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)

Lipopolysaccharide (LPS), an outer-membrane component of Gram-negative bacteria, interacts with LPS-binding protein and CD14, which present LPS to toll-like receptor 4 (refs 1, 2), which activates inflammatory gene expression through nuclear factor kappa B (NF kappa B) and mitogen-activated protein-kinase signalling. Antibacterial defence involves activation of neutrophils that generate reactive oxygen species capable of killing bacteria; therefore host lipid peroxidation occurs, initiated by enzymes such as NADPH oxidase and myeloperoxidase. Oxidized phospholipids are pro-inflammatory agonists promoting chronic inflammation in atherosclerosis; however, recent data suggest that they can inhibit expression of inflammatory adhesion molecules. Here we show that oxidized phospholipids inhibit LPS-induced but not tumour-necrosis factor-alpha-induced or interleukin-1 beta-induced NF kappa B-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock. Thus, in severe Gram-negative bacterial infection, endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Furthermore, identified chemical structures capable of inhibiting the effects of endotoxins such as LPS could be used for the development of new drugs for treatment of sepsis.
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PMID:Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. 1221 35

The acute respiratory distress syndrome (ARDS) is a major cause of morbidity after injury. We hypothesized that alveolar macrophage (AMPhi) chemokine and cytokine release after hemorrhage and sepsis is regulated by NF-kappaB and MAPK. Adult male rats underwent soft tissue trauma and hemorrhagic shock (~90 min) followed by crystalloid resuscitation. Sepsis was induced by cecal ligation and puncture (CLP) 20 h after resuscitation. AMPhi were harvested, and TNF-alpha, IL-6, and macrophage inflammatory protein (MIP)-2 release and serum IL-6 and TNF-alpha levels were measured at 5 h after HCLP. Lung tissues were analyzed for activation of NF-kappaB, myeloperoxidase activity, and wet/dry weight ratio. In control animals, AMPhi were stimulated with LPS with or without inhibitors of NF-kappaB and MAPK. Serum TNF-alpha and IL-6 levels and spontaneous AMPhi TNF-alpha and MIP-2 release were elevated (P < 0.05) after HCLP, concomitantly with the development of lung edema and leukocyte activation. Activation of NF-kappaB increased in lungs from the hemorrhage and CLP group compared with shams. Inhibition of NF-kappaB or the upstream MAPK significantly decreased LPS-stimulated AMPhi activation. Because enhanced release of inflammatory mediators by AMPhi may contribute to ARDS after severe trauma, inhibition of intracellular signaling pathways represents a target to attenuate organ injury under those conditions.
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PMID:Alveolar macrophage activation after trauma-hemorrhage and sepsis is dependent on NF-kappaB and MAPK/ERK mechanisms. 1222 57

Chronic Pseudomonas aeruginosa lung infection is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. One P. aeruginosa virulence factor unique to CF isolates is overproduction of alginate, phenotypically termed mucoidy. Mucoidy is the result of increased transcription from the algD gene and is activated by the transcriptional regulator AlgR. Mutations in algR result in a nonmucoid phenotype and loss of twitching motility. Additionally, AlgR controls transcription of algC, encoding a dual-function enzyme necessary for both lipopolysaccharide (LPS) and alginate production. Therefore, to determine the effect of algR on P. aeruginosa virulence, an algR mutant was examined for sensitivity to reactive oxygen intermediates, killing by phagocytes, systemic virulence, and the ability to maintain a murine lung infection. We found that P. aeruginosa PAO700 (algR::Gm(r)) was less lethal than PAO1, as tested in an acute septicemia infection mouse model, and was cleared more efficiently in a mouse pneumonia model. Additionally, the algR mutant (PAO700) was more sensitive to hypochlorite. However, PAO700 was more resistant to hydrogen peroxide and killed less readily in an acellular myeloperoxidase assay than PAO1. There was little difference in killing between PAO1 and PAO700 with macrophage-like J774 cells and human polymorhonuclear leukocytes. Two-dimensional gel analysis of P. aeruginosa algR mutant and wild-type protein extracts revealed 47 differentially regulated proteins, suggesting that AlgR plays both a positive role and a negative role in gene expression. Together, these results imply that AlgR is necessary for virulence and regulates genes in addition to the genes associated with alginate and LPS production and pilus function.
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PMID:The transcriptional regulator AlgR is essential for Pseudomonas aeruginosa pathogenesis. 1237 85

