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)

We developed two models of sepsis with different degrees of severity, sublethal and lethal sepsis, induced by cecal ligation and puncture. Lethal sepsis induced by cecal ligation and puncture (L-CLP) resulted in failure of neutrophil migration to the infection site and high mortality. Treatment of septic animals with aminoguanidine (AG), a nitric oxide (NO) synthase inhibitor, precluded the failure of neutrophil migration and protected the animals from death. However, cytokine-induced NO synthase (iNOS)-deficient (iNOS(-/-)) mice subjected to L-CLP did not present neutrophil migration failure, but 100% lethality occurred. iNOS(-/-) mice subjected to sublethal sepsis induced by cecal ligation and puncture (SL-CLP) also suffered high mortality despite the occurrence of neutrophil migration. This apparent paradox could be explained by the lack of microbicidal activity in neutrophils of iNOS(-/-) mice present at the infection site due to their inability to produce NO. Notably, SL- and L-CLP iNOS(-/-) mice showed high bacterial numbers in exudates. The inhibition of neutrophil migration by NO is due to inhibition of a neutrophil/endothelium adhesion mechanism, since a reduction in leukocyte rolling, adhesion, and emigration was observed in L-CLP wild-type mice. These responses were prevented by AG treatment and were not observed in the iNOS(-/-) L-CLP group. There was no significant change in L-selectin expression in neutrophils from L-CLP mice. Thus, it seems that the decrease in leukocyte rolling is due to a defect in the expression of adhesion molecules on endothelial surfaces mediated by iNOS-derived NO. In conclusion, the results indicate that despite the importance of NO in neutrophil microbicidal activity, its generation in severe sepsis reduces neutrophil migration by inhibiting leukocyte rolling and their firm adhesion to the endothelium, in effect impairing the migration of leukocytes and consequently their fundamental role in host cell defense mechanisms.
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PMID:Inhibition of leukocyte rolling by nitric oxide during sepsis leads to reduced migration of active microbicidal neutrophils. 1206 1

Neutrophil migration to an infectious focus is essential for control and resolution of infection. Early studies demonstrated that the failure of such migration is observed in lethal sepsis induced by cecal ligation and puncture (L-CLP), whereas intense neutrophil migration is seen in sublethal CLP (SL-CLP). In this study, we found that inhibition of synthesis of prostaglandins or leukotriene B4 (LTB4) did not modify the failure of neutrophil migration or the survival rate of L-CLP mice. In addition, pretreatment of L-CLP mice with a platelet activating factor (PAF) receptor antagonist (UK74505), despite not interfering with the failure process, significantly increased (33%) the survival rate of the animals. Inhibitors of prostaglandin synthesis (indomethacin and meloxican) and UK74505 did not modify the neutrophil migration observed in SL-CLP. On the other hand, the blockade of LTB4 synthesis (MK886, a 5-lipoxygenase-activating protein inhibitor) or of its receptors (CP-105,696) resulted in reduced neutrophil migration to the peritoneal cavity in SL-CLP mice (62% and 60%, respectively), a consequent increase in the number of bacteria in the inflammatory focus, and a reduced survival rate of the animals (43% and 38%, respectively). Both SL-CLP and L-CLP animals presented significant levels of LTB4 in the peritoneal exudate (3- and 8-fold higher than sham group, respectively) and these were reduced by the pretreatment of mice with LTB4 inhibitors. In conclusion, our results suggest that LTB4, but not prostaglandins or PAF, is an important chemoattractant involved in neutrophil recruitment to infection sites in SL-CLP, a crucial event in confining the invading pathogens to a restricted area. However, in circumstances in which the infection turns to a lethal sepsis, LTB4 is not involved in the observed failure of neutrophil migration to the infectious focus.
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PMID:A critical role of leukotriene B4 in neutrophil migration to infectious focus in cecal ligaton and puncture sepsis. 1255 46

