters of general well-being to judge the success of the operation. For the same reason, complications usually require re-operation, with the associated morbidity of a laparotomy and additional general anesthetic. This places a great responsibility on the surgeon to be cognizant of all the preoperative, intraoperative, and postoperative factors relating to anastomotic healing that might compromise the healing process. Bearing these in mind, along with attention to technical detail, should limit complications to an acceptable level. Patients most at risk are (1) those who perioperatively develop physiologic problems that lead to shock, hypoxia, and resultant anastomotic ischemia, (2) those with radiation-induced tissue injury, (3) those with sepsis, and (4) those with preoperative bowel obstruction. Malnourishment, malignancy, diabetes, steroids, and age also influence outcome to varying degrees. Future advancement in the field of GI healing lies in our ability to manipulate the early struggle between collagen synthesis and collagen breakdown. A profound understanding of the molecular and biochemical pathways and the factors that control them will bring us closer to this goal. Clinically, this may be accomplished by the introduction of wound healing enhancers into the anastomotic site, possibly by incorporating them into suture materials, biofragmentable anastomotic rings, or staple materials. Already much is known about the influence of different cytokines and growth factors on collagen regulation, knowledge that will help resolve many of the long-standing problems associated with GI surgery.
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PMID:Healing in the gastrointestinal tract. 919 80

Although intra-abdominal sepsis is known to impair colon healing by inhibiting anastomotic collagen synthesis, the effect of systemic sepsis on this process is unknown. Endotoxins and cytokines associated with sepsis induce nitric oxide synthesis both systemically and locally within colonic tissue. We hypothesized that systemic sepsis impairs colonic healing and examined a possible correlation with nitric oxide expression. Male Sprague-Dawley rats received intraperitoneal injections of either saline (sham group) or Escherichia coli endotoxin (lipopolysaccharide 1 mg/100 g body weight) at Times -24 and -12 hr (LPS group). All animals underwent laparotomy and left colonic anastomosis at Time 0. At 24 and 96 hr postlaparotomy rats were sacrificed, the anastomoses excised, and [3H]-proline incorporation into protein measured as an index of total new protein synthesis (TNP). Digestion with purified collagenase yielded incorporation into the collagen fraction (CDP). Additional sham and LPS-treated rats were sacrificed at 24, 72, and 120 hr, the anastomoses excised, and nitric oxide synthase activity in the tissue measured by the conversion of [3H]-arginine to [3H]citrulline in an ex vivo culture system. Finally, sham and LPS rats were sacrificed at 120 hr for measurement of colon anastomotic bursting pressure. Systemic sepsis significantly impaired new collagen synthesis in anastomotic tissue at 24 hr compared to control samples (P < 0.02). No difference was noted at 96 hr. TNP synthesis was similar in both groups at 24 or 96 hr. Northern blot analysis confirmed a significant decrease in Type I and Type III collagen mRNA expression at 24 hr in septic rats. Anastomotic bursting pressure was also decreased in the septic group (P < 0.003). Sepsis elevated nitric oxide synthase activity in anastomotic tissue 24 hr postanastomosis, when compared to sham tissue (P < 0.0001). These data suggest that systemic endotoxin induces nitric oxide synthesis at the anastomotic site. The simultaneous dysregulation of collagen gene expression and synthesis with decreased anastomotic strength suggests a possible regulatory role for nitric oxide in gastrointestinal healing.
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PMID:Sepsis impairs anastomotic collagen gene expression and synthesis: a possible role for nitric oxide. 920 51

Staphylococcus aureus is a major cause of nosocomial and community-acquired infections. Morbidity and mortality due to infections such as sepsis, osteomyelitis, septic arthritis, and invasive endocarditis remain high despite the use of antibiotics. The emergence of antibiotic resistant super bugs mandates that alternative strategies for the prevention and treatment of S. aureus infections are developed. We investigated the ability of vaccination with a recombinant fragment of the S. aureus collagen adhesin to protect mice against sepsis-induced death. Actively immunized NMRI mice were intravenously inoculated with the S. aureus clinical isolate strain Phillips. 14 d after inoculation, mortality in the collagen adhesin-vaccinated group was only 13%, compared with 87% in the control antigen immunized group (P < 0.001). To determine if the protective effect was antibody mediated, we passively immunized naive mice with collagen adhesin-specific antibodies. Similar to the active immunization strategy, passive transfer of collagen adhesin-specific antibodies protected mice against sepsis-induced death. In vitro experiments indicated that S. aureus opsonized with sera from collagen adhesin immunized mice promoted phagocytic uptake and enhanced intracellular killing compared with bacteria opsonized with sera from control animals. These results indicate that the collagen adhesin is a viable target in the development of immunotherapeutics against S. aureus.
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PMID:Vaccination with a recombinant fragment of collagen adhesin provides protection against Staphylococcus aureus-mediated septic death. 963 97

