Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of free oxygen radicals by polymorphonuclear cells (PMNs) was studied in 25 patients after blunt trauma. Superoxide generation significantly increased immediately after trauma and returned to normal soon after the event. Patients were subsequently divided into two groups: those who developed sepsis and those who did not develop infectious complications. Superoxide production by intact PMNs following stimulation by three different stimulants was initially not different in trauma patients who developed sepsis. Follow-up showed an increase in superoxide production when infection complicated the course of trauma patients. Further studies were performed in a cell-free system containing cell membranes and cytosol from patients or healthy controls. No difference in the production of superoxide was found when membranes from trauma patients or controls were mixed with cytosols from controls. When cytosols from patients were mixed with membranes from controls, a significant increase in superoxide production was observed in the group that developed sepsis. Immunoblotting analysis of two protein components of the cytosolic portion of the NADPH oxidase, p47 and p67, were done. The increase in quantity of p47 correlated with the increase in superoxide production during sepsis, and thus may be the major contributor to the high activity.
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PMID:Superoxide production by neutrophils from trauma patients: regulation of NADPH oxidase activity. 802 54

The molecular sources of reactive oxygen species (ROS) in skeletal muscles are not well understood. We hypothesized that nonphagocyte NAD(P)H oxidase could be a source of ROS in muscle fibers. We thus investigated the existence, structure, and contribution of nonphagocyte NAD(P)H oxidase to ROS production in rat skeletal muscles. ROS production and NAD(P)H oxidase activity were evaluated by lucigenin-enhanced chemiluminescence and NADH consumption rate, whereas enzyme composition was monitored by reverse transcription-polymerase chain reaction and immunoblotting. Basal O(-)(2) production in muscle strips from normal rats averaged 1.4 nmol/mg per 10 min and increased to approximately 18 nmol/mg per 10 min in the presence of NADH. Muscle O(-)(2) production and NADH consumption were inhibited by Tiron, superoxide dismutase, apocynin, and diphenyleneiodonium but not by inhibitors of cyclo-oxygenases, xanthine oxidase, nitric oxide synthases (NOS), and mitochondrial enzymes. We detected mRNA and proteins of p22(phox), gp91(phox), p47(phox), and p67(phox) subunits in normal rat muscles. These subunits were localized in close proximity to the sarcolemma. Induction of sepsis in rats doubled muscle O(-)(2) production with no major changes in muscle NADPH oxide subunit expression. In lipopolysaccharide-treated but not in control muscles, O(-)(2) production was increased significantly by NOS inhibition. We conclude that a constitutively active NAD(P)H oxidase enzyme complex exists in normal skeletal muscle fibers and contributes to ROS production. In septic rats, this production is increased but measurable O(-)(2) is reduced by enhanced NO production.
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PMID:Molecular characterization of a superoxide-generating NAD(P)H oxidase in the ventilatory muscles. 1255 34

We addressed the role of O(2) generated by the NADPH oxidase complex in the mechanism of polymorphonuclear leukocyte (PMN) accumulation and transalveolar migration and lung microvascular injury. Studies were made in mice lacking the p47(phox) and gp91(phox) subunits of NADPH oxidase (p47(phox-/-) and gp91(phox-/-)) in which PMN are incapable of the respiratory burst. The mice were challenged i.p. with live Escherichia coli to induce sepsis. We observed time-dependent increases in PMN sequestration and migration from 1 to 6 h after challenge with 2 x 10(8) E. coli. The responses in knockout mice were greater post-E. coli challenge compared with control mice; i.e., transalveolar PMN migration post-E. coli challenge increased by approximately 50% in the null mice above values in wild type. The increased PMN infiltration was associated with decreased lung bacterial clearance. The generation of the chemoattractant macrophage-inflammatory protein-2 in lung tissue was greater in NADPH oxidase-defective mice after E. coli challenge than control mice; moreover, macrophage-inflammatory protein-2 Ab pretreatment prevented the PMN infiltration. We also observed that E. coli failed to increase lung microvascular permeability in p47(phox-/-) and gp91(phox-/-) mice despite the greater lung PMN sequestration. Thus, O(2) production is required for the induction of sepsis-induced lung microvascular injury. We conclude that NADPH oxidase-derived O(2) generation has an important bactericidal role, such that an impairment in bacterial clearance in NADPH oxidase-defective mice results in increased chemokine generation and lung tissue PMN infiltration.
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PMID:Role of NADPH oxidase in the mechanism of lung neutrophil sequestration and microvessel injury induced by Gram-negative sepsis: studies in p47phox-/- and gp91phox-/- mice. 1193 54

