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)

Transient potential vanilloid 1 (TRPV1) receptor is an ion channel receptor primarily localized on sensory nerves and activated by specific stimuli to initiate and amplify pain and inflammation, as typified by murine models of scald and arthritis. Little is known of the role of TRPV1 in sepsis, an infective disease associated with inflammation. Through use of a sublethal murine model of lipopolysaccharide-induced peritoneal sepsis, we provide novel evidence that genetic deletion of TRPV1 leads to an enhanced onset of various pathological components of systemic endotoxemia. Paired studies of TRPV1 knockout (KO) and wild-type mice demonstrate significantly enhanced hypotension (56+/-2% vs. 38+/-6% decrease in blood pressure, n=12), hypothermia (13+/-3% vs. 7+/-1% decrease in core temperature, n=6), and peritoneal exudate mediator levels (TNF-alpha, 0.78+/-0.2 vs. 0.38+/-0.1 ng/ml; nitrite, for NO, 35+/-10 vs. 15+/-3 microM; n=8) in TRPV1 KO mice, indicating loss of protective effect. Findings correlated with liver edema and raised plasma levels of aspartate aminotransferase in TRPV1 KO mice. These data suggest that TRPV1 may play an important regulatory role in sepsis independent of the major sensory neuropeptide substance P. The findings are relevant to developing strategies that increase the beneficial, and reduce the harmful, components of sepsis to prevent and treat this often fatal condition.
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PMID:The transient receptor potential vanilloid 1 (TRPV1) receptor protects against the onset of sepsis after endotoxin. 1760 84

To investigate clinical course and outcome of dengue with acute respiratory failure (ARF), and to identify related risk factors for acquiring ARF in dengue, we retrospectively studied 11 dengue patients with ARF. From June to December 2002, a total of 606 adult patients were diagnosed as having dengue. Eleven (1.8%) of 606 dengue patients had complications of ARF. The main causes of ARF were sepsis (n = 6, 54.5%) and upper gastrointestinal (UGI) bleeding (n = 3, 27.3%). The mortality rate was 72.7% (n = 8). Additionally, univariate analysis showed that age, dyspnea, cough, prothrombin time, activated partial thromboplastin time, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, albumin, renal insufficiency, acute renal failure, acute hepatic failure, UGI bleeding, and combination bacterial infection were significantly predictive variables associated with dengue patients with ARF.
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PMID:Acute respiratory failure in adult patients with dengue virus infection. 1762 Jun 47

Biliary complications after liver transplantation (LT) using organs retrieved from donors after cardiac death are not well characterized. The aim of this study was to evaluate the severity of biliary complications and outcomes after donation after cardiac death liver transplantation (DCD-LT). A retrospective evaluation of 20 DCD-LTs from 1997-2006 was performed. The recipient age was 53+/-8.7, and the donor age was 35+/-11 years. The warm ischemia time, cold ischemia time, peak alanine aminotransferase level, and peak aspartate aminotransferase level were 33+/-12 minutes, 8.7+/-2.7 hours, 1757+/-1477 U/L, and 4020+/-3693 U/L, respectively. The bilirubin and alkaline phosphatase levels at hospital discharge after LT were 3.2+/-5.4 mg/dL and 248+/-200 U/L, respectively. During a median follow-up of 7.5 months (range: 1-73), 5 patients (25%; 1 death after re-LT) died (3 from sepsis, 1 from recurrent hepatocellular carcinoma at 4 months, and 1 from a cardiac event at 46 months), and additionally, 4 patients (20%) required re-LT (1 because of hepatic artery thrombosis, 1 because of primary graft nonfunction, and 2 because of biliary strictures). Twelve (60%) developed biliary complications, and of these, 11 (55%) had serious biliary complications. The biliary complications were as follows: a major bile leak for 2 patients (10%; both eventually underwent retransplantation), anastomotic strictures for 5 patients (25%), hilar strictures for 7 patients (35%), extrahepatic donor duct strictures for 9 patients (45%), intrahepatic strictures for 10 patients (50%), stones for 1 patients (5%), casts for 7 patients (35%), and debris for 2 patients (10%). More than 1 biliary complication was seen in most patients, and these were unpredictable and required multiple diagnostic or therapeutic procedures. Serious biliary complications are common after DCD-LT, and research should focus on identifying donor and recipient factors that predict and prevent serious biliary complications.
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PMID:Biliary complications and outcomes of liver transplantation from donors after cardiac death. 1804 64

