Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF alpha), both by direct action and by trafficking cells of the immune system, is implicated in cardiopulmonary derangements and PMN-mediated microvascular injury associated with gram-negative sepsis. We examined the effects of pretreatment with a monoclonal antibody to TNF alpha on PMN function, hemodynamic derangements, and alveolar capillary membrane damage in a septic porcine model. Anti-TNF alpha profoundly improved hemodynamic consequences in this model. Reduction in PMN CD11/18 receptor expression, lung myeloperoxidase activity, and attenuation of peripheral neutropenia (all P < 0.05) indicate that pretreatment significantly reduced lung sequestration of PMNs seen in septic controls. In contrast, PMN oxygen radical (O2-) generation was not significantly different from unprotected septic animals. Despite the presence of circulating PMNs primed for O2- burst, alveolar capillary membrane damage, assessed by bronchoalveolar lavage protein content and arterial PO2 was markedly attenuated in the treatment group (P < 0.05). We conclude that anti-TNF alpha suppresses systemic hemodynamic actions of TNF alpha. Further, it prevents upregulation of PMN adhesion receptors inhibiting PMN/endothelial cell interaction. This prevents formation of a "microenvironment," protected from circulating oxidant scavengers, into which sepsis-activated PMNs release their toxic products. Pretreatment with anti-TNF alpha monoclonal antibody thus affords global protection in porcine Gram-negative sepsis.
 ...
PMID:Tumor necrosis factor-alpha blockade prevents neutrophil CD18 receptor upregulation and attenuates acute lung injury in porcine sepsis without inhibition of neutrophil oxygen radical generation. 809 6

Injection of bacterial lipopolysaccharide (LPS) into experimental animals induces septic shock associated with the release of tumor necrosis factor (TNF) and platelet-activating factor (PAF). Because both TNF and PAF stimulate neutrophil adhesion to endothelial cells in vitro, and because neutrophils are important effector cells in sepsis-induced lung vascular injury, the role of TNF and PAF in LPS-induced lung neutrophil sequestration was investigated. Lung myeloperoxidase (MPO) activity was measured as a quantitative assessment of pulmonary leukostasis. Injection of Salmonella enteritidis LPS into rats caused dose-dependent increases in lung MPO that peaked at 2 hours and persisted for up to 24 hours. Injection of purified human recombinant TNF (2 to 200 micrograms/kg i.v.) mimicked the effect of LPS on lung MPO activity. Injection of synthetic PAF increased lung MPO only at the highest and lethal dose (10 micrograms/kg). Lower doses (0.1 and 1 microgram/kg) of PAF had no effect on lung MPO by itself and did not enhance LPS- or TNF-induced lung neutrophil sequestration. Furthermore, pretreatment of the rats with two different PAF receptor-antagonists, WEB 2086 (10 mg/kg IP) and SRI 63-441 (10 mg/kg IP), failed to block LPS-induced (1 mg/kg) increase in lung MPO. These data suggest that TNF, not PAF, mediates LPS-induced pulmonary neutrophil sequestration in the intact rat.
 ...
PMID:Endotoxin-induced pulmonary leukostasis in the rat: role of platelet-activating factor and tumor necrosis factor. 828 63

Pulmonary edema and sepsis-like syndrome are grave complications of interleukin-2 (IL-2) therapy. Recent animal studies have suggested IL-2-induced microvascular injury as the underlying mechanism. Since complement factors have been shown to mediate increased vascular permeability in diverse conditions that lead to pulmonary injury and recombinant human IL-2 is known to activate the complement system in patients undergoing IL-2 therapy, we hypothesized that complement factors play a pivotal role in the development of increased vascular permeability after IL-2 treatment. To test this hypothesis, we evaluated the capacity of recombinant soluble human complement receptor type 1 (sCR1, BRL 55730), a new highly specific complement inhibitor, to attenuate IL-2-induced lung injury in the rat. Recombinant human IL-2 (intravenously for 60 minutes) at 10(6) U per rat (n = 4) elevated lung water content (37 +/- 6%, P < .05), myeloperoxidase activity (162 +/- 49%, P < .05), and serum thromboxane B2 (30 +/- 1 pg/100 microL, P < .01) and had no effect on serum tumor necrosis factor-alpha sCR-1 at 30 mg/kg (n = 5), but not at 10 mg/kg (n = 6), attenuated the elevation of lung water content (18 +/- 2%, P < .05) and myeloperoxidase activity (42 +/- 9%, P < .05) but failed to alter serum thromboxane B2 response to IL-2. These data suggest the involvement of complement in the pathogenesis of IL-2-induced pulmonary microvascular injury and point to the potential therapeutic capacity of complement inhibitors in combating this toxic effect of IL-2 therapy.
 ...
PMID:Interleukin-2-induced lung injury. The role of complement. 829 71