Pericytes are contractile cells of the microvasculature which may contribute to the hypotension and increase in permeability that are present during inflammation and late-stage sepsis. The purpose of this study was to examine the contractile effects, if any, of septic modulators on the lung pericyte. Contractile effects were qualitatively examined using a previously developed silicone rubber method. This study further demonstrates a quantitative method for measuring the contraction of lung pericytes cultured on a collagen lattice. Contraction was measured by the change in collagen matrix area in response to vasoactive stimuli. Bradykinin and serotonin significantly increased contraction in a dose-dependent manner, with a maximum increase in contraction twice that of control. Forskolin and adenosine caused relaxation, also in a significant dose-dependent manner, with a maximum decrease in contraction of 80 and 30-40%, respectively. Histamine had no effect on contractility in either the silicone rubber or the collagen lattice assay. These results show that the lung pericyte, like the retinal pericyte, is a contractile cell and can be stimulated to contract or relax in vitro by the presence of certain inotropic agents present during inflammation and sepsis. These responses may play a role in microvascular regulation.
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PMID:Effects of vasoactive mediators on the rat lung pericyte: quantitative analysis of contraction on collagen lattice matrices. 1004 61

In fetuses and neonates hepatic subcapsular hematomas are relatively common lesions and may be life-threatening. Conditions previously associated with these hematomas include trauma, coagulopathies, hypoxia, sepsis, pneumothorax, maternal diseases, and placental lesions. In this study of 755 perinatal autopsies, hepatic subcapsular hematomas were found in 52 (6.9%) cases, including 31 stillborn fetuses and 21 liveborn infants. The average body weight was 690 g. A comparison group consisted of 52 temporally proximal autopsies of fetuses and neonates without hematomas. Body weights, gender, maternal age, and stillbirth or postnatal survival were matched as closely as possible while evaluating the presence or absence of sepsis, pneumothorax, cerebral germinal matrix hemorrhage, trauma, coagulopathy, placental lesions, and maternal diseases. Sepsis was associated with 62% of the cases with hepatic subcapsular hematomas and with 25% of the comparison group (P =.0001). Group B streptococcus infection was the most common cause of sepsis, but many different organisms were isolated. Cerebral germinal matrix hemorrhages were present in 35% of the cases with hematomas and in 14% of the comparison group (P =.0001). No other lesions or conditions were statistically different in the study group versus the comparison group. The delicacy of the hepatic capsule and its connections to the collagen along the sinusoids provide insight for the pathogenesis of hematomas in premature fetuses and neonates. We conclude that sepsis is present in most perinatal cases of hepatic subcapsular hematomas and that such patients also frequently have cerebral germinal matrix hemorrhages. Each of these lesions is a greater hazard among very small premature fetuses or neonates than among older fetuses and neonates.
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PMID:Hepatic subcapsular hematomas in fetuses and neonatal infants. 1019 44

Tumor necrosis factor-alpha (TNF-alpha) plays a role in several disease states such as sepsis, cachexia, and non-insulin-dependent diabetes. TNF-alpha interferes with insulin signaling and inhibits differentiation-specific gene expression in adipose tissue and skeletal muscle. We have examined the mechanisms by which TNF-alpha, in comparison to basic fibroblast growth factor (bFGF), inhibits the insulin-like growth factor-I (IGF-I)-induced differentiation of C2C12 myoblasts. Adhesion of quiescent, suspended myoblasts to collagen in high concentrations of IGF-I (10 nM) induced these cells to proliferate during the initial 24 h postplating and in so doing transiently inhibited the expression of myogenin, an essential transcription factor controlling myoblast differentiation. Low doses of IGF-I (1 nM) were minimally mitogenic and enhanced muscle-specific gene expression. Quiescent myoblasts treated with bFGF in combination with IGF-I did not express myogenin, but expressed proliferating cell nuclear antigen and underwent DNA synthesis. In contrast, TNF-alpha in the presence or absence of 1 nM IGF-I, did not stimulate DNA synthesis in myoblasts. However, TNF-alpha inhibited myogenin mRNA and protein expression. Expression of the cyclin-dependent kinase inhibitor p21 correlated with myogenin expression and myoblast differentiation, but not with growth arrest. These results indicate that both TNF-alpha and bFGF inhibit myogenin expression but differentially influence myoblast proliferation.
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PMID:Tumor necrosis factor-alpha and basic fibroblast growth factor differentially inhibit the insulin-like growth factor-I induced expression of myogenin in C2C12 myoblasts. 1032 64

