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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and autopsy studies have shown an association between clotting, microembolism, and inhibition of fibrinolysis and respiratory distress after trauma or sepsis. Prophylaxis and treatment with the aim of decreasing the deposition of fibrin in the lungs were associated with a large decrease in the incidence and death rate of this syndrome. Small fibrin degradation products (peptides) are accumulated in the lungs and are only slowly cleared from this organ, especially during states of inhibition of fibrinolysis. These peptides may contribute to the pulmonary damage in several ways. As well as having a direct effect on the endothelium, they act by interfering with other vasoactive substances as bradykinin, histamine, and products of the arachidonic acid cascade. Products of the cyclooxygenase pathway such as thromboxane A2 play a major role in early microembolism, whereas lipoxygenase products seem to be involved in later stages. Pulmonary microembolism thus seems to be one important, but certainly not the only, pathogenetic factor in acute "idiopathic" respiratory failure. Other factors, such as pulmonary contusion, aspiration of gastric contents or blood, or oxygen toxicity, might well be contributory in some cases. Pulmonary microemboli containing fibrin and leukocytes are probably also involved as contributory agents in some cases in the large group of acute respiratory failures due to "known factors."
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PMID:Clotting, microembolism, and inhibition of fibrinolysis in adult respiratory distress. 619 Feb 36

Protein degradation in skeletal muscle increases with fever and sepsis. Our studies indicate that prostaglandin E2 (PGE2) is an important regulator of muscle proteolysis that seems to signal this increase in fever. When rat skeletal or cardiac muscles were incubated with arachidonate, rates of protein breakdown rose and protein balance became more negative. Aspirin or indomethacin, which prevented synthesis of PGE2, markedly reduced this effect. By itself PGE2 stimulated proteolysis without altering protein synthesis. PGE2 seems to increase proteolysis in the lysosomes, inasmuch as leupeptin and Ep-475 inhibit this response. These inhibitors inactivate lysosomal thiol proteases in the muscles without affecting the Ca2+-activated protease. (In fact, complete inactivation of the latter enzyme with mersalyl did not reduce overall proteolysis in the muscles). When muscles from feverish rats were incubated in vitro, they showed greater protein breakdown and PGE2 synthesis than muscles from normal animals. Addition of indomethacin eliminated this difference. Leukocytic pyrogen (interleukin 1), a protein released by monocytes that signals the onset of fever, also seems to signal increased muscle PGE2 synthesis and muscle proteolysis. This protein enhanced both processes dramatically in the isolated muscles. These findings suggest that cyclooxygenase inhibitors may be useful in the treatment of patients showing excessive protein breakdown.
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PMID:Control of protein degradation in muscle by prostaglandins, Ca2+, and leukocytic pyrogen (interleukin 1). 632 20

To clarify the mechanisms underlying the loss of body protein during fever and sepsis, we incubated rat muscles with highly purified human leukocytic pyrogen. This polypeptide, which appears identical to interleukin-1, is released by leukocytes and signals the onset of fever in the hypothalamus. In muscles incubated at 37 degrees C, leukocytic pyrogen stimulated net protein degradation by 62 to 118 per cent (P less than 0.001). Proteolysis increased, but rates of muscle-protein synthesis did not change. The pyrogen also dramatically stimulated muscle synthesis of prostaglandin E2, which promotes protein breakdown in this tissue. Addition of indomethacin with leukocytic pyrogen prevented prostaglandin E2 synthesis and abolished the increase in proteolysis. The acceleration of protein breakdown induced by pyrogen was also blocked by Ep-475, an inhibitor of lysosomal thiol proteases. When muscles were incubated at 39 degrees C to mimic fever, protein breakdown increased, but addition of leukocytic pyrogen caused a further marked increase in proteolysis and prostaglandin E2 production. Thus, human leukocytic pyrogen can act on skeletal muscle to stimulate intralysosomal proteolysis by increasing the production of prostaglandin E2. These findings suggest that cyclooxygenase inhibitors may be useful in the treatment of negative nitrogen balance in fever. In addition, the release of prostaglandin E2 induced by leukocytic pyrogen may account for the myalgia that accompanies fever.
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PMID:Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). A mechanism for the increased degradation of muscle proteins during fever. 640 99