In the process of sepsis, the failing organ is not necessarily directly injured or involved in the primary disease process, and the development of distant organ failure may be induced by the host's primed response on an initial insult followed by subsequent insult. We hypothesized that enhancement of nitric oxide (NO) production in the presence of interleukin (IL)-1beta in hepatocytes, isolated under septic conditions, could be implicated in the change in liver energy metabolism, thus resulting in hepatocellular dysfunction. We performed cecal ligation and puncture (CLP group) or a sham operation (sham group) in rats and then isolated hepatocytes from the liver at 6 h postoperatively. The cultured hepatocytes were treated with IL-1beta in the absence and presence of N(G)-monomethyl-L-arginine (L-NMMA) or L-arginine. Effects on nitric oxide production, ATP content, and ketone body ratio (KBR) were then compared between the CLP and sham groups. IL-1beta augmented the induction of NO production in hepatocytes from the CLP group compared with the sham group. IL-1beta markedly decreased cellular ATP content and KBR in the CLP group. The addition of L-arginine further enhanced the decreases of ATP content and KBR concomitantly with the increase of NO production in the CLP group. In contrast, L-NMMA, an inhibitor of nitric oxide synthase, abolished the effects of IL-1beta on ATP content and KBR, as well as on NO production. These results demonstrate that enhancement of NO production by IL-1beta stimulation is involved in cellular failure through mitochondrial dysfunction in the liver of septic rats. This experimental finding may explain clinical phenomenon that an initial insult primes the host so that the host's response is greatly amplified on a second or subsequent insult, resulting in the development of distant organ failure.
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PMID:Hepatocellular dysfunction induced by nitric oxide production in hepatocytes isolated from rats with sepsis. 1268 50

The cardiovascular response to sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase. Ghrelin, a newly-identified endogenous ligand for growth hormone secretagogue receptor (i.e., ghrelin receptor), was recently demonstrated to be a potent vasoactive peptide in addition to its effects on growth hormone release and energy homeostasis. We have shown that ghrelin (via its receptor) may play an important role in regulating cardiovascular responses in the progression of polymicrobial sepsis. However, it remains unknown whether the clearance of this peptide is altered in sepsis. To determine this, male adult rats were injected with 125I-ghrelin through the jugular vein at 5 or 20 h after cecal ligation and puncture (CLP, i.e., sepsis model) or sham operation. The blood sample was collected every 2 min for 30 min for determining half-life (t1/2). Tissue samples (i.e., kidneys, liver, brain, heart, lungs, spleen, stomach, small intestine, large intestine, skin and muscle) were then harvested. The radioactivities of samples were counted. The results indicate that 125I-ghrelin's t1/2 and its distribution were not significantly altered in early sepsis (5 h after CLP). However, the t1/2 increased significantly in late sepsis (20 h after CLP). Tissue distribution of 125I-ghrelin was far greater in the kidneys than in any other tissues tested in both sham and septic animals. Moreover, the kidneys and liver had significantly less radioactive uptake at 20 h after CLP, but the radioactivity in blood was much higher at the same time point. There were no significant changes in 125I-ghrelin distribution in other organs at the late stage of sepsis. These results indicate that the kidneys are the primary site of ghrelin clearance, which is significantly diminished in late sepsis. In addition, the liver also plays a role in the clearance of ghrelin, which was also reduced in late sepsis. The decreased clearance of ghrelin by the kidneys and liver may be due to renal and hepatic dysfunctions under such conditions.
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PMID:Ghrelin clearance is reduced at the late stage of polymicrobial sepsis. 1453 9

Systemic inflammatory response conditions are associated with capillary leak and haemodynamic compromise. Fluid resuscitation to reverse the ensuing hypovolaemia is, however, complicated by the decreased endothelium reflection coefficient to albumin and other colloids. We developed PEG-Alb (albumin covalently linked to polyethylene glycol) as a potential resuscitative agent. PEG was covalently linked to human albumin at multiple sites on the protein. The modified protein was heterogeneous when examined by SDS/PAGE, size-exclusion chromatography and SELDI-TOF MS (surface-enhanced laser-desorption ionization-time of flight MS). Based on size-exclusion chromatography and osmotic pressure data, the effective volume of PEG-Alb is increased 13- to 16-fold compared with unmodified albumin. In an LPS (lipopolysaccharide) model of shock, rats treated with PEG-Alb showed better blood pressure, lower Hct (haematocrit) consistent with haemodilution and less lung injury than rats treated with unmodified albumin or saline. In a CLP (caecal ligation and puncture) model of sepsis, PEG-Alb was more effective than albumin or saline in maintaining blood pressure and in decreasing Hct. When fluorescein-labelled PEG-Alb and Texas Red-labelled albumin were administered to rats with LPS- or CLP-induced shock, PEG-Alb was retained within blood vessels, whereas albumin extravasates into the interstitial space. Based on these data, PEG-Alb appears to be retained within blood vessels in models of capillary leak. PEG-Alb may ultimately be effective in the clinical treatment of shock associated with capillary leak.
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PMID:Plasma expansion by polyethylene-glycol-modified albumin. 1504 8