Patients with sepsis and acute lung injury have increased interleukin (IL)-18 levels systemically. We hypothesize that IL-18 stimulates neutrophils (PMNs) at physiologic concentrations. IL-18 primed the oxidase at 15 min (10-100 ng/ml), 30 min (0.1-100 ng/ml), and 60 min (100 ng/ml; P<0.05) and caused translocation of p47(phox) to the membrane similar to lipopolysaccharides. CD11b surface expression was increased by IL-18 in a time- and concentration-dependent manner. IL-18 caused up-regulation of the formyl-Met-Leu-Phe receptor, changes in PMN size, and elastase release. Investigation of signaling demonstrated IL-18-mediated activation of p38 mitogen-activated protein (MAP) kinase in a concentration (0.1-100 ng/ml)-, time (5-15 min)-, and Ca2+-dependent manner. IL-18 directly increased cytosolic Ca2+ concentration. IL-18 activation of PMNs was blocked by inhibition of p38 MAP kinase activity (SB203580) or by inhibition of p38 MAP kinase activation by chelation of cytosolic Ca2+. We conclude that IL-18, at physiologic concentrations, is an effective PMN priming agent that requires p38 MAP kinase activity.
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PMID:Physiological levels of interleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation. 1214 32

This study defines the molecular basis for defects in innate immunity involving neutrophils during cecal ligation/puncture (CLP)-induced sepsis in rats. Blood neutrophils from CLP rats demonstrated defective phagocytosis and defective assembly of NADPH oxidase, the latter being due to the inability of p47(phox) to translocate from the cytosol to the cell membrane of neutrophils after cell stimulation by phorbol ester (PMA). The appearance of these defects was prevented by in vivo blockade of C5a in CLP rats. In vitro exposure of neutrophils to C5a led to reduced surface expression of C5aR and defective assembly of NADPH oxidase, as defined by failure in phosphorylation of p47(phox) and its translocation to the cell membrane, together with failure in phosphorylation of p42/p44 mitogen-activated protein kinases. These data identify a molecular basis for defective innate immunity involving neutrophils during sepsis.
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PMID:Complement-induced impairment of innate immunity during sepsis. 1221 41