Steroids and cyclooxygenase inhibitors have been advocated as adjunctive treatment for sepsis. We studied the influences of these treatments on the survival of 98 male Sprague-Dawley rats in which sepsis was induced by cecal ligation and puncture. Rats received one of four treatments: sodium chloride (NaCl); methylprednisolone, 30 mg/kg (MP); ibuprofen, 12.5 mg/kg (I); methylprednisolone, 30 mg/kg, plus ibuprofen, 12.5 mg/kg (MP + I). Cumulative survival statistics were determined daily for 14 days thereafter. Survival was not altered by either MP or I when compared to animals receiving NaCl only. However, the combination of MP + I increased mortality from day 2 through day 14. The authors conclude that (1) MP administration alone does not increase mortality in septic rats; therefore, the results do not support the contention that steroid treatment in the absence of antibiotic therapy may be detrimental; (2) the cyclooxygenase inhibitor I does not improve survival in septic rats; and (3) the combined administration of MP and I increases mortality in septic rats and the possibility that this combination might be harmful in septic patients should be considered also.
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PMID:Methylprednisolone plus ibuprofen increases mortality in septic rats. 650 29

Thromboxane (TX) has been reported to cause mortality in endotoxin or septic shock. Cyclooxygenase inhibition improves survival in gram-negative or gram-positive shock. The exact level in the prostaglandin system of which the protection occurs is unknown. This study was designed to compare the effects of a cyclooxygenase inhibitor (indomethacin, IND) to a thromboxane synthetase inhibitor (IMI) on survival and on the production of Tx and prostacyclin (PGI2) in a clinically relevant rat gram-negative sepsis model. Three groups were studied: 1) control (N = 35) animals received E coli only; 2) IND (N = 35) treated animals received 3 mg/kg IP; 3) IMI (N = 35) treated animals received 30 mg/kg IP. All drugs were given 1 h after an IP injection of E coli (LD70) organisms. In this model only IND significantly improved survival. IND and IMI significantly blocked the production of Tx seen in septic shock. IND blocked PGI2 production whereas IMI increased the production. These results show that Tx may not be important in the irreversible stages of shock. Shunting prostaglandin production to PGI2 with thromboxane synthetase inhibitors needs to be considered when using this group of compounds. The mechanism of protection by IND remains unknown.
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PMID:Thromboxane synthetase inhibitors in septic shock. 668 24

Blockade of the arachidonic acid cascade has been shown to improve survival and hemodynamic alterations in animal models of sepsis and acute respiratory failure (ARF). The effects of intravenous ibuprofen, a cyclooxygenase inhibitor, were observed in 20-30 kg pigs with ARF induced by a continuous LD100 infusion of live Pseudomonas aeruginosa (2 X 10(8)/20 kg/min). Cardiopulmonary parameters were monitored in animals intubated, paralyzed, and ventilated at a 250-ml tidal volume and 0.5 FiO2. Pigs were randomly assigned to three groups: Group I received 2 bolus infusions of ibuprofen (12.5 mg/kg) at 20 and 210 min after baseline; Group II had Ps. aeruginosa (2 X 10(8) CFU/20 kg/min) only; Group III received Ps. aeruginosa and 12.5 mg/kg of ibuprofen at 20 and 210 min of ARF. Ibuprofen alone caused no significant changes in cardiorespiratory parameters. With Ps. aeruginosa infusion, significant pulmonary hypertension, hypoxemia, increased intrapulmonary shunt fraction, and systemic hypotension occurred. In the septic animals treated with ibuprofen, oxygenation was improved by a significant decrease in shunt, pulmonary edema, and pulmonary hypertension.
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PMID:Effects of ibuprofen on a porcine model of acute respiratory failure. 670 94

Prostaglandins released during inflammatory reactions cause increases in microvascular hydrostatic pressure, a primary cause of edema. Ibuprofen, a nonsteroidal, anti-inflammatory agent that reduces prostaglandin synthesis via inhibition of cyclooxygenase, was used to investigate the possible role of prostaglandins in the cardiopulmonary responses during sepsis. Sheep, surgically prepared for cardiopulmonary studies and collection of lung lymph, were given 0.75 micrograms/kg per 30 min of E. coli endotoxin iv. Ibuprofen (14 mg/kg) was given 15 min before and 1 h 45 min after the administration of endotoxin. We had previously noted a triphasic character to the hypovolemia encountered in endotoxin sepsis. The initial phase occurs during the first hour after endotoxin administration; it is characterized by decreases in PaO2, neutrophil count, and lymph-to-plasma (L/P) protein concentration ratios and by increases in mean arterial pressure, body temperature, hematocrit, lymph flow, and total plasma protein concentration. In the second phase these variables return toward their baseline values. In Phase 3 the same changes are observed an in Phase 1 except for a decrease in total plasma protein concentration and an increase in L/P ratios. Ibuprofen administration results in a statistically significant reduction in magnitude of Phase 1 changes, without notable effect on Phase 2 or Phase 3 values. These observations support the hypothesis that prostaglandins released during inflammatory reactions contribute to the extravascular fluid movement. Ibuprofen appears to lessen the severity of microvascular hydrostatic pressure-induced edema and the hypovolemia that occurs in the early stages of endotoxin.
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PMID:The effects of a prostaglandin synthetase inhibitor, ibuprofen, on the cardiopulmonary response to endotoxin in sheep. 675 68