In an isolated perfused lung model, bradykinin induced pulmonary vasoconstriction in rats made septic by the injection of lipopolysaccharide (LPS). To mimic the pathophysiology of sepsis in humans more closely, we investigated pulmonary endothelial injury in a peritonitis model (cecal ligation and perforation; CLP). Male Sprague-Dawley rats were randomly divided into nine groups (n = 6-8). LPS and CLP rats were compared after 6 h with and without treatment with a selective inhibitor of inducible nitric oxide synthase (iNOS), L-N(6)-(1-iminoethyl)-lysine. Time dependency was investigated in CLP-treated rats at 24 h. The pulmonary circulation was isolated and perfused with a constant flow after the rats' tracheas were intubated and ventilated. Bradykinin (1, 3, and 6 microg) was injected, and changes in perfusion pressure were measured. Lungs were harvested for Western blot analysis to determine the role of iNOS in pulmonary endothelial dysfunction. In contrast to CLP 24 h rats, dose-dependent bradykinin-induced pulmonary vasoconstriction was observed in LPS and CLP 6 h rats. Concomitant administration of L-N(6)-(1-iminoethyl)-lysine significantly attenuated this vasoconstriction in both groups. The iNOS protein was expressed in lung homogenates from LPS 6 h and CLP 6 h but not from CLP 24 h rats. Both sepsis models caused bradykinin-induced pulmonary vasoconstriction, with the CLP groups demonstrating a time dependency of this effect. In conjunction with the time-dependent decrease in iNOS protein, the attenuated bradykinin-induced vasoconstriction due to selective iNOS inhibition suggests an important role for iNOS in pulmonary endothelial injury for both sepsis models.
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PMID:Bradykinin-induced pulmonary vasoconstriction is time and inducible nitric oxide synthase dependent in a peritonitis sepsis model. 1533 23

Sepsis is a syndrome characterized by infection and generalized inflammatory response that can lead to organ failure and death. In this study we standardize a model to investigate acupuncture's effects upon sepsis. the objectives were to study the use of acupuncture in the infectious process and to formulate acupuncture's treatment protocol for sepsis. The CLP (cecal ligation and puncture) model in rats was used to induce sepsis through bacterial entrance into the peritoneal cavity. An acupuncture treatment protocol that enhanced survival and reversed the neutrophil impairment migration toward the peritoneal cavity in rats with sepsis was achieved. It seems that acupuncture can be used for the treatment of experimental infectious processes. The effects of acupuncture and related mechanisms are discussed.
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PMID:Effect of various acupuncture treatment protocols upon sepsis in Wistar rats. 1560 2

Highly activated neutrophils play a critical role in mediating organ injury in sepsis by releasing neutrophil elastase (NE). Toll-like receptors (TLRs) play an important role in the host defense against invading microbes, and their signaling pathway is critical to the activation of the proinflammatory response. However, the relationship between TLR expression and the host defense mechanism during sepsis has not been fully elucidated. In this paper, we investigated the relationships among chemokine (MIP-2), TLR-4, and NE expression in human sepsis and murine peritonitis (CLP). TLR-4 expression on monocytes/macrophages was examined in patients with sepsis and in murine peritonitis and was markedly increased in both populations. LPS-induced MIP-2 production by bronchoalveolar cells and liver mononuclear cells in mice with peritonitis was also significantly increased compared with sham-operated mice. Pretreatment of the macrophage cell line, RAW 264.7 cells, with a NE inhibitor before their exposure to LPS resulted in a significant dose-dependent decrease in MIP-2 production, which was comparable to that seen following pretreatment with TLR-4 antibody. Furthermore, NE and LPS both up-regulated TLR-4 expression on human peripheral blood monocytes. Thus, chemokine-induced recruitment of neutrophils in sepsis may result in further increased chemokine production and increased expression of TLR-4. Neutrophil-derived NE may be associated with increased expression of monocyte/macrophage TLR-4, thereby serving as a positive feedback loop for the inflammatory response among the different cell populations.
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PMID:Neutrophil elastase, MIP-2, and TLR-4 expression during human and experimental sepsis. 1561 30

