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

Postsplenectomy bacterial sepsis may be fatal, due to defects in both cellular and humoral immune responses. The objective of this study was to assess the efficacy of peritoneal macrophage antibacterial function in the early postsplenectomy period. Murine models of splenectomy and sham operation were characterized and peritoneal macrophages were harvested 24 h to 1 wk after surgery. Cells from splenectomized animals demonstrated a nonsignificant delay in phagocytosis of Escherichia coli at 24 h with, however, significantly impaired killing of intracellular organisms at 24 h and 1 wk compared to the sham group. Paradoxically, the production of the macrophage antibacterial product superoxide anion was not impaired at either time point in the splenectomy group compared with sham-operated and control mice. Nitric oxide release was significantly lower in the splenectomized group (p = 0.006), a possible explanation for reduced bacterial killing. Mortality from bacterial peritonitis was significantly higher with concomitant splenectomy than in the sham splenectomy group at 24 h (p < 0.02). The production of TNF from macrophages was up-regulated immediately following splenectomy, a cytokine which may contribute to mortality from bacteremic shock. Local defects in macrophage antimicrobial function may contribute significantly to bacteremia and to subsequent mortality in the early postsplenectomy period.
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PMID:Characterization of the defects in murine peritoneal macrophage function in the early postsplenectomy period. 760 13

Bacterial translocation from the gastrointestinal tract and macrophage activation are central to current theories of sepsis. The relevance of both in obstructive jaundice is unclear. The effect of bile duct ligation for 7 days on bacterial translocation to mesenteric lymph nodes and on macrophage activation in a rat model was examined. Compared with an incidence of zero in sham-ligated controls, bile-duct ligated rats had a 67 per cent incidence of Gram-negative colonization of mesenteric lymph nodes. This was associated with a significant (P < 0.001) decrease in macrophage tumour necrosis factor, superoxide anion and nitric oxide production compared with that in sham controls. Spontaneous bacterial translocation occurs in experimental obstructive jaundice and is associated with marked suppression of macrophage activation. This suggests a mechanism whereby jaundiced patients may be more susceptible to persistent infection but relatively protected against uncontrolled sepsis.
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PMID:Failure of macrophage activation in experimental obstructive jaundice: association with bacterial translocation. 748 87

The normal or hyperdynamic circulatory response during the early phases of the systemic septic response is associated with renal microvascular constriction and can result in renal dysfunction. Intrarenal redistribution of blood flow from the outer cortex to the medulla appears to account for decreased glomerular filtration in spite of normal or elevated renal blood flow, but the mechanisms of this response are not well described. Nitric oxide is recognized as an important regulator of regional blood flow during both normal and pathologic conditions including sepsis, and we hypothesized that alterations in nitric oxide contribute to redistribution of renal blood flow during sepsis. The current study used laser Doppler fluximetry and clearance of p-aminohippuric acid (effective renal plasma flow, ERPF) to study intrarenal distribution of blood flow during basal conditions and during normodynamic Escherichia coli bacteremia, with and without inhibition of nitric oxide. Inhibition of nitric oxide in normal animals resulted in a decrease in ERPF (-19%) with a decrease in cortical flux (-39%) without alteration of medullary flux. Bacteremia resulted in a decrease in cortical flow (-17%), an increase in medullary flow (36%), and a modest reduction (-9%) in ERPF. Inhibition of nitric oxide synthase during bacteremia worsened cortical flow (-43%), reversed the increase in medullary flux (-42%), and further impaired ERPF (-28%). These data suggest that nitric oxide regulates renovascular tone during normal conditions and bacteremia, and indicate that it is a prime mediator of intrarenal redistribution of blood flow during sepsis.
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PMID:Nitric oxide mediates redistribution of intrarenal blood flow during bacteremia. 763 15

We have previously proposed that cytokine-stimulated nitric oxide (NO) production is responsible for reversible myocardial depression in sepsis, trauma and ischemia. NO previously has been found to inhibit mitochondrial activity in other cell types. Accordingly, we sought to determine if cytokine-stimulated NO production inhibited cardiac myocyte mitochondrial activity. Treatment of neonatal rat cardiac myocytes with interleukin-beta (IL-1) resulted in the expression of mRNA for inducible NO synthase (iNOS) and stained positively for iNOS protein by immunohistochemistry. No iNOS staining was detected in untreated cells. IL-1 treatment resulted in significant nitrite levels vs control over 48 hrs (4.2 +/- 0.7 vs 0.3 +/- 0.2 nmol/1.25 x 10(5) cells, respectively) (n = 12) that was inhibited by 1mM NMA (0.3 +/- 0.2 nmoles; p < .01; n = 12). Mitochondrial activity was assessed by the MTT colorimetric assay using (3-4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and OD 570-630. Mitochondrial activity was significantly inhibited by IL-1 vs control cells (0.436 +/- 0.01 vs 0.608 +/- 0.03) and reversed by 1mM NMA (0.549 +/- 0.03) or removal of IL-1 (0.662 +/- 0.02) (p < .01; n = 12 for each). These data strongly suggest that cytokine-stimulated NO production by cardiac myocytes results in reversible inhibition of mitochondrial activity.
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PMID:Cytokine-stimulated nitric oxide production inhibits mitochondrial activity in cardiac myocytes. 765 17