IL-19, a proinflammatory cytokine, belongs to the IL-10 family. IL-19 is induced in systemic inflammatory response syndrome, but its pathophysiological function in sepsis is unclear. Our aim was to determine the roles of IL-19 in endotoxin-induced tissue damage in vivo and in vitro. We examined serum levels of IL-19 in sepsis patients and healthy volunteers, determined the in vitro effects of IL-19 on lung epithelial cells, liver cells, and neutrophils, and analyzed the tissue expression of IL-19 and its receptors in murine endotoxic shock. Electroporation-mediated gene transfer of mouse IL-19-soluble receptor plasmid DNA was used to determine the effects of IL-19 depletion in preventing endotoxic shock-induced tissue damage in mice. We found that serum levels of IL-19 were higher in patients than in healthy volunteers (n = 28, P = 0.001). IL-19 induced apoptosis in lung epithelial cells and reactive oxygen species production in liver cells in vitro. IL-19 also promoted neutrophil chemotaxis, reduced neutrophil apoptosis, and induced the production of proinflammatory cytokines and chemokines (IL-1[beta], IL-6, IL-8, CCL5, and CXCL9) in lung epithelial cells. In LPS-challenged mice, transcripts of IL-19 and its receptors were up-regulated in heart, lung, liver, and kidney tissue. Neutrophil infiltration in lung and liver tissue, and serum levels of alanine transaminase and aspartate transaminase, were lower in mice electroporated with IL-19-soluble receptor plasmid DNA before LPS treatment compared with control mice. These results suggest that up-regulated IL-19 may be involved in lung and liver tissue injury in murine endotoxic shock.
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PMID:IL-19 is involved in the pathogenesis of endotoxic shock. 1824 2

To investigate the effects of the cholinergic anti-inflammatory pathway on hemodynamics, blood biochemistry, the plasma TNF-alpha level, and the nuclear factor-kappaB (NF-kappaB) activation during septic shock, male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP, a model of polymicrobial sepsis) or sham operation. Forty-eight rats were randomly assigned into six equal groups: sham CLP group; CLP group; VGX group was subjected to bilateral cervical vagotomy after CLP; STM group was subjected to bilateral cervical vagotomy after CLP plus the left vagus nerve trunk electrical stimulation; THA group was administered tetrahydroaminoacridine after CLP and bilateral cervical vagotomy; and alpha-BGT group was administered alpha-bungarotoxin before electrical stimulation of the vagus nerve. The right carotid artery was cannulated to monitor MAP. The plasma TNF-alpha level was measured using enzyme-linked immunosorbent assays. The hepatic NF-kappaB activation was determined by Western blotting. Cecal ligation and puncture produced progressive hypotension. Serum aspartate transaminase and alanine transaminase levels significantly increased after CLP challenge. The plasma TNF-alpha level and the hepatic NF-kappaB activation significantly increased after CLP alone or with bilateral cervical vagotomy compared with sham-operated group. Application of constant voltage pulses to the caudal vagus trunk significantly prevented the development of CLP-induced hypotension, alleviated the hepatic damage, and reduced the plasma TNF-alpha production, but electrical stimulation had no effect on the hepatic NF-kappaB activation. Tetrahydroaminoacridine administration after bilateral cervical vagotomy reversed hypotension and attenuated the plasma TNF-alpha response; in addition, it had no effect on the hepatic NF-kappaB activation. alpha-Bungarotoxin pretreatment significantly reversed the inhibitory effect of vagal electrical stimulation, but it had no effect on the hepatic NF-kappaB activation. Our results showed that the cholinergic anti-inflammatory pathway might produce a potential protective effect on polymicrobial sepsis in rats.
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PMID:The protective effect of the cholinergic anti-inflammatory pathway against septic shock in rats. 1839 58

