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

Nitric oxide (NO) plays a key role in the pathophysiology of inflammation and sepsis. The regulation of the peripheral inducible NO synthase (iNOS-responsible for the massive NO synthesis in inflammation) has been extensively studied in sepsis, but little is known about the actual NO production and its dependence on the location of the primary stimulus (endotoxin, LPS). We measured the activation of the NO pathway after a central (intracerebroventricular) or systemic (intravenous) low dose of LPS (2.5 micrograms/mouse) in three ways: the accumulation of its stable end products (nitrites/nitrates) in the circulation, the induction of iNOS mRNA and the decrease in sodium nitroprusside-dependent ADP ribosylation of proteins in the liver and brain. Plasma nitrites/nitrates increased after LPS by either route. iNOS mRNA was induced in the liver after intravenous and, to a lower extent, in the brain after intracerebroventricular LPS. Ex vivo ADP ribosylation was decreased in both organs after both administration routes, although to different degrees (higher in the liver after intravenous and in the brain after intracerebroventricular administration), suggesting that NO had been produced in the periphery and in the brain after both routes of LPS administration, despite the fact that no LPS is expected to reach the brain after peripheral low-dose injection. Our data thus demonstrate a cross-talk between periphery and brain in the regulation of NO by LPS. Additionally, the possibility of iNOS-independent NO synthesis stimulated by LPS is implied by the discrepancy between the amount of local NO production suggested by ADP ribosylation and the iNOS mRNA levels.
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PMID:Regional production of nitric oxide after a peripheral or central low dose of LPS in mice. 926 48

Nitric oxide (NO) is a gas with diverse biological activities produced from arginine by NO synthases. It is capable of interacting with a number of molecules, most notably superoxide, forming peroxynitrite, which, in turn, can mediate bactericidal or cytotoxic reactions. Nitric oxide also mediates smooth muscle relaxation, neurotransmission, and modulation of inflammation in a number of organ systems and pathophysiologic conditions. Modulation of NO by administration of inhaled NO for respiratory distress syndromes and infusion of NO synthase inhibitors in bacterial sepsis are ongoing. Levels of exhaled NO are being evaluated for their utility in assessing inflammation in respiratory disorders such as asthma.
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PMID:Nitric oxide. 930 99

Hypoxic pulmonary vasoconstriction (HPV) is inhibited by inhaled nitric oxide (NO) in healthy animals and is blunted in endotoxemia. We investigated whether the loss of HPV during sepsis could be reversed by NO synthase (NOS) inhibition. Hypoxic challenges were induced in intubated, awake sheep breathing 100% nitrogen to the left lung and 100% oxygen to the right lung. HPV was assessed as the decrease in left pulmonary blood flow during hypoxia, measured with an ultrasonic flow probe around the left pulmonary artery. Group I (n = 5) received carrier solutions and Groups II (n = 6) and III (n = 8) received an infusion containing Pseudomonas aeruginosa. After 24 h, Group III also received an infusion of 6.6 mg.kg.h-1 N omega-monomethyl-L-arginine (L-NMMA). After 24 h of sepsis, HPV decreased from 60 +/- 9% in Group II and 56 +/- 4% in Group III to 27 +/- 2% and 26 +/- 4%, respectively. Group I showed no change in HPV. During infusion of L-NMMA, HPV increased to 38 +/- 4%. Pulmonary shunt during hypoxia increased in Group III to 161 +/- 10% of its baseline value, and decreased to 121 +/- 11% during infusion of L-NMMA. We conclude that L-NMMA improves but does not restore HPV, indicating that other vasodilatory mediators besides NO also influence HPV in sepsis.
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PMID:Nitric oxide synthase inhibition restores hypoxic pulmonary vasoconstriction in sepsis. 931 1

Ischemia and reperfusion stun the myocardium and the coronary vasculature. We have previously shown that a short period (15 min) of global ischemia in the isolated rat heart causes impaired coronary constriction in response to a thromboxane analog U46619 during reperfusion. Sepsis has also been shown to affect myocardial and vascular function. In the present study, we determined whether Escherichia coli-induced sepsis would exacerbate the effects of ischemia on the coronary circulation. Sepsis prolonged the impairment in the coronary constriction response to U46619 following short term ischemia. We hypothesized that sepsis-induced increases in nitric oxide (NO) production caused the delay in the recovery of the contractile response to U46619. Perfusion with NO synthase inhibitors however indicated that the impaired response was not due to NO. However, NO did appear to have a significant role in the development of myocardial ischemic contracture and on the recovery of diastolic function after ischemia. Inhibitors of NO synthase also caused a significant increase in basal coronary perfusion pressure as well as in the maximum coronary pressure generated in response to U46619, suggesting a role of NO in regulating basal coronary vascular resistance in the isolated rat heart. Some of these effects were more pronounced in septic rat hearts than in the sham surgical rat hearts, consistent with altered nitric oxide production in the septic rat hearts.
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PMID:The effects of Escherichia coli sepsis and short-term ischemia on coronary vascular reactivity and myocardial function. 932 33