Sepsis is associated with increased production of reactive oxygen species (ROS); however, the metabolic sources of increased ROS are not well understood. We hypothesized that the recently described nonphagocytic NAD(P)H oxidase system could be an important source of the ROS superoxide anion (O2-) during sepsis, and the interaction of O2- with nitric oxide (NO) may contribute to sepsis-induced vascular Injury. To evaluate this issue, we measured O2- production before and after treatment with lipopolysaccharide (LPS) in rats, who are Inducible NO synthase producers (NOSII) and in pigs, who do not produce NOSII. LPS increased O2- production in aorta from rats from 0.38 +/- 0.07 nmol/mg/10 min to 1.18 +/- 0.23 nmol/mg/10 min, (P = 0.001) in rats, and 0.63 +/- 0.05 nmol/mg/10 min to 1.5 +/- 1.6 nmol/mg/10 min (P = 0.001) in carotid arteries from pigs. Components of NAD(P)H oxidase, including p22(phox), gp91(phox), p47(phox), p67(phox), mRNA and p22(phox), and gp91(phox) proteins were present in rat aorta and aorta and carotid arteries from pigs. Expression mildly increased in rats, but not in pigs. In rats, NADH and NADPH greatly increased O2- production with no difference in untreated versus LPS-treated rats. The addition of L-NAME increased NADH-dependant O2- production from 75 +/- 3 nmol/O2-/mg/10 min to 113 +/- 7 nmoVO2-/mg/10 min in LPS-treated rats, but had no effect in untreated rats. In pigs, the NADH-stimulated O2- production was 43 +/- 8 nmol/mg/10 min before and 63 +/- 4.3 nmol/mg/10 min after LPS even without L-NAME (P < 0.05). In contrast to LPS-treated rats, L-NAME markedly decreased NADH-stimulated O2- production (63 +/- 4 nmol/mg/10 min to 33 +/- 5.6 nmol/mg/10 min, P < 0.01). Luminol-enhanced chemiluminescence was also Increased in porcine carotid arteries after LPS treatment, which is consistent with peroxynitrite formation. Our results indicate that components of NAD(P)H oxidase are present in vessels of pigs and rats and there is substantial NADH-dependent O2- production that is increased after LPS. However, the behavior of NAD(P)H oxidase in NOSII-producing and nonproducing species differs with a reduction of O2- by NO in rats and NO-dependent production in pigs.
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PMID:Superoxide production in the vasculature of lipopolysaccharide-treated rats and pigs. 1274 95

Cyclooxygenase-2 (COX-2) is induced in response to lipopolysaccharide (LPS). However, the signaling mechanisms of LPS-induced COX-2 expression in cardiomyocytes are not well understood. The aim of this study was to investigate the role of gp91(phox)-containing NADH oxidase signaling pathway in LPS-induced COX-2 expression in cardiomyocytes. Cultured neonatal mouse cardiomyocytes showed basal COX-2 expression and PGE2 production. In response to LPS, COX-2 expression and PGE2 production increased by two- to four-fold, which were completely blocked by a selective COX-2 inhibitor NS398. LPS also increased NADH oxidase (gp91(phox) and p47(phox) subunits) expression and superoxide generation. Deficiency of gp91(phox) or suppression of p22(phox) expression decreased NADH oxidase activity and down-regulated COX-2 expression and PGE2 production stimulated by LPS. Pharmacological inhibitors of NADH oxidase prevented LPS-induced COX-2 expression and PGE2 production. The effect of NADH oxidase was mediated through MAPK activation, since inhibition of NADH-oxidase activity prevented phosphorylation of ERK1/2, p38, and JNK1/2, as well as selective inhibition of each subfamily of MAPK by siRNAs and a dominant negative mutant of JNK1 decreased COX-2 expression and completely abrogated PGE2 production in response to LPS. Furthermore, LPS-induced NF-kappaB activation was decreased by inhibition of NADH oxidase, ERK1/2 or JNK1/2 activation, suggesting that LPS increases NF-kappaB activity and COX-2 expression via NADH oxidase-dependent activation of ERK1/2 and JNK1/2. In conclusion, NADH oxidase signaling represents a novel pathway leading to COX-2 expression via MAPK/NF-kappaB-dependent mechanisms in cardiomyocytes during LPS stimulation. Our study suggests that gp91(phox)-containing NADH oxidase is a potential therapeutic target of sepsis.
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PMID:NADH oxidase signaling induces cyclooxygenase-2 expression during lipopolysaccharide stimulation in cardiomyocytes. 1554 60