Skeletal muscle is a target organ during sepsis; nevertheless, there is no evidence of a possible free radical overproduction with tissue damage in this situation. We studied Sprague Dawley female rats in two groups: a septic group with cecal ligation and double cecal perforation and a control group that was sham operated. Hind limb adductor muscles spontaneous chemiluminescence was measured at 2, 4, 6, 12, 24, and 30 hr after the surgical procedure as the expression of oxygen excited species generation. Muscle samples were also taken and activity of the principal antioxidant enzymes--superoxide dismutase (SOD), catalase, and glutathione peroxidase--as well as myeloperoxidase, an index of neutrophil infiltration was determined. CPK seric assays at 12 and 24 hr were used to reflect muscle injury and revealed high levels. Previously administered bovine superoxide dismutase was employed to prevent or attenuate oxidative stress. The results showed that light emission by rat skeletal muscle doubled from 4 to 12 hr of sepsis and could be attenuated with SOD pretreatment. Observed changes may be attributed to the production of oxygen free radicals that do not depend on local neutrophil infiltration. The detoxifying antioxidant enzyme activities in skeletal muscle were diminished (Mn SOD 46% at 6 hr, catalase 83% at 12 hr glutathione peroxidase 55% at 12 hr), which would also facilitate muscle septic damage.
 ...
PMID:Oxidative stress in skeletal muscle during sepsis in rats. 838 98

We have described a 45-year-old obese white man found to have myeloperoxidase (MPO) deficiency of the granulocytic and monocytic series. Pancreatic necrosis due to bacterial infection developed as a complication of acute pancreatitis. Subsequently, he died of sepsis. MPO staining of terminal antemortem blood smears and postmortem bone marrow aspirates showed absence of MPO in cells of the myelocytic and monocytic series. Family members' neutrophils and monocytes stained positive for MPO. MPO deficiency associated with severe sepsis is rarely reported. This case serves as a review of the association between hereditary and acquired MPO deficiency and severe infection.
 ...
PMID:Myeloperoxidase deficiency and severe sepsis. 839 23

Neutrophil accumulation in rat lungs during fecal peritonitis was estimated by the increase in myeloperoxidase content. The oxidative response of lung neutrophils was monitored as the increase in low-level chemiluminescence from intact lungs, before and after stimulation by phorbol myristate acetate (PMA). Myeloperoxidase activity increased 20-fold within 6 h of the surgical procedure, declining over the next 10 h to 12 times control. There was no significant increase over controls in either bronchoalveolar lavage protein or spontaneous chemiluminescence unless neutrophils were stimulated by PMA. When neutrophils were stimulated with PMA, lung chemiluminescence was not proportional to neutrophil content. The oxidative response increased as sepsis progressed from 51 +/- 4.5 cps/pair lungs in controls to 410 +/- 204 at 16 h after surgery, even though at that time point myeloperoxidase content had begun to decrease. The oxidative response of bronchoalveolar lavage cells was threefold greater in 16-h septic rats than in controls.
 ...
PMID:Characteristics of neutrophil influx in rat lungs following fecal peritonitis. 839 92

During sepsis, the systemic inflammatory response is characterized by the release of numerous mediators supporting and dispersing inflammation. In Gram negative sepsis, the endotoxins play a starting role, while in other sepsis, the triggering mediators or mechanisms are unknown but lead to a similar inflammatory reaction. Coagulation and complement cascades are activated, with the release of chemoattractive substances, mediators and proteases and the activation of phagocytic cells. Macrophages/monocytes and polymorphonuclear leucocytes produce then active oxygen species and cytokines; they degranulate (releasing active enzymes such as myeloperoxidase), they express an increasing number of membrane receptors able to interact with endothelial cells and release a supplementary lot of inflammatory mediators (prostanoids, platelet activating factor, leukotrienes ... ). Platelets, also activated, produce the same mediators (TXA2, PAF ...) or specific ones such as serotonine, platelet factor 4, growth factors. Last, but not least, the endothelial cells are stimulated, directly (by endotoxins) or undirectly (by cytokines, C5a, PAF ...). These cells play then a main role by their own phagocytic activity, by alteration of their antithrombotic and fibrinolytic potential, by their secretion of inflammatory mediators and by an increased expression of receptors of adhesivity for the activated phagocytes or platelets, what leads to endothelium injury with membrane permeability alterations. These cascades of activation, these extensions of the inflammatory reaction by the mediators and by the phagocytes and platelets can explain the frequency of multiple organ failure during sepsis as well as the difficulty of an adequate pharmacological therapy.
 ...
PMID:[Other mediators of inflammation and sepsis]. 846 93