We studied the effect of PPM-18, a chemically synthesized naphthoquinone derivative and also an anti-inflammatory agent, on the lipopolysaccharide (LPS)-activated inducible NO synthase (iNOS) expression in rat alveolar macrophages. Pretreatment of macrophages with PPM-18 (0.1-10 microM) significantly inhibited nitrite production, iNOS protein expression and iNOS mRNA accumulation. PPM-18 did not directly affect the enzymic activities of iNOS and other constitutive NOS forms. The LPS-induced increase in nuclear transcription factor kappaB (NF-kappaB) p65 and p50 in nucleus was suppressed by PPM-18 (10 microM). Moreover electrophoretic mobility-shift assays demonstrated that PPM-18 inhibited DNA binding to NF-kappaB induced by LPS in whole cells but not when added in the nuclear extract, suggesting that PPM-18 did not interfere directly with the binding of NF-kappaB to DNA and that some events had to be processed before NF-kappaB could bind DNA. Examination of NF-kappaB showed that PPM-18 stabilized the NF-kappaB inhibitor, IkappaBalpha, by preventing its degradation from NF-kappaB. Therefore the stabilization of IkappaBalpha might have contributed to the inhibition of NF-kappaB activation. These results also indicate strongly that NF-kappaB is involved in the production of NO on stimulation by LPS. PPM-18 significantly decreased the production of tumour necrosis factor alpha in response to LPS. PPM-18 protects mice against LPS-induced lethal toxicity. These results also indicate that PPM-18 is a potent inhibitor of iNOS expression by blocking the binding of NF-kappaB to promoter and exerts a beneficial effect in the mouse model of sepsis.
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PMID:Inhibition of nitric oxide synthase expression by PPM-18, a novel anti-inflammatory agent, in vitro and in vivo. 937 89

Lipopolysaccharide (LPS) plays a key role in the pathogenesis of sepsis. Cardiac function and the inotropic response to beta-adrenergic stimulation are impaired in sepsis. We hypothesized that LPS, in clinically relevant levels (1 ng/mL), directly depresses contractility and beta-adrenergic responses in cardiac myocytes. Cardiac myocytes were isolated from the left ventricle of adult rabbits using digestive enzymes (collagenase and protease). We depyrogenated the enzymes (LPS contamination lowered from 100 to 300 ng/mL to < 0.7 ng/mL) to minimize development of LPS tolerance during cell isolation. After 6 hours of incubation with 1 ng/mL LPS, there was a decrease in the extent of active cell shortening with no change in Ca2+ transients (measured with indo 1 fluorescence), indicating decreased myofilament responsiveness to Ca2+. This was related to NO pathways, since cGMP (a second messenger of NO) increased in cardiac myocytes and LPS effects were completely reversed with a 1 mmol/L NG-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor). LPS did not alter the intracellular Ca2+ response to beta-adrenergic stimulation with isoproterenol but attenuated the contractile response (maximal cell shortening, 15.5 +/- 1.0% versus 23.3 +/- 1.1% in control myocytes; P < .001). LPS attenuation of the contractile response to isoproterenol was restored completely by L-NMMA and almost completely restored (to 86% of the control response) by an inhibitor of cGMP-dependent protein kinase. We conclude that LPS depresses cardiac contractility and the contractile response to beta-adrenergic stimulation by a NO-cGMP-mediated decrease in myofilament responsiveness to Ca2+. The direct effects of low levels of LPS on cardiac myocytes may contribute to cardiac depression and hemodynamic decompensation during sepsis.
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PMID:Lipopolysaccharide depresses cardiac contractility and beta-adrenergic contractile response by decreasing myofilament response to Ca2+ in cardiac myocytes. 940 Mar 82

Recent advances in nitric oxide (NO) research have begun to elucidate the roles of NO in sepsis and infection. Although adequate levels of NO production are necessary to preserve perfusion and carry out cytoprotective functions in sepsis, overproduction appears to contribute to hemodynamic instability and tissue damage. These observations have led to the development of strategies to inhibit NO synthesis or scavenge excess NO in patients with septic shock. Local expression of the inducible NO synthase also has antimicrobial functions. The combination of NO with superoxide forms peroxynitrite which participates in bacterial killing in the peritoneal cavity. The capacity of red blood cells and hemoglobin to remove NO most likely accounts for the adjuvant effect of blood in peritonitis. This review will summarize the pathobiology of NO in surgical sepsis and infection.
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PMID:Roles of nitric oxide in surgical infection and sepsis. 945 35