Hepatic ischemia should be considered in serious liver injury, liver tumor resection and liver transplantation. There are other conditions that decrease hepatic blood flow and cause hepatic ischemia, such as hemorrhagic shock, sepsis, hepatic artery ligation, trauma, and certain vascular lesions. In this study, effects of nimodipine (a calcium channel blocker) and pentoxyfylline (a derivative of methylxanthine) on duration and degree of hepatic ischemia in rats at normothermic and hypothermic conditions are investigated. This study was performed on 6 groups of Wistar Albino type rats, each group consisting of 7 rats. Groups were separated into normothermic (A) and hypothermic (B) conditions AI-Control group, AII-Nimodipine group and AIII-Pentoxyfylline group, B IV-Control group, BV-Nimodipine group and BVI-Pentoxyfylline group respectively. After hepatic pedicle occlusion lasting 45 min, blood samples were drawn from the rats for evaluation of alanine aminotransferase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) values. Moreover, hepatic biopsies were taken to assess pathological changes under electron microscopy. These changes were evaluated through a grading system. As a result; it has been shown that both nimodipine and pentoxyfylline delayed effects of hepatic ischemia in a statistically significant manner in comparison with the control group and these effects were found to be more significant in hypothermic conditions.
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PMID:Effects of nimodipine and pentoxyfylline in prevention of hepatic ischemic damage in rats at normal and hypothermic conditions. 1849 96

Sepsis remains the leading cause of death in intensive care units. Uncontrolled systemic inflammation and an impaired protein C pathway are two important contributors to sepsis pathophysiology. Based on the beneficial effects of the saponin fraction from Astragalus membranaceus roots (SAM) against inflammation, liver dysfunction, and endothelium injury, we investigated the potential protective roles and underlying mechanisms of SAM on polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice. SAM, orally administered 1 h before and after CLP, significantly elevated the survival rate of mice. At 96 h after CLP operation, all mice in the model group died, whereas 33.3% of mice in the SAM (400 mg/kg)-treated group survived. SAM attenuated both inflammatory factors and their abilities to induce tissue dysfunction, which was mainly evidenced by decreased infiltration of polymorphonuclear leukocytes, tissue edema, and lung wet-to-dry weight ratio, lowered levels of myeloperoxidase (MPO), nitric oxide (NO), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in serum, as well as downregulated expressions of iNOS and IL-1beta mRNA in livers. Furthermore, we addressed the effects of SAM on the protein C (PC) pathway, closely linked with sepsis. In CLP-induced septic mice, SAM elevated the impaired expression of PC mRNA in livers. In vitro, SAM reversed the decreased expressions of thrombomodulin (TM) and endothelial PC receptor (EPCR) mRNA induced by lipopolysaccharide (LPS) in endothelial cells. These findings suggest that SAM is able to restore the impaired protein C pathway. Taken together, the current study demonstrates that SAM has protective effects on polymicrobial sepsis in mice. The mechanisms of action involve anti-inflammation and upregulation of the PC pathway.
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PMID:Saponin fraction from Astragalus membranaceus roots protects mice against polymicrobial sepsis induced by cecal ligation and puncture by inhibiting inflammation and upregulating protein C pathway. 1954 65

Human melioidosis caused by Burkholderia pseudomallei is a severe septic disease that is associated with high mortality, even under appropriate antibiotic treatment. The therapeutic effects of low-dose hydrocortisone plus ceftazidime, and of ceftazidime alone, have recently been investigated in the treatment of acute, severe sepsis caused by B. pseudomallei, both in normal BALB/c mice and in BALB/c mice with streptozotocin-induced diabetes. The mice were infected and then treated intravenously, from day 1 or day 2 post-infection, with saline (as a control, given twice daily for 10 days), low-dose hydrocortisone (given in twice-daily doses of 5 mg/kg, for 5 days) plus ceftazidime (given in twice-daily doses of 1200 mg/kg, for 10 days), or the same doses of ceftazidime alone. Although the infected, untreated mice all died within 14 days, almost all of the treated animals were still alive at the end of the follow-up, 30 days post-infection. The addition of the steroid appeared to have no benefit, with bacterial loads and plasma concentrations of tumour necrosis factor, aspartate aminotransferase, alanine aminotransferase and creatinine decreasing similarly in all the treated groups. The infected diabetic mice given hydrocortisone-ceftazidime from day 1 (but not those given just ceftazidime from day 1) showed an increase in their blood glucose concentrations. When infected mice were treated with the low-dose steroid and lower doses of the antibiotic (in twice-daily doses of 120-600 mg/kg), the steroid not only offered no apparent benefit but seemed to reduce survival. It therefore appears that low-dose hydrocortisone, as an adjunct to antibiotic treatment, does not provide benefit in the treatment of murine melioidosis and may have negative effects on human cases of the disease who have diabetes mellitus.
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PMID:Use of a low-dose steroid as an adjunct in the treatment, in mice, of severe sepsis caused by Burkholderia pseudomallei. 1982 85

