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

Hemorrhagic shock/reperfusion (HS/R) followed by sepsis triggers systemic microcirculatory disturbances that may induce multiple organ failure. The present study evaluated the effects of HS/R and cecal ligation and puncture, followed by necrotic cecal resection/peritoneal lavage (REL) on leukocyte-endothelium interactions at the mesentery. Eighty-one anesthetized Wistar rats (200-250 g) were randomly assigned to a first injury: (1) control-HS-no hemorrhagic shock/no reperfusion group, (2) HS/blood-HS/R with 25% shed blood, and (3) HS/blood + LR-HS/R with 25% of the shed blood + lactated Ringer's solution, 3x shed blood volume. Twenty-four hours post-HS/R, animals were submitted to cecal ligation and puncture and, 24 h thereafter, to REL. Leukocyte-endothelium interactions were assessed by intravital microscopy and intercellular adhesion molecule (ICAM) 1 and P-selectin expression by immunohistochemistry. Lungs were observed for ICAM-1 expression and neutrophil infiltration. Single and double injury induced significant increases in rolling (approximately 2-fold), adherent (approximately 5-fold), and migrated leukocytes (approximately 7-fold); ICAM-1 expression (approximately 1/2-fold), and P-selectin expression (approximately 1/2-fold) at the mesentery compared with control-HS group. REL normalized leukocyte-endothelium interactions at the mesentery in single-injured animals. However, in double-injured rats, adherence and migration of leukocytes decreased but did not normalize. Similar results were observed on ICAM-1 expression and neutrophil infiltration in the lungs from these animals. In conclusion, the current in vivo observation of the mesenteric microcirculation after a double injury followed by REL is a suitable model for the systematic evaluation of the inflammatory reaction at local and distant sites. In addition, data presented herein emphasized the importance of surgical removal of the septic focus in controlling the otherwise lethal sepsis-induced multiple organ dysfunction syndrome.
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PMID:Leukocyte-endothelium interactions after hemorrhagic shock/reperfusion and cecal ligation/puncture: an intravital microscopic study in rat mesentery. 1687 27

Caveolin-1, the principal structural and signaling protein of caveolae, is implicated in NO-mediated cell signaling events, but its precise role in inflammation is not well understood. Using caveolin-1-knockout (Cav-1(-/-)) mice, we addressed the role of caveolin-1 in the lung inflammatory response to sepsis induced by i.p. injection of LPS. LPS-challenged wild-type (WT) lungs exhibited significant increases in neutrophil sequestration (approximately 16-fold), lung microvascular permeability K(f,c) (approximately 5.7-fold), and edema formation (approximately 1.6-fold). Compared with WT, Cav-1(-/-) lungs showed marked attenuation of LPS-induced neutrophil sequestration (approximately 11-fold increase) and inhibition of microvascular barrier breakdown and edema formation. Prevention of lung injury in Cav-1(-/-) mice was associated with decreased mortality in response to LPS challenge. To address the basis of the reduced inflammation and injury in Cav-1(-/-) lungs, we examined the role of NO because its plasma concentration is known to be increased in Cav-1(-/-) mice. Cav-1(-/-) mouse lungs demonstrated a significant increase in endothelial NO synthase (eNOS)-derived NO production relative to WT, which is consistent with the role of caveolin-1 as a negative regulator of eNOS activity. Cav-1(-/-) lungs concurrently showed suppression of NF-kappaB activity and decreased transcription of inducible NO synthase and ICAM-1. Coadministration of LPS with the NO synthase inhibitor nitro-L-arginine in Cav-1(-/-) mice prevented the suppression of NF-kappaB activity and restored lung polymorphonuclear leukocyte sequestration in response to LPS challenge. Thus, caveolin-1, through its ability to regulate eNOS-derived NO production, is a crucial determinant of NF-kappaB activation and the lung inflammatory response to LPS.
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PMID:Caveolin-1 regulates NF-kappaB activation and lung inflammatory response to sepsis induced by lipopolysaccharide. 1698 27