The response to injury is dependent on several factors, including the type and extent of the injury, genetics, and the environment. In the present study, the genetic contribution to sepsis was evaluated in a mouse model. Sepsis was induced in two inbred mouse strains, C57BL/6J (B6) and A/J, by cecal ligation and single puncture (CLP). Frequency of mortality was significantly higher in B6 than A/J mice from 36 to 132 h after CLP. Plasma TNF-alpha, IL-1beta, and IL-6 levels were similar in both strains after CLP. IL-10 plasma levels were significantly higher in B6 mice as opposed to A/J mice after 24 h of CLP. Similarly, hepatic myeloperoxidase activity, an index of polymorphonuclear leukocytes, was elevated in B6 mice as compared with A/J mice after 24 h of CLP. On the contrary, metallothionein mRNA levels were higher in A/J mice compared with B6 mice. Finally, leptin levels were also higher in A/J than B6 mice within 19 h of CLP. This study demonstrates a genetic contribution in the response to sepsis.
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PMID:Genetic contribution to the septic response in a mouse model. 1239 78

Antithrombin (AT) supplementation in patients with severe sepsis has been shown to improve organ failures in which activated leukocytes are critically involved. However, the precise mechanism(s) for the therapeutic effects of AT is not well understood. We examined in rats whether AT reduces ischemia/reperfusion (I/R)-induced renal injury by inhibiting leukocyte activation. AT markedly reduced the I/R-induced renal dysfunction and histologic changes, whereas neither dansyl glutamylglycylarginyl chloromethyl ketone-treated factor Xa (DEGR-F.Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Renal tissue levels of 6-keto-PGF(1 alpha), a stable metabolite of prostacyclin (PGI(2)), increased after renal I/R. AT enhanced the I/R-induced increases in renal tissue levels of 6-keto-PGF(1 alpha), whereas neither DEGR-F.Xa nor Trp49-modified AT had any effect. AT significantly inhibited I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability. Ischemia/reperfusion-induced increases in renal tissue levels of tumor necrosis factor-alpha, cytokine-induced neutrophil chemoattractant, and myeloperoxidase were significantly inhibited in animals given AT. Pretreatment of animals with indomethacin reversed the effects induced by AT. Iloprost, an analog of PGI(2), produced effects similar to those induced by AT. These observations strongly suggest that AT reduces the I/R-induced renal injury by inhibiting leukocyte activation. The therapeutic effects of AT might be mainly mediated by PGI(2) released from endothelial cells through interaction of AT with cell surface glycosaminoglycans.
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PMID:Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production. 2354 58

Natural killer (NK) cells have a well-established role in host defense against viral infections and malignancies. However, their function in bacterial infection and sepsis is poorly defined. We hypothesized that NK cells, as a major producer of interferon-gamma during sepsis, would be important in host defense against bacterial infections. Cecal ligation and puncture (CLP) was performed on Swiss Webster mice depleted of NK cells by pretreatment with anti-asialo GM1 and control mice given immunoglobulin G (IgG) antibody. NK cell-depleted mice had significantly higher anaerobic bacterial counts in the liver and peritoneal lavage fluid, as well as higher aerobic counts in the liver and blood 4 h after CLP. Macrophage phagocytosis, nitric oxide production, and interleukin (IL)-6 levels at 4 h were also decreased in mice depleted of NK cells compared with controls. Greater neutrophil influx into the peritoneum, indicated by higher myeloperoxidase levels, was also seen in NK cell-depleted mice. At 8 and 18 h after CLP, bacterial counts were similar between groups, and overall survival rates were not significantly different. Peritoneal IL-12 levels significantly increased by 18 h in normal mice, but not in NK cell-depleted animals. Our data suggest that NK cells participate in the early local and systemic eradication of bacteria and regulation of IL-12 during polymicrobial sepsis. These effects are likely due to their interactions with macrophages.
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PMID:Natural killer cells participate in bacterial clearance during septic peritonitis through interactions with macrophages. 1257 23