Abdominal sepsis due to secondary fecal peritonitis following anastomosis insufficiency is a rare but life threatening complication of colorectal surgery. The induction of IFN-gamma by IL-12 is believed to play a key role in sepsis as it promotes antibacterial effector mechanisms such as oxidative burst or nitric oxide induction. The impact of gene deficiency for IL-12 (IL-12p40 KO), oxidative burst (p47(phox) KO), or NO induction (iNOS KO) on the outcome of fecal peritonitis was characterized using the murine Colon Ascendens Stent Peritonitis model (CASP). In the IL-12p40 KO model, 3 and 12 h after surgery, serum cytokine levels of IL-1beta, TNF, IL-18, and IL-10 were analyzed. Expression of IL-1beta, IL-10, IP-10, and MIP-1alpha was measured in lung and liver by RNAse Protection Assay. IL-12p40 and iNOS-deficient mice exhibited a significantly higher susceptibility to CASP as compared to the controls, whereas no significant difference was observed in p47(phox) KO mice. Absence of IL-12 resulted in delayed expression of proinflammatory cytokines and chemokines in both the liver and the lung, and was associated with significant reduction of IL-1beta levels in the serum 12 h after CASP. IL-12 and iNOS possess protective functions in fecal murine peritonitis. Surprisingly, no significant contribution of oxidative burst to the immune response was observed. Overall, these findings suggest that IL-12 deficiency causes a profound delay of the immune response after polymicrobial challenge resulting in significantly increased susceptibility in the CASP model.
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PMID:Impact of interleukin-12, oxidative burst, and iNOS on the survival of murine fecal peritonitis. 1575 96

The generation of reactive oxygen species (ROS) in the vasculature plays a major role in the genesis of endothelial cell (EC) activation and barrier function. Of the several potential sources of ROS in the vasculature, the endothelial NADPH oxidase family of proteins is a major contributor of ROS associated with lung inflammation, ischemia/reperfusion injury, sepsis, hyperoxia, and ventilator-associated lung injury. The NADPH oxidase in lung ECs has most of the components found in phagocytic oxidase, and recent studies show the expression of several homologues of Nox proteins in vascular cells. Activation of NADPH oxidase of nonphagocytic vascular cells is complex and involves assembly of the cytosolic (p47(phox), p67(phox), and Rac1) and membrane-associated components (Noxes and p22(phox)). Signaling pathways leading to NADPH oxidase activation are not completely defined; however, they do appear to involve the cytoskeleton and posttranslation modification of the components regulated by protein kinases, protein phosphatases, and phospholipases. Furthermore, several key components regulating NADPH oxidase recruitment, assembly, and activation are enriched in lipid microdomains to form a functional signaling platform. Future studies on temporal and spatial localization of Nox isoforms will provide new insights into the role of NADPH oxidase-derived ROS in the pathobiology of lung diseases.
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PMID:Regulation of NADPH oxidase in vascular endothelium: the role of phospholipases, protein kinases, and cytoskeletal proteins. 1882 98

Reactive oxygen species (ROS) and oxidative stress are thought to play a central role in the etiology of cell dysfunction and tissue damage in sepsis. However, there is limited and controversial evidence from in vivo studies that ROS mediate cell signaling processes that elicit acute inflammatory responses during sepsis. Because NADPH oxidase is one of the main cellular sources of ROS, we investigated the role of this enzyme in lipopolysaccharide (LPS)-induced acute inflammation in vivo, utilizing mice deficient in the gp91(phox) or p47(phox) subunits of NADPH oxidase. Age-and body weight-matched C57BL/6J wild-type (WT) and gp91(phox-/-) and p47(phox-/-) mice were injected ip with 50 microg LPS or saline vehicle and sacrificed at various time points up to 24 h. We found that LPS-induced acute inflammatory responses in serum and tissues were not significantly diminished in gp91(phox-/-) and p47(phox-/-) mice compared to WT mice. Rather, genetic deficiency of NADPH oxidase was associated with enhanced gene expression of inflammatory mediators and increased neutrophil recruitment to lung and heart. Furthermore, no protection from LPS-induced septic death was observed in either knockout strain. Our findings suggest that NADPH oxidase-mediated ROS production and cellular redox signaling do not promote, but instead limit, LPS-induced acute inflammatory responses in vivo.
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PMID:Genetic deficiency of NADPH oxidase does not diminish, but rather enhances, LPS-induced acute inflammatory responses in vivo. 1912 74


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