Nitric oxide (NO), a paracrine-acting gas enzymatically synthesized from L-arginine, is a unique biologic mediator that has been implicated in a myriad of physiologic and pathophysiologic states. It is an important regulator of vascular tone and may be the mediator of the hemodynamic changes involved in sepsis and cirrhosis. In addition, there is increasing evidence that NO is involved in coagulation, immune function, inhibitory innervation of the gastrointestinal tract, protection of gastrointestinal mucosa, and the hepatotoxicity of cirrhosis. It has already been speculated that NO may represent a point of control or intervention in a number of disease states. The purpose of this paper is to provide the surgeon with a broad overview of the scientific and clinical aspects of this important molecule.
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PMID:Nitric oxide: an overview. 766

Sepsis has been shown to cause right ventricular (RV) dysfunction, which may be related to pulmonary hypertension and increased RV afterload. This study evaluates the effects of inhaled nitric oxide (NO), a selective pulmonary vasodilator, on RV function in a porcine model of endotoxemia. After an infusion of Escherichia coli lipopolysaccharide (LPS; 200 micrograms/kg), animals were resuscitated with saline (1 mL/kg/min) and observed for 3 hours while being mechanically ventilated (Fio2 = 0.6, tidal volume = 12 mL/kg, and peak end-expiratory pressure = 5 cm H2O). The LPS group (n = 5) received no additional treatment. The NO group (n = 5) received inhaled NO (40 ppm) for the last 2 hours. The control group (n = 5) received only saline without LPS. Hemodynamic data and blood gases were collected hourly for 3 hours. LPS resulted in pulmonary hypertension and RV dysfunction as indexed by a decreased RV ejection fraction and increased RV end-diastolic volume. Inhaled NO significantly decreased pulmonary hypertension and significantly increased RV ejection fraction and oxygen delivery without adverse effects. In conclusion, inhaled NO significantly improved pulmonary hypertension and RV dysfunction in a porcine model of endotoxemia and should be a useful therapeutic modality in selected septic patients.
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PMID:Effects of inhaled nitric oxide on right ventricular function in endotoxin shock. 767 83

The catastrophic pulmonary failure that complicates management of patients with multiple trauma or sepsis syndrome with shock is recognizable to nearly all experienced surgeons. However, the spectrum of injury is broad, the distribution of lung injury may be heterogeneous within a single patient, and many patients will not develop acute respiratory distress syndrome (ARDS) even after a major predisposing insult. The lung responds stereotypically to many disparate insults, so a better conceptual construct of ARDS may be to consider it as one component of the multiple organ dysfunction syndrome. Support of oxygen transport with positive pressure ventilation and high levels of positive end-expiratory pressure, long the mainstay of pulmonary support, has been criticized for its predilection to cause barotrauma. Newer modes of ventilation, such as pressure-controlled, inverse-ratio ventilation and permissive hypercapnia, are under investigation but have not yet been reported with scientific rigor. However, pulmonary support extends beyond the support of gas exchange. Fluid management requires close attention so that the circulation is supported but lung water accumulation is minimized. Nosocomial pneumonia greatly increases the mortality rate in ARDS, but is difficult to diagnose and must be sought aggressively. Until recently, pharmacologic therapy has held little promise, but inhalation of very low concentrations of nitric oxide appear to decrease pulmonary vascular pressures and intrapulmonary shunt. It remains unknown whether nitric oxide is effective therapy for the underlying injury, or is simply treatment for certain manifestations.
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PMID:Organ-specific support in multiple organ failure: pulmonary support. 767 4