Acute renal failure (ARF) in septic patients drastically increases the mortality to 50-80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-alpha and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-alpha and/or by improving endothelial function. In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 +/- 6.6 vs. 50.2 +/- 6.6 microl/min, P < 0.01) at 16 h of LPS administration (2.5 mg/kg ip). This renal protective effect of pentoxifylline was associated with an inhibition of the rise in serum TNF-alpha (1.00 +/- 0.55 vs. 7.02 +/- 2.40 pg/ml, P < 0.05) and serum IL-1beta (31.3 +/- 3.6 vs. 53.3 +/- 5.9 pg/ml, P < 0.01) induced by LPS. Pentoxifylline also reversed the LPS-related increase in renal iNOS and ICAM-1 and rise in serum nitric oxide (NO). Enhanced red blood cell deformability by pentoxifylline may have increased shear rate and upregulated eNOS. Studies were therefore performed in eNOS knockout mice. The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 +/- 18.0 vs. 44.5 +/- 16.2 microl/min, P < 0.05) and renal blood flow (0.86 +/- 0.08 vs. 0.59 +/- 0.05 ml/min, P < 0.05). Renal vascular resistance significantly decreased with the pentoxifylline (91.0 +/- 5.8 vs. 178.0 +/- 7.6 mmHg.ml(-1).min(-1), P < 0.01). Thus pentoxifylline, an FDA-approved drug, protects against endotoxemia-related ARF and involves a decrease in serum TNF-alpha, IL-1beta, and NO as well as a decrease in renal iNOS and ICAM-1.
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PMID:Pentoxifylline protects against endotoxin-induced acute renal failure in mice. 1698 10

Acute lung injury (ALI) causes high mortality, but its molecular mechanisms are poorly understood. Acid aspiration is a frequent cause of ALI, leading to neutrophil sequestration, increased permeability, and deterioration of gas exchange. We investigated the role of platelet-neutrophil interactions in a murine model of acid-induced ALI. Acid aspiration induced P-selectin-dependent platelet-neutrophil interactions in blood and in lung capillaries. Reducing circulating platelets or blocking P-selectin halted the development of ALI. Bone marrow chimeras showed that platelet, not endothelial, P-selectin was responsible for the injury. The interaction of platelets with neutrophils and endothelia was associated with TXA(2) formation, with detrimental effects on permeability and tissue function. Activated platelets induced endothelial expression of ICAM-1 and increased neutrophil adhesion. Inhibition of platelet-neutrophil aggregation improved gas exchange, reduced neutrophil recruitment and permeability, and prolonged survival. The key findings were confirmed in a sepsis-induced model of ALI. These findings may translate into improved clinical treatments for ALI.
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PMID:Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. 1714 25

Sepsis is a complex clinical syndrome resulting from a harmful host inflammatory response to infection. Chemokines and their receptors play a key role in the pathogenesis of sepsis. BX471 is a potent nonpeptide CC chemokine receptor-1 (CCR1) antagonist in both human and mouse. The aim of the present study was to evaluate the effect of prophylactic and therapeutic treatment with BX471 on cecal ligation and puncture-induced sepsis in the mouse and to investigate the underlying mechanisms. In sepsis induced by cecal ligation and puncture, treatment with BX471 significantly protected mice against lung and liver injury by attenuating MPO activity, an indicator of neutrophil recruitment in lungs and livers and attenuating lung and liver morphological changes in histological sections. Blocking CCR1 by BX471 also downregulated ICAM-1, P-selectin, and E-selectin expression at mRNA and protein levels in lungs and livers compared with placebo-treated groups. These findings suggest that blockage of CCR1 by specific antagonist may represent a promising strategy to prevent disease progression in sepsis.
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PMID:Treatment with BX471, a CC chemokine receptor 1 antagonist, attenuates systemic inflammatory response during sepsis. 1723 93

