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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although there are no specific therapies for septic shock or acute lung injury that have proven efficacy in humans, a growing understanding of mechanisms of tissue injury has suggested interventions that may prevent or treat this injury. These therapies range from immunization against the glycopolysaccharide core of endotoxin to cyclooxygenase inhibitors to specific oxygen radical scavengers. Each of these treatments is effective in ameliorating at least one of the pathophysiologic manifestations of acute lung injury, although the effect of these agents in the prevention of the sequelae of fibrosis is unknown. Interaction between several factors and mediators is likely necessary for the development of acute lung injury. It is hoped that with additional knowledge regarding mechanisms of injury gained through basic science and clinical research, we can apply definitive therapy that may salvage patients who now die with sepsis and acute lung injury.
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PMID:Therapeutic implications of acute lung injury. 333 66

The blood coagulation system is activated regularly in severe forms of shock, polytrauma, and sepsis. Arising thrombin cleaves the fibrinopeptides A and B from fibrinogen, and it generates monomers of fibrin, which are initially kept in solution by the remaining excess fibrinogen. The effects of soluble fibrin (fibrin monomer/oligomer-fibrinogen complexes) and fibrinopeptides A and B were investigated in blood-free perfused, isolated rabbit lungs. Urea Tris buffer-dissolved fibrin monomers were injected into the pulmonary artery in the presence of circulating excess fibrinogen. In doses above 5 mg, the monomers consistently provoked a sharp rise in pulmonary artery pressure, which was followed by an elevated pressure plateau. Changing to fresh perfusate devoid of soluble fibrin did not restore the pressure to baseline, and a second administration of the soluble fibrin caused a pressor response larger than the first. Only a modest increase in lung weight (less than 2 g) was observed, and lung inflation pressure was not altered. The pressor responses were accompanied by a rapid release of thromboxane A2 and a more delayed release of prostaglandin I2 into the perfusion fluid. A significant correlation between the height of the fibrin-induced pressure rise and the amount of thromboxane release was noted. Inhibition of cyclooxygenase (indomethacin) suppressed the generation of both prostanoids, whereas inhibition of thromboxane synthetase (OKY-046 and imidazole) selectively blocked the liberation of thromboxane. All three inhibitors caused an immediate decline in pulmonary artery pressure, which had been previously elevated due to administration of soluble fibrin, and markedly reduced the pressor response evoked by a subsequent fibrin application in the same lung.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary vasoconstrictor response to soluble fibrin in isolated lungs: possible role of thromboxane generation. 334 71

It has been recently suggested that increased muscle protein degradation during injury or infection is at least partially mediated by the increased production of prostaglandin E2 in muscle, and some have suggested that cyclooxygenase inhibitors might decrease protein loss in injured or septic patients. In these experiments, fractional synthesis rates of mixed muscle and liver protein and whole-body tyrosine flux were measured by constant intravenous infusion of tyrosine labeled with carbon 14 in 17 rats with sham operations and 15 severely septic rats with or without indomethacin treatment (20 mg/kg/d). Fractional synthesis rates in muscle and liver were decreased in late sepsis and were lowest in the septic group receiving indomethacin. Unlike the fractional synthesis rate, which was affected by indomethacin in septic rats only, tyrosine flux was significantly lower in indomethacin-treated rats with sham operations and those with sepsis. Although indomethacin reduced total-body protein breakdown during sepsis, it was also associated with lower plasma albumin levels and with decreased protein synthesis in muscle and liver at a time when the survival of the septic host may be dependent on its ability to produce new protein for a variety of vital functions. These results do not support the use of indomethacin in sepsis.
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PMID:The effect of indomethacin on muscle and liver protein synthesis and on whole-body protein degradation during abdominal sepsis in the rat. 346 35

Infusions of group B streptococci cause pulmonary hypertension in several neonatal animal models. A continuous infusion of prostaglandin D2 reduced the magnitude of this pulmonary hypertensive response; indomethacin completely blocked the response. Prostaglandin D2 or cyclooxygenase inhibitors may be important therapeutic agents for infants with group B streptococcal sepsis who manifest pulmonary hypertension.
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PMID:Influence of prostaglandin D2 on hemodynamic effects of group B streptococcus in neonatal lambs. 353 Jun 74

The role of steroids in the treatment of sepsis and septic shock remains controversial, and it is not known if a possible beneficial effect is due to inhibition of the cyclooxygenase or lipoxygenase pathway of arachidonic acid metabolism. In this investigation we studied the effect of methylprednisolone (MP), the cyclooxygenase inhibitor indomethacin (IM), and the lipoxygenase inhibitor diethylcarbamazine (DE) on survival rate in an experimental trauma-sepsis model in rats consisting of laparotomy and intravenous infusion of live E. coli. Groups of rats received saline (control) or MP (30 mg/kg) intravenously 30 min before or after induction of trauma-sepsis. In other groups of animals IM (4 mg/kg) or DE (0.2 mmol/kg) was administered intravenously 30 min before trauma-sepsis. Survival rate was significantly improved by MP or DE given 30 min before trauma-sepsis while the other treatments did not affect the outcome. The results indicate that the beneficial effect of MP on survival rate in the present trauma-sepsis model did not reflect inhibited prostaglandin synthesis but might have been due to inhibited production of leukotrienes.
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PMID:Effect of methylprednisolone, indomethacin, and diethylcarbamazine on survival rate following trauma and sepsis in rats. 354 76

Endotoxemia and gram negative sepsis remain a clinically important problem since mortality rate is still high in these diseases. Recently, the participation of some new potential mediators in this pathology is beginning to be demonstrated but the results obtained on animal models with specific inhibitors are contradictory. In order to clarify the pathological importance of icosanoids and PAF-acether in the septicemic process, we investigated the effects of indomethacin (IND) a cyclooxygenase inhibitor, NDGA and EP 10045 two lipoxygenase inhibitors, dexamethasone (DXM) a phospholipase A2 inhibitor and BN 52021 a PAF-acether receptor antagonist, on the Salmonella enteritidis-induced endotoxic shock (E.S.) in the rat. Injected subcutaneously 15 min before the test, NDGA, EP 10045 and IND were moderately effective when DXM completely prevented the endotoxin lethality. BN 52021 decreased the death rate in a dose-related manner and exerted at a non-active dose a synergistic effect on IND treatment. Furthermore, given orally 1 hour before endotoxin, it provided a potent protective effect. Our results seem to confirm that PAF-acether exerted alone, or in conjunction with products of the cyclooxygenase pathway, a key role in E.S. when LTs seem to play a role of minor importance.
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PMID:The relative role of PAF-acether and icosanoids in septic shock. 377 51

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


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