We describe a new unique case of acute myeloid leukemia (AML) in a 21-yr-old male presenting with abdominal pain, bilateral testicular masses and gynecomastia. Further work-up with computed tomography of the chest, abdomen and pelvis revealed massive retroperitoneal, peripancreatic and mediastinal lymphadenopathy, suggesting primary testicular neoplasm. The patient was subjected to right orchiectomy that showed infiltration of testicular tissue with malignant cells, originally misinterpreted as undifferentiated carcinoma. Immunohistochemistry studies, however, showed these cells to be strongly positive for myeloperoxidase and CD45, indicating a myeloid cell origin. Bone marrow (BM) aspirate and biopsy demonstrated replacement of marrow with immature myeloid cells. Both the morphology and immunophenotype of the blast cells were consistent with AML type M4 (acute myelo-monocytic leukemia), using French-American-British (FAB) classification. The patient received standard induction chemotherapy with cytosine arabinoside (ARA-C) and daunorubicin followed with two cycles of consolidation therapy with high dose ARA-C, which resulted in remission of BM disease and resolution of lymphadenopathy and left testicular masses. After the second cycle of consolidation therapy, the patient developed sepsis that was complicated by refractory disseminated intravascular coagulopathy. He expired with a clinical picture of multiple organ failure. The unique features of this case are presented and the related literature is reviewed.
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PMID:Acute myeloid leukemia mimicking primary testicular neoplasm. Presentation of a case with review of literature. 1265 49

Apoptotic loss of parenchymal cells may lead to organ dysfunctions in critically ill patients with septic states. As an antioxidant, the protective effects of N-acetylcysteine (NAC) are documented in many experimental and clinical studies. In this experimental study, we investigated the role of chronically used NAC in septic lung injury on a cecal ligation and puncture (CLP) model. To evaluate this, 30 male Wistar rats were randomly divided into four groups as sham (n = 7), CLP (n = 8), sham + NAC (n = 7) and CLP + NAC (n = 8) groups. NAC was administered 150 mg kg(-1) day through intramuscular route beginning 6 h after the operations and lasting for a period of 1 week. One week later, histopathology and epithelial apoptosis were assessed by hematoxylin-eosin and immunohistochemically by M30 and caspase 3 staining to demonstrate septic lung injury. Additionally, lung tissue myeloperoxidase (MPO) activity, malondialdehyde (MDA), and nitrite/nitrate levels were measured. The MPO activity and MDA levels in lung homogenates were found to be increased in CLP group and the administration of NAC prevented their increase significantly (P < 0.05). However, there were no significant differences among the groups regarding nitrite/nitrate levels. The number of apoptotic cells was significantly lower in CLP+NAC group than CLP group, and this finding was supported by M30 and caspase 3 expression in lung (P < 0.05). Lung histopathology was also protected by NAC in CLP-induced sepsis. In conclusion, the chronic use of NAC inhibited MPO activity and lipid peroxidation, which resulted in reduction of apoptosis in lung in this CLP model. Because lung tissue nitrite/nitrate levels did not change significantly, organs other than the lungs may be responsible for producing the increased nitric oxide during sepsis. The chronic use of NAC needs further investigation for its possible antiapoptotic potential in septic states besides its documented antioxidant and antiinflammatory effects.
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PMID:The protective effect of N-acetylcysteine on apoptotic lung injury in cecal ligation and puncture-induced sepsis model. 1268 49