This study elucidates the mechanism through which heat shock treatment influences the outcome of sepsis. Post-heat shock sepsis was induced in rats by CLP 24 h after whole-body hyperthermia. Liver cytosolic and nuclear fractions were collected and analyzed in early and late sepsis rats (sacrificed 9 and 18 h after CLP, respectively). During sepsis, levels of I-kappaB and nuclear factor-kappaB (NF-kappaB) declined in the cytosol of liver, whereas NF-kappaB increased in nucleus. NF-kappaB activity was significantly enhanced during sepsis, and the products of NF-kappaB target genes, such as TNF-alpha and inducible nitric oxide synthase (iNOS), were overexpressed. Heat shock treatment, inducing heat shock protein synthesis, prevented down-regulation of cytosolic I-kappaB and decreased translocation of NF-kappaB into the nucleus. Therefore, the sepsis-induced acceleration of NF-kappaB activation was inhibited. Expression of TNF-alpha and iNOS mRNA was also down-regulated. Coimmunoprecipitation with anti-NF-kappaB (p65) and anti-IkappaB antibodies verified an assembling phenomenon of heat shock protein (HSP) 72 with NF-kappaB and I-kappaB. We suggest that the mechanism preventing septic activation of NF-kappaB is that oversynthesized HSP72 forms a complex with NF-kappaB/I-kappaB, thus inhibiting nuclear translocation of NF-kappaB. HSP72 appears to play a crucial protective role in modulating the gene expression controlled by NF-kappaB in sepsis.
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PMID:In vivo heat shock protein assembles with septic liver NF-kappaB/I-kappaB complex regulating NF-kappaB activity. 1613 62

Acute lung injury (ALI) is identified with the targeting/sequestration of polymorphonuclear leukocytes (PMN) to the lung. Instrumental to PMN targeting are chemokines [e.g., macrophage inflammatory protein-2 (MIP-2), keratinocyte-derived chemokine (KC), etc.] produced by macrophage, PMN, and other resident pulmonary cells. However, the relative contribution of resident pulmonary macrophages as opposed to PMN in inducing ALI is poorly understood. We therefore hypothesize that depletion of peripheral blood PMN and/or the oblation of a macrophage-mediated PMN chemokine signal (via macrophage deficiency) will reduce the inflammation and ALI observed in mice following hemorrhage (Hem) and subsequent sepsis (CLP) in our murine model of ALI. To examine this we pretreated mice with either 500 microg anti-mouse Gr1 antibody/animal (to deplete PMN) or subjected mice deficient in mature macrophage (B6C3Fe-a/a-CsF1op) to Hem (90 min at 35 +/- 5 mmHg) followed by resuscitation. Twenty-four hours post-Hem, mice were subjected to CLP and killed 24 h later, and lung tissue samples were collected. Our data showed that in the absence of either peripheral blood PMN or mature tissue macrophages there was a suppression of IL-6, KC, and MIP-2 levels in lung tissue from Hem/CLP mice as well as a reduction in PMN influx to the lung and lung injury (bronchoalveolar lavage fluid protein). In contrast, lung tissue IL-10 and TNF-alpha levels were suppressed in the macrophage-deficient Hem/CLP mice compared with PMN-depleted Hem/CLP mice. Together, these data suggest that both the PMN and the macrophage are required to induce inflammation seen here, however, macrophage not PMN regulate the release of IL-10, independent of local changes in TNF.
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PMID:Role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ALI subsequent to septic challenge. 1615 17


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