Clinical and autopsy studies have shown an association between pulmonary microembolism and acute respiratory failure after trauma or sepsis. Prophylaxis and treatment with the aim of decreasing the fibrin deposition in the lungs were associated with a decrease in the incidence and death rate of this syndrome. Small fibrin degradation products (peptides) are accumulated in the lungs and are only slowly cleared from this organ, especially during states of fibrinolysis inhibition. These peptides may contribute to the pulmonary damage in several ways. They act by interfering with other vasoactive substances as bradykinin, histamine and products of the arachidonic acid cascade. Products of the cyclooxygenase pathways as thromboxane A2 play a major role in early microembolism whereas lipoxygenase products seem to be involved in delayed microembolism. Pulmonary microembolism thus seems to be one important, but certainly not the only pathogenetic factor in acute "idiopathic" respiratory failure. Other factors such as pulmonary contusion, aspiration of gastric contents or blood, or oxygen toxicity, might well be contributory in some cases. Pulmonary microemboli containing fibrin and leukocytes are probably also involved as contributory agents in some cases in the large group of acute respiratory failure due to "known factors".
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PMID:Pulmonary microembolism as a cause of acute respiratory failure. 696 76

To test the hypothesis that release of endothelium-derived relaxing factor/nitric oxide is inhibited by Gram-negative lipopolysaccharide (LPS; endotoxin), we examined endothelium-independent and endothelium-dependent vasodilator agents in aortic vascular smooth muscle isolated from guinea pigs 4 h after injection of saline (controls) or induction of Escherichia coli endotoxemia. LPS significantly inhibited vasodilator responses to the endothelium-dependent agonists acetylcholine (ACh; 10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). However, LPS did not affect vasodilator responses to the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase (NOS) inhibitor N gamma-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to ACh; whereas, the cyclooxygenase inhibitor indomethacin (INDO) did not reduce vasodilator effects of ACh. Neither L-NAME nor INDO affected the vasodilator effects of nitroprusside in LPS or control vessels. In contrast, L-NAME converted the vasodilator action of ADP to a vasoconstrictor response that was blocked individually by INDO and the thromboxane synthase inhibitor dazoxiben, suggesting that ADP releases NO and also the vasoconstrictor and platelet aggregating eicosanoid thromboxane A2. These findings suggest that acute (4 h) endotoxemia inhibits function of the constitutive isoform of NOS in vascular endothelial cells. Since L-NAME unmasked a vasoconstrictor action of the endogenous purinoceptor agonist ADP, pharmacologic agents that inhibit NOS may exacerbate LPS-induced inhibition of endothelial NOS; this series of events could lead to diminution of vasodilator reserves and perhaps to augmentation of platelet aggregation during Gram-negative sepsis.
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PMID:Inhibition of endothelium-dependent vasodilation by Escherichia coli endotoxemia. 753 38

In conventional usage, "sepsis" denotes a clinical syndrome caused by excessive release of a variety of proinflammatory mediators, including tumor necrosis factor alpha, interleukin-1, and metabolites of arachidonic acid. Because this condition can be precipitated by infectious or noninfectious causes (eg, acute pancreatitis), a recent consensus conference has advocated replacing the term sepsis with the phrase systemic inflammatory response syndrome. Improvements in our understanding of the pathophysiologic basis for systemic inflammatory response syndrome have resulted in the development of a number of novel approaches for treating, preventing, or limiting its deleterious consequences. Although much of this work remains confined to the laboratory, several of these approaches are undergoing (or recently have undergone) clinical evaluation. Among these are the use of monoclonal antibodies against endotoxin, monoclonal antibodies against tumor necrosis factor, recombinant proteins that antagonize the effects of or bind to circulating interleukin-1 or tumor necrosis factor, and drugs that inhibit the enzyme cyclooxygenase, which is responsible for the formation of certain key metabolites of arachidonic acid.
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PMID:Surgical infections: blocking the mediator cascade responsible for sepsis and septic shock. 758 65


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