Previously we reported that alcohol abuse increases the incidence of the acute respiratory distress syndrome (ARDS) in septic patients, and that chronic ethanol ingestion in rats depletes alveolar epithelial glutathione and increases endotoxin-mediated lung edema. In this study we examined a potential mechanism by which ethanol-induced glutathione depletion could predispose to acute lung injury. We hypothesized that glutathione depletion activates matrix metalloproteinases (MMPs), thereby increasing degradation of the alveolar extracellular matrix (ECM) during sepsis. Ethanol-fed rats (20% vol/vol in water for 6 wk) were given endotoxin (2 mg/kg, intraperitoneally) followed 2 h later by lung isolation and ex vivo perfusion with n-formyl-methionyl-leucyl-phenylalanine (fMLP) (10(-)(7) M). Ethanol ingestion increased (p < 0.05) MMP-9 and MMP-2 activity, as determined by zymography, in the lung tissue and lavage fluid compared with control-fed rats, and increased (p < 0.05) levels of the 7S fragment of type IV collagen in the lung lavage fluid. Ethanol ingestion increased activation, but not production, of the MMP-9 and MMP-2 zymogens. Finally, although concomitant ingestion of N-acetylcysteine had no effect (p > 0.05) on MMP production, it increased (p > 0.05) lung glutathione levels, blocked (p < 0.05) MMP-9 and MMP-2 activation, and decreased (p < 0.05) levels of the 7S fragment of type IV collagen. We conclude that chronic ethanol ingestion, via glutathione depletion, activates MMPs during sepsis, thereby increasing degradation of the alveolar epithelial ECM. Lois M, Brown LAS, Moss IM, Roman J, Guidot DM. Ethanol ingestion increases activation of matrix metalloproteinases in rat lungs during acute endotoxemia.
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PMID:Ethanol ingestion increases activation of matrix metalloproteinases in rat lungs during acute endotoxemia. 1050 28

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder, a group that includes Ehlers-Danlos syndrome, Marfan's syndrome and pseudoxanthoma elasticum. OI is a heterogeneous disease of collagen I biosynthesis characterized by variable clinical phenotypes, including skeletal and cardiovascular manifestations. A 65-year-old man with OI who had extensive prior successful cardiac valve surgeries is described. He survived for 18 years after his initial valve surgery, but died of multiorgan failure and sepsis after repair of a spontaneous type A aortic dissection. This is the fourth reported case of aortic dissection secondary to OI and illustrates the extensive cardiovascular pathology associated with OI. Aggressive management of arterial dissection risk factors, such as systemic arterial hypertension, is advocated for patients with OI.
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PMID:Aortic dissection: a rare complication of osteogenesis imperfecta. 1052 81

Progress in understanding mechanisms of disease are necessary to usher in major changes in treatment. A new era in rheumatoid arthritis (RA) and related chronic autoimmune/inflammatory diseases is now beginning, with a variety of anti-TNFalpha treatments licensed for use in both RA and Crohn's disease. The rationale for this new treatment lies in an understanding that cytokines are critical, rate limiting molecules lying at the heart of the chronic autoimmune/inflammatory disease process. This understanding was developed from the critical evaluation of a hypothesis that was proposed linking cytokines, antigen presentation and autoimmunity in 1983. Detailed analysis focusing on the major site of the disease, the rheumatoid synovium was essential to developing indications that blockade of TNFalpha might be efficacious. This clue was validated using anti-TNFalpha treatment of an animal model of RA, murine collagen induced arthritis, and by immunohistochemical demonstration of upregulated TNF and TNF-R expression in the synovium. With this three pronged rationale, the authors were able to convince Centocor, Inc, which had developed a chimaeric anti-TNFalpha antibody for use in sepsis, to work with them to test the concept that TNFalpha blockade would be beneficial in RA. With the success of that first trial, other companies have subsequently tested their anti-TNF strategies successfully. Current interests extend to understanding the processes that regulate TNF production in the rheumatoid joint. Progress in this area is discussed, using adenoviruses to infect normal macrophages and rheumatoid synovium.
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PMID:The rationale for the current boom in anti-TNFalpha treatment. Is there an effective means to define therapeutic targets for drugs that provide all the benefits of anti-TNFalpha and minimise hazards? 1057 70


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