An acute septic inflammatory response with access to the portal circulation was created in a rat model using an intra-abdominal abscess composed of a sterile agar pellet, or one contaminated with 102 Escherichia coli (E. coli) and 109 Bacteriodes fragilis (B. fragilis). After 3 days postimplantation, a well-formed intra-abdominal abscess occurred whose wall showed IL-6 DNA by PCR and IL-6 mRNA by in situ hybridization. Portal venous blood draining into the liver from the intra-abdominal abscess had increased levels of TNF-alpha, IL-1beta, and IL-6 in both sterile and septic groups compared with a control normal animal group. Increased levels of these cytokines were also found in suprahepatic inferior vena caval blood, but were correlated with the higher portal vein levels, suggesting a gradient from abscess wall to portal vein into the systemic circulation via the liver. Liver histology demonstrated sinusoidal congestion centering on the central vein, growing worse with progression from normal in control, to sterile, to septic. Similarly, the degree of intrahepatic myeloperoxidase-positive inflammatory cell infiltration and hepatocellular lipid deposition and apoptosis also increased from control, to sterile, to septic. Gene expression by in situ hybridization demonstrated a significant increase in IL-6 and fibrinogen mRNAs in cells surrounding the central vein in sterile and septic animals, being greatest in animals with sepsis, associated with an increased deposition of collagen in the central vein area, most prominent in the septic liver. The pericentral vein cells with IL-6 and fibrinogen mRNA increases paralleled the increases in cells containing IL-6 and fibrinogen mRNAs in the abscess walls of sterile and septic animals, respectively. The data suggest that an intra-abdominal abscess, especially when contaminated with gram-negative bacteria, induces mRNA-generated cytokine responses in the abscess wall that are related to increased portal venous levels of the inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 perfusing the liver. These, in turn, induce localized production of IL-6 and fibrinogen mRNAs in cells at the central vein area with resultant outflow fibrosis and increased inflammatory cell sequestration within the liver lobular sinuses. This is associated with a generalized inflammatory response and intrahepatic portal sinusoid congestion. There is also increased hepatocellular lipid deposition and apoptosis. Thus, the cytokine production of the abscess wall itself appears to be a major mediator of the septic hepatic response.
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PMID:The septic abscess wall: a cytokine-generating organ associated with portal venous cytokinemia, hepatic outflow fibrosis, sinusoidal congestion, inflammatory cell sequestration, hepatocellular lipid deposition, and focal cell death. 1281 73

Sepsis is the most common morbidity in preterm infants, who often receive total parenteral nutrition (TPN). We hypothesized that gut barrier function is compromised in TPN-fed compared with enterally fed newborn piglets (ENT pigs). Colostrum-deprived newborn pigs were implanted with jugular venous and bladder catheters under general anesthesia. Pigs were either administered TPN (n = 15) or fed formula (ENT pigs, n = 15). After 6 days, pigs were gavaged a solution of mannitol, lactulose, and polyethylene glycol 4000 (PEG 4000) and urine was collected for 24 h. At 7 days, small bowel samples were assayed for myeloperoxidase activity, morphometry, and tight junction protein abundance. Intestinal contents and peripheral organ sites were cultured for bacteria. Urinary recovery (%dose) of mannitol (53 vs. 68) was lower, whereas that of lactulose (2.93 vs. 0.18) and PEG 4000 (12.78 vs. 0.96) were higher in TPN vs. ENT pigs, respectively (P < 0.05). Incidence of translocation was similar in TPN and ENT pigs. Myeloperoxidase activity was increased in TPN vs. ENT pigs in the jejunum (P < 0.001) and was weakly correlated with lactulose (R2 = 0.32) and PEG 4000 (R2 = 0.38) recovery. Goblet cell counts did not change, but intraepithelial lymphocyte numbers decreased with TPN. Only claudin-1 protein abundance was increased in the TPN group. We conclude that TPN is associated with impairment of neonatal gut barrier function as measured by permeability but not translocation.
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PMID:Total parenteral nutrition adversely affects gut barrier function in neonatal piglets. 1296 31


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