The systemic inflammatory response to infection is the leading cause of mortality in North American intensive-care units. Although much is known about inflammatory mediators, the relationships between microregional inflammation, microvascular heterogeneity, hypoxia, hypoxia-inducible gene expression, and myocardial dysfunction are unknown. Male Sprague-Dawley rats were injected intraperitoneally with LPS to test the hypothesis that sepsis-induced local inflammation and increased microvascular heterogeneity are spatially and temporally associated with hypoxia, hypoxia-inducible gene expression, and decreased left-ventricular contractility. Using a combination of three-dimensional microvascular imaging, tissue Po(2), and pressure-volume conductance measurements, we found that 5 h after LPS, minimum oxygen-diffusion distances increased (P < 0.05), whereas tissue oxygenation and contractility both decreased (P < 0.05) in the left ventricle. Real-time RT-PCR analysis revealed that the hypoxia-inducible genes hypoxia-inducible factor (HIF)-1alpha, VEGF, and glucose transporter (GLUT) 1 were all upregulated (P < 0.05) in the left ventricle. Tissue regions expressing ICAM-1, obtained by using laser-capture microdissection, had increased HIF-1alpha and GLUT1 (P < 0.05) gene expression. VEGF gene expression was more diffuse. In LPS rats, GLUT1 gene expression correlated (P < 0.05) with left-ventricular contractility. In 5-h hypoxic cardiomyocytes, we found strong transient HIF-1alpha, weak VEGF, and greater prolonged GLUT1 gene expression. By comparison, the HIF-1alpha-GLUT1 gene-induction pattern was reversed in the left ventricle of LPS rats. Together, these results show that LPS induces hypoxia in the left ventricle associated with increased microvascular heterogeneity and decreased contractility. HIF-1alpha and GLUT1 gene induction are related to a heterogeneous ICAM-1 expression and may be cardioprotective during the onset of septic injury.
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PMID:Myocardial hypoxia-inducible HIF-1alpha, VEGF, and GLUT1 gene expression is associated with microvascular and ICAM-1 heterogeneity during endotoxemia. 1736 72

Sepsis is one of the most important risk factors in acute respiratory distress syndrome (ARDS). beta-Glucan is a potent reticuloendothelial modulating agent, the immunobiological activity of which is mediated in part by an increase in the number and function of macrophages. In this study, we investigated the putative protective role of beta-glucan against sepsis-induced lung injury. Sepsis was induced by cecal ligation and puncture (CLP) in Wistar rats. The control group received saline, and the treatment groups received beta-glucan or beta-glucan + beta-1,3-D-glucanase. Five hours thereafter, plasma tumor necrosis factor (TNF) alpha, interleukin (IL) 1beta, and IL-6 levels were determined. Presence of lung injury was determined via lung tissue myeloperoxidase (MPO) activity, intercellular adhesion molecule (ICAM) 1 levels, and histopathological examination at 18 h after CLP. In a separate set of experiments, survival was monitored for 7 days after CLP. beta-Glucan treatment led to a significant increase in survival rate (63% in glucan-treated rats vs 38% in saline-treated rats). Administration of the beta-glucan inhibitor abrogated beta-glucan's survival benefit (50%). After CLP, plasma TNF-alpha, IL-1beta, and IL-6 concentrations were increased in control animals. When beta-glucan was administered, it completely blocked the elevation of TNF-alpha, IL-1beta, and IL-6. Administration of beta-1,3-D-glucanase suppressed glucan-induced decrease in cytokines. Animals treated with beta-glucan showed a significant reduction in lung injury score, a marked decrease in ICAM-1 expression, and a significant decrease in MPO levels. In contrast, beta-1,3-D-glucanase caused a significantly increased MPO and ICAM-1 levels in the lung. These data reveal that beta-glucan treatment improved the course of CLP-induced peritonitis and attenuated the lung injury. Administration of beta-glucanase inhibited the beta-glucan activity and resulted in enhanced lung injury.
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PMID:Beta-glucan attenuates inflammatory cytokine release and prevents acute lung injury in an experimental model of sepsis. 1741 22

Adhesion molecules may play a role in the evolution and severity of neonatal sepsis. The purposes of this study were to determine whether serum soluble intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, L-selectin, and P-selectin levels are useful tools in the diagnosis of proven sepsis in newborn infants, and whether their levels are related to the clinical severity of the disease. A cohort of 25 consecutive newborns meeting criteria for clinical sepsis, 10 hemoculture-negative (HC - ) and 15 hemoculture-positive (HC + ), were prospectively followed and compared with 12 healthy newborns (six </= 38 weeks of gestational age and six >/= 39 weeks). Serum soluble (s)ICAM-1, sVCAM-1, sL-selectin, and sP-selectin concentrations were measured at the time of the septic workup, then followed by up to three determinations in each newborn every third day. The Score for Neonatal Acute Physiology (SNAP)-II severity was assessed at the moment of highest clinical severity of the disease. At the beginning of sepsis, sICAM-1 levels increased in both groups, being higher in HC + sepsis than in HC - ; sVCAM-1 only increased slightly in HC + sepsis. Soluble ICAM-1 levels were independently related to group of sepsis, and not to days of life. The best initial sICAM-1 cutoff level for diagnosing HC + neonatal sepsis was 274 microg/L. The highest sICAM-1 levels were positively correlated with SNAP-II scores. Soluble L-selectin and sP-selectin did not change. Soluble ICAM-1 levels increased in HC - and HC + sepsis, but concentrations > 274 microg/L suggest HC + sepsis. These levels were related to the clinical severity of the disease. Soluble VCAM-1 levels increased only slightly in HC + sepsis. Soluble L-selectin and sP-selectin did not change.
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PMID:Serum soluble ICAM-1, VCAM-1, L-selectin, and P-selectin levels as markers of infection and their relation to clinical severity in neonatal sepsis. 1756 56