Airway acid aspiration leads to severe microvascular lung injury and pulmonary edema. Recent studies have demonstrated that other conditions associated with microvascular injury such as sepsis and burns can be effectively treated with low-volume hypertonic saline (HTS). Thus, the present study aimed to test whether HTS attenuates aspiration-induced lung injury in the rat. Intratracheal administration of 0.2 ml of 0.1 N HCl (n = 7) induced pulmonary leukosequestration [myeloperoxidase (MPO) activity +446 +/- 34%, P < 0.05; bronchoalveolar lavage (BAL) fluid neutrophil count + 178 +/- 23%, P < 0.05], edema (division 43 +/- 6%, P < 0.01), and microvascular permeability defect (BAL protein concentration +675 +/- 34%, P < 0.01). These changes were associated with tissue hypoxia (skeletal muscle PO2, 49 +/- 8 mm Hg, P < 0.05) and elevated serum TNF alpha (750 +/- 38 pg/ml, P < 0.01). HTS (2400 mosmole/liter) at 5 ml/kg, administered 20 min after aspiration (n = 7), reduced lung pulmonary edema by 58 +/- 7% (P < 0.05) and improved tissue oxygen tension (PO2, 85 +/- 7 mm Hg, P < 0.05) but failed to alter lung MPO and BAL fluid protein and leukocyte count response. Also, HTS did not reduce TNF alpha response to aspiration. These data point to a potential therapeutic role for low-volume HTS in treating aspiration-induced lung injury. In addition, our data suggest that HTS is acting by rapidly shifting fluid from the pulmonary interstitium to the intravascular compartment because it did not inhibit the inflammatory response to aspiration.
 ...
PMID:Hypertonic saline treatment of acid aspiration-induced lung injury. 859 11

The protective effects of hydroxyethyl starch-conjugated deferoxamine (HES-DFO), a macromolecular iron chelator, on the initial pathophysiological cascade in septic shock were evaluated following cecal ligation puncture (CLP) in rats. Animals were given an intravenous dose of 3.0 mL of either vehicle (HES) or HES-DFO immediately following completion of the CLP procedure. Animals were sacrificed 30, 60, 120, and 240 min following CLP, and samples of lung, kidney, bowel, and liver were collected for subsequent analysis of glutathione, myeloperoxidase, and evidence for lipid peroxidation based on measurement of thiobarbituric acid reactive substances and conjugated dienes. In addition, the endotoxin levels were determined in the plasma and histomorphological examination was conducted on tissue samples collected at each time point. At almost all time points, a reduction in lipid peroxidation was noted in the HES-DFO-treated rats (p < .05). Glutathione and myoloperoxidase levels were less affected. Lung tissue from animals receiving HEs demonstrated marked microatelectases, septal destruction, and splicing of basal membranes, which were greatly attenuated in animals having received HES-DFO. Similarly, tubulotoxic and mitochondrial damages observed in kidney samples from HES-treated animals were noticeably reduced in the animals having received the chelator. Liver and gut samples demonstrated unspecific inflammatory injury in both groups of animals. In summary, oxygen radical-mediated tissue damage occurs rapidly following CLP-induced sepsis. Based on histological and biochemical endpoints, treatment with the polymeric iron chelator, HES-DFO, significantly attenuates systemic oxidant injury, the degree of protection being most impressive in the lung and kidney.
 ...
PMID:Protective effects of hydroxyethyl starch-deferoxamine in early sepsis. 860

Vibrio vulnificus is an estuarine bacterium that causes septicemia and serious wound infection. Cytolysin produced by V. vulnificus has been incriminated as one of the important virulence determinants of bacterial infection. Cytolysin (8 hemolytic units) given intravenously to mice via their tail veins caused severe hemoconcentration and lethality. Cytolysin treatment greatly increased pulmonary wet weight and vascular permeability as measured by (125)I-labeled albumin leakage without affecting those factors of other organs significantly. Blood neutrophils were markedly decreased in number after cytolysin injection, with a concomitant increase in the level of pulmonary myeloperoxidase activity, indicating that cytolysin-induced neutropenia might be due to pulmonary sequestration of neutrophils. By microscopic examination, severe perivascular edema and neutrophil infiltration were evident in lung tissues. These results suggest that increased vascular permeability and neutrophil sequestration in the lungs are important factors in lethal activity by cytolysin.
 ...
PMID:Pulmonary damage by Vibrio vulnificus cytolysin. 911 7


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>