Sepsis is a systemic inflammatory response syndrome (SIRS) when an infection is the etiology of SIRS. Our previous studies have indicated that the release of the sympathetic neurotransmitter, norepinephrine (NE), from the gut is increased in sepsis, and that NE potentiates endotoxin-induced tumor necrosis factor (TNF)-alpha upregulation via the A subtype of alpha(2)-adrenoceptors (i.e., alpha(2A)-AR) expressed on the surface of Kupffer cells. A specific antagonist for alpha(2A)-AR, 2-[(4,5-dihydro-1H-imidazol-2-yl) methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL-44408 maleate), reduces TNF-alpha secretion in cultured Kupffer cells. We, therefore, hypothesize that administration of BRL-44408 maleate inhibits inflammatory responses and reduces organ injury in sepsis. To study this, sepsis was induced in male rats by cecal ligation and puncture (CLP). At 5 h after CLP, BRL-44408 maleate (0.3125, 0.625, 1.25, 2.5, or 5.0 mg/kg BW) or vehicle (1-ml normal saline) were administered intravenously over a period of 30 min. Blood and intestinal samples were collected at 20 h after CLP. Serum levels of TNF-alpha, interleukin (IL)-6, IL-10, keratinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2), liver enzymes (i.e., aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), and lactate were measured. The intestinal levels of TNF-alpha, IL-6, and myeloperoxidase (MPO) activities were also analyzed. In additional groups of animals, the necrotic cecum was excised at 20 h post-CLP, and the 10-day survival was recorded. Our results showed that serum levels of proinflammatory cytokines (TNF-alpha and IL-6), anti-inflammatory cytokine (IL-10), chemokines (KC, MIP-2), liver enzymes (AST and ALT), lactate, and intestinal levels of TNF-alpha, IL-6, and MPO were significantly elevated at 20 h after CLP. Administration of BRL-44408 maleate significantly reduced serum levels of proinflammatory cytokines, chemokines, liver enzymes, and lactate, and dramatically decreased TNF-alpha, IL-6, and MPO levels in the gut. However, it has no statistical effects on the elevated serum levels of IL-10. Moreover, BRL-44408 maleate at the doses of 2.5 or 5.0 mg/kg BW significantly increased the survival rate after CLP and cecal excision. In conclusion, modulation of the sympathetic nervous system by blocking alpha(2A)-AR appears to be a novel treatment for inflammatory conditions such as sepsis.
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PMID:Antagonism of alpha2A-adrenoceptor: a novel approach to inhibit inflammatory responses in sepsis. 1989 27

The aim of this study was to evaluate the actions of the non-steroidal anti-inflammatory drug flunixin-meglumin (FM) on the changes caused by lipopolysaccharide (LPS)-induced sepsis in the rat liver. Eight groups of five adult male Wistar rats were analysed: (1) saline injected (controls), (2) FM treated with 1.1 mg/kg, (3) FM treated with 2.2 mg/kg, (4) LPS-injected (10 mg/kg), (5) LPS-injected with 1.1 mg/kg FM pretreatment, (6) LPS-injected with 2.2 mg/kg FM pretreatment, (7) LPS-injected with 1.1 mg/kg FM post-treatment and (8) LPS-injected with 2.2 mg/kg FM post-treatment. All drugs were intraperitoneally injected. The following parameters were evaluated: plasma levels of hepatic enzymes and urea, hepatic histological characteristics, antioxidant enzymes and several metabolic fluxes. The latter comprised gluconeogenesis, ureagenesis and oxygen consumption. Liver damage in LPS-induced sepsis was characterized by histological changes, increased plasma levels of alanine aminotransferase and aspartate aminotransferase (P < 0.001) and diminished gluconeogenesis (P < 0.001) and ureagenesis (P < 0.01). LPS also induced oxidative stress as evidenced by increased catalase (P < 0.05) and superoxide dismutase activities and enhanced lipid peroxidation (P < 0.001). Pretreatment of the animals with FM minimized the histological changes and normalized, in part, all enzymatic activities. Pretreatment of the animals with FM also normalized gluconeogenesis and partly restored ureagenesis (P < 0.05). These and other results show that LPS-induced sepsis may lead to severe liver damage, affecting both structure and function. Treatment with FM can be used to avoid this damage. The antioxidant properties of FM can be, partly at least, responsible for this protective action.
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PMID:Hepatic effects of flunixin-meglumin in LPS-induced sepsis. 2003 Jul 36


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