Increased release of endothelium-derived relaxing factor/nitric oxide has been proposed as the final common pathway for vasodilator responses to gram-negative lipopolysaccharide (endotoxin). To test this hypothesis, we examined endothelium-dependent and endothelium-independent vasodilator agents in vascular smooth muscle isolated from guinea pigs 16 hours after injection of saline (control group) or induction of Escherichia coli endotoxemia; aortic rings (approximately 1 mm in diameter) were studied with standard isometric tension techniques. Endotoxemia resulted in a significant loss of vasodilator responses to the endothelium-dependent receptor agonists acetylcholine (10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). In contrast, endotoxemia did not affect vasodilator responses to either the endothelium-dependent receptor agonist substance P (10(-11)-10(-7) M), the endothelium-dependent and receptor-independent agonist A23187 (10(-9)-10(-6) M), or the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to acetylcholine more in vessels from lipopolysaccharide-injected than control guinea pigs. Unexpectedly, L-NAME converted the endothelium-dependent vasodilator action of ADP to an endothelium-dependent vasoconstrictor response that was blocked individually by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor dazoxiben, and the thromboxane A2 receptor antagonist SQ29548. We conclude that in vivo endotoxemia inhibits the constitutive isoform of nitric oxide synthase in endothelial cells by selectively disrupting receptor-coupled activation mechanisms shared by acetylcholine and ADP. Furthermore, since L-NAME unmasks a thromboxane A2-mediated vasoconstrictor action of the endogenous purinoceptor agonist ADP, drugs that inhibit nitric oxide synthase could exacerbate sepsis-induced vasoconstriction and ischemia by synergizing with lipopolysaccharide-induced inhibition of endothelial nitric oxide synthase.
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PMID:Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia. 767 34

Gram-negative sepsis and administration of tumor necrosis factor alpha (TNF alpha) are associated with hypotension and peripheral neuropathies suggestive of impaired sympathetic neurotransmission. We examined the effect of TNF alpha on the responses of the bovine pulmonary artery (BPA) to transmural sympathetic nerve stimulation (SNS). BPA contracted to SNS (0.5-32 Hz, 5-10 V, 2-msec duration, 2-msec delay) in a frequency-dependent manner. The contractions of the BPA to SNS were mediated by norepinephrine and activation of postsynaptic alpha 1-adrenoceptors, since they were attenuated by prazosin. Maximum contraction of the BPA to SNS was significantly enhanced (148 +/- 37% increase, n = 6) after inhibition of nitric oxide synthase with L-NG-monomethylarginine (LNMMA, 500 microM), an effect abrogated by L-arginine (1 mM). TNF alpha (0.0042, 0.042, and 0.42 micrograms/ml) selectively inhibited contractions of the BPA to SNS without affecting the contraction of the BPA to exogenous norepinephrine. In BPA incubated with LNMMA (5-500 microM), TNF alpha facilitated rather than inhibited SNS. TNF alpha increased the formation of amperiometrically measured free nitric oxide in bovine adrenal chromaffin cells in primary culture. The data show that in the absence of LNMMA, TNF alpha releases free nitric oxide from a sympathetic neuron and selectively inhibits the contractions of the BPA to SNS. In BPA in which nitric oxide synthase I is inhibited by LNMMA, TNF alpha amplifies the contractions to SNS, even in the absence of endothelium. Thus, TNF alpha can modify vascular smooth muscle tone by affecting SNS. TNF alpha inhibits SNS at the level of the neuron by a mechanism involving the L-arginine-nitric oxide pathway. TNF alpha-induced suppression of SNS and neurotransmission may contribute to the hypotension and peripheral neuropathy of sepsis.
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PMID:Tumor necrosis factor alpha inhibits contractions to sympathetic nerve stimulation by a nitric oxide-dependent mechanism. 768 1

NG-monomethyl-L-arginine (L-NMMA) is an inhibitor of the enzyme nitric-oxide-synthetase. Nitric oxide (NO), produced by endothelial and vascular cells regulates physiological vascular tone, blood pressure and tissue perfusion via guanylate-cyclase and cGMP. In an advanced stage of therapy resistant septic shock in response to inflammatory mediators, NO is overproduced. This leads to vasodilatation, a fall in systemic blood pressure and an attenuated vasoconstriction-response to sympathetic-stimuli. Two episodes of severe and prolonged hypotension in a patient with sepsis were successfully treated twice by bolus therapy of L-NMMA within 4 weeks. On both occasions blood pressure was reversed to normal and the continuous use of high doses of catecholamines were stopped. In contrast to the immediate response of blood pressure, heart rate and central venous pressure remained stable. Cardiac output dropped to 68% and PaO2 increased. These findings indicate that NO-synthetase-inhibitors may be of value in the therapy of human septic shock.
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PMID:A new approach in the treatment of hypotension in human septic shock by NG-monomethyl-L-arginine, an inhibitor of the nitric oxide synthetase. 769 53


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