Nitric oxide (NO) is an effector molecule with multiple effects on various organ systems. The most prominent physiological actions of NO as a biological mediator include cGMP-dependent vasodilation and cytotoxicity against pathogens in the unspecific immune defense. Sepsis syndrome is a complex disease entity mostly caused by overwhelming bacterial infections. It has a high mortality rate of 40 to 60%. Catecholamine-resistant hypotension and myocardial depression are regarded as major factors contributing to death in septic patients. In septic shock, a pathophysiologically increased NO production occurs due to an excessive induction of the inducible NO synthase (iNOS). Inducible nitric oxide synthase up-regulation is probably caused by bacterial endo- and exotoxins as well as by an increase of circulating pro-inflammatory cytokines. It may be a key factor leading to pronounced vasodilation and myocardial toxicity. Experimental studies have confirmed that NO overproduction causes severe hypotension in septic animals. Treatment with competitive NOS-inhibitors abolishes this hypotension in animals as well as in septic patients. However, their use is complicated by concomitant decreases in cardiac index and oxygen delivery. Conclusive data on mortality in animals and patients with sepsis-syndrome treated by NOS antagonists are not available. This article discusses current concepts concerning the L-arginine/NO system in the pathophysiology of and as a potential therapeutic target in septic shock.
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PMID:Nitric oxide in sepsis-syndrome: potential treatment of septic shock by nitric oxide synthase antagonists. 947 85

Although sepsis is known to affect vascular function, little is known about changes at the capillary level. We hypothesized that sepsis attenuates the "upstream" arteriolar response to vasoactive agents applied locally to capillaries. Sepsis in rats was induced by cecal ligation and perforation. After 24 h, extensor digitorum longus muscle was prepared for intravital microscopy. Phenylephrine (PE, 10 mM) and acetylcholine (ACh, 10 mM) were applied iontophoretically on terminal arterioles and on their downstream daughter capillaries (300 micron from arteriole). There was no significant difference between control and septic rats in baseline arteriolar diameters [8.0 +/- 0.6 vs. 9.8 +/- 0.8 (SE) micron- or baseline red blood cell velocity (VRBC) in perfused daughter capillaries (255 +/- 10 vs. 264 +/- 13 micron/s). Application of PE onto arterioles resulted in comparable constrictions (i.e., -22% diameter change) and VRBC reductions (-100%) in control and septic rats. In contrast, arteriolar diameter and VRBC increases after application of ACh were attenuated in sepsis (diameter: from 41 to 14%; VRBC: from 67 to 24%). Application of PE onto the capillary reduced VRBC to the same level (-100%) in both groups, whereas application of ACh increased VRBC less in septic than in control rats (20 vs. 73%). On the basis of arteriolar-capillary pair stimulations, sepsis affected VRBC responses to ACh more in the capillary than in the arteriole. When the adenosine analog 5'-N-ethylcarboxamidoadenosine (0.1 mM) was used instead of ACh, similar effects of sepsis were seen. To test for a possible involvement of inducible NO synthase (iNOS) in sepsis-induced attenuated ACh responses, arterioles and capillaries in septic animals were locally pretreated with the iNOS blocker aminoguanidine (10 mM). In both microvessels, aminoguanidine restored the ACh response to the control level. We conclude that impaired capillary VRBC and arteriolar diameter responses to vasodilators applied to capillaries in septic rat skeletal muscle were due to dysfunction at arteriolar and capillary levels. The study underscores the significant role iNOS/NO may play in sepsis-induced alteration of vascular reactivity in vivo.
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PMID:Capillary and arteriolar responses to local vasodilators are impaired in a rat model of sepsis. 948 Sep 41

Nitric oxide (NO), produced in large amounts by inducible NO synthase (iNOS), has emerged recently as an important microbicidal and immunomodulatory mediator. We have investigated its role in bacterial septic arthritis caused by Staphylococcus aureus infection using iNOS-deficient mice. The incidence, rate of development, and severity of arthritis were greater in iNOS-deficient than in heterozygous or wild-type control mice. Similarly, the incidence and severity of septicemia and mortality were significantly higher in iNOS-deficient mice compared with controls. Increased TNF-alpha synthesis in vivo and in vitro and enhanced IFN-gamma compared with IL-4 production in vitro in iNOS-mutant mice demonstrated exaggerated Th1 polarization of the host response. These data indicate that high output NO production is not a prerequisite for severe articular destruction and imply that NO is of importance in synovial defense against staphylococcal infection.
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PMID:Septic arthritis following Staphylococcus aureus infection in mice lacking inducible nitric oxide synthase. 955 85


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