Earlier work from our laboratory has suggested a role for the neuropeptide substance P (SP) in inducing lung injury in sepsis. In that study, mice lacking the preprotachykinin-A gene, which encodes for SP, were protected against lung injury in sepsis. To further substantiate the role of SP in sepsis and to study its mechanism, we have evaluated the effect of SR140333, a SP receptor antagonist, on lung injury in sepsis, which was induced in male Swiss mice by cecal ligation and puncture (CLP). Sham-operated animals received the same surgical procedure, except CLP. Vehicle or SR140333 (1 mg/kg, s.c.) was administered to CLP mice 30 min before or 1 h after the CLP. Eight hours after surgery, lung tissue was collected and analyzed for myeloperoxidase (MPO) activity, chemokines, cytokines, and adhesion molecules. The CLP procedure alone caused a significant increase in the lung levels of MIP-2, MCP-1, IL-1beta, IL-6, ICAM-1, E- and P-selectin, and MPO activity when compared with sham-operated mice. SR140333 injected 30 min before or 1 h after CLP significantly attenuated the increased lung MPO activity and levels of MIP-2, MCP-1, IL-1beta, IL-6, ICAM-1, and E- and P-selectin compared with CLP-operated mice injected with the vehicle. Histological evaluation of the lung sections further supported the beneficial effect of SR140333 on lung inflammation. Therefore, SP receptor antagonism can be a potential therapeutic target in polymicrobial sepsis, and this effect is brought about via reduction in leukocyte recruitment.
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PMID:Neurokinin-1 receptor antagonist treatment protects mice against lung injury in polymicrobial sepsis. 1756 47

Hydrogen sulfide (H(2)S) is recognized increasingly as a proinflammatory mediator in various inflammatory conditions. Here, we have investigated the role of H(2)S in regulating expression of some endothelial adhesion molecules and recruitment of leukocytes to inflamed sites in sepsis. Male Swiss mice were subjected to cecal ligation and puncture (CLP)-induced sepsis and treated with saline (i.p.), DL-propargylglycine (PAG; 50 mg/kg, i.p.), an inhibitor of H(2)S formation or NaHS (10 mg/kg, i.p.), an H(2)S donor. PAG was administered 1 h before or after the induction of sepsis, and NaHS was given at the same time of CLP. Using intravital microcopy, we found that in sepsis, prophylactic and therapeutic administration of PAG reduced leukocyte rolling and adherence significantly in mesenteric venules coupled with decreased mRNA and protein levels of adhesion molecules (ICAM-1, P-selectin, and E-selectin) in lung and liver. In contrast, injection of NaHS up-regulated leukocyte rolling and attachment significantly, as well as tissue levels of adhesion molecules in sepsis. Conversely, normal mice were given NaHS (10 mg/kg, i.p.) to induce lung inflammation, with or without NF-kappaB inhibitor BAY 11-7082 pretreatment. NaHS treatment enhanced the level of adhesion molecules and neutrophil infiltration in lung. These alterations were reversed by pretreatment with BAY 11-7082. Moreover, expression of CXCR2 in neutrophils obtained from H(2)S-treated mice was up-regulated significantly, leading to an obvious elevation in MIP-2-directed migration of neutrophils. Therefore, H(2)S acts as an important endogenous regulator of leukocyte activation and trafficking during an inflammatory response.
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PMID:Endogenous hydrogen sulfide regulates leukocyte trafficking in cecal ligation and puncture-induced sepsis. 1759 3


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