Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endotoxins (lipopolysaccharides; LPS) are known to cause multiple organ failure, including renal dysfunction. The present report elucidates LPS distribution and effect on renal proximal tubules in an attempt to gain a better understanding of the cellular mechanism underlying the pathogenesis of renal dysfunction in endotoxemia and sepsis. Rats were intravenously treated with biotin-linked or regular Escherichia coli (0111:B4) LPS (3 mg/kg) and sacrificed at different times. Kidneys were retrieved and examined for LPS localization, tubular permeability, ultracytochemical alterations, leukocyte sequestration, and ICAM-1 expression. The functional impact of endotoxemia was also assessed by monitoring the changes in urine levels of glucose in timed collections up to 6 h. LPS was localized on the plasma membranes of the apical microvilli, the labyrinth of the lateral intercellular spaces, in various organelles of epithelial cells, and in the endothelial cells of the peritubular capillaries. LPS caused structural damage and calcium accumulation in the mitochondria, leakage of tight junctions, widening of the basolateral intercellular spaces, intracellular and extracellular edema, leukocyte margination and accumulation, vascular expression of ICAM-1, and decrease of plasma membrane and mitochondrial Ca2(+)-ATPase. Physiological study showed that both urine volume and glucose were greatly increased after LPS infusion. The pathological alterations in the proximal tubules may directly contribute to the reduction in the reabsorption ability of the proximal tubules.
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PMID:Distribution and role of lipopolysaccharide in the pathogenesis of acute renal proximal tubule injury. 860 2

We measured the levels of soluble intercellular adhesion molecule-1 (sICAM-1), CD11a, CD11b, CD18, endotoxin, and various inflammatory cytokines to clarify the relationship between adhesive molecules and cytokines in sepsis. We studied 21 patients with sepsis (sepsis group) and 13 patients with trauma not complicated by infection (trauma group). The mean sICAM-1 level was significantly higher in the sepsis group than in the trauma group. No significant difference was observed in the CD11a, CD11b, and CD18 levels between the two groups. The sICAM-1 levels significantly correlated with the levels of endotoxin, tumor necrosis factor alpha (TNF-alpha), and IL-8, but CD11a, CD11b, and CD18 levels did not correlate with endotoxin or cytokine levels. These findings suggest that ICAM-1 production is induced by endotoxins and cytokines produced in excess by inflammatory reactions and that endotoxins and cytokines are involved in qualitative, but not quantitative changes in LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18).
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PMID:Changes in adhesion molecule levels in sepsis. 882 72

The microvascular endothelial cell (MVEC) is a major target of inflammatory cytokines overproduced in conditions such as sepsis and infectious diseases. We addressed the direct and indirect effects of tumor necrosis factor (TNF) on endothelial cells that can be relevant for the pathogenesis of septic shock, with particular attention to the acute respiratory distress syndrome (ARDS) and to cerebral malaria (CM). To identify functional and phenotypical changes occurring in MVEC during sepsis, we isolated these cells from the lungs of patients who died of ARDS. The constitutive expression of ICAM-1 and, to a lesser extent, VCAM-1, CD14, and TNFR2 were significantly increased on MVEC isolated from ARDS patients compared with control MVEC, whereas ELAM-1 and TNFR1 were not increased. We found that lung MVEC from ARDS patients present a procoagulant profile and a higher production capacity of interleukin-6 (IL-6) and IL-8 when compared with those from controls. As in pulmonary MVEC derived from ARDS patients, the only TNFR type found up-regulated in brain microvessels during CM was TNFR2. This increase in TNFR2 expression only occurred in CM-susceptible mice at the onset of the neurological syndrome. We therefore investigated the role of TNFR2 in the development of this brain pathology by comparing the incidence of CM in wild-type and TNF receptor knock-out mice. Unexpectedly, the genetic deficiency in TNFR2, but not in TNFR1, conferred protection against CM and its associated mortality. No ICAM-1 up-regulation was detected in the brain of Tnfr2 knockout mice, indicating a close correlation between protection against CM-associated brain damage, absence of TNFR2, and absence of ICAM-1 up-regulation in the brain. Our results in ARDS and CM indicate a specific up-regulation of TNFR2, but not of TNFR1, on lung and brain MVEC, respectively. This increased expression leads to a reduced sensitivity toward TNFR1-mediated phenomena, such as the sensitized TNF cytolytic activity on lung MVEC. In contrast, the sensitivity toward TNFR2-mediated effects, such as ICAM-1 induction by membrane-bound TNF, is increased on brain and lung MVEC expressing increased levels of TNFR2. Therefore, the ICAM-1-inducing effect, rather than the direct cytotoxicity of inflammatory cytokines, such as TNF, appears to be crucial in ARDS and CM-induced endothelial damage, and TNFR2 seems to play an important role in this activity in vivo.
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PMID:TNF receptors in the microvascular pathology of acute respiratory distress syndrome and cerebral malaria. 912 3

The role of T-lymphocytes (T cells) and interferon-gamma (IFN-gamma) in the pathogenesis of sepsis-induced microvascular endothelial injury remains unclear. We sought to determine whether the syngeneic coculture of human T cells in the presence of LPS promoted subsequent neutrophil (PMN)-mediated endothelial cytotoxicity. Syngeneic T cells were cocultured with 51Cr-loaded human adipose microvascular endothelial cell (HAMVEC) monolayers in the absence and presence of LPS. Subsequent PMN-mediated HAMVEC cytotoxicity (measured as percent specific 51Cr release) was absent in cultures that contained T cells but no LPS and was significantly increased when T cells were cocultured in the presence of LPS. This was true both following addition of unstimulated PMNs (-0.8 +/- 3.0% vs 4.9 +/- 4.7% for T cells alone vs T cells plus LPS, respectively) and PMNs stimulated with f-Met-Leu-Phe (-0.4 +/- 3.1% vs 10.7 +/- 3.0% for T cells alone vs T cells plus LPS, respectively). Increased cytotoxicity was associated with increased expression of the endothelial adhesion molecules ICAM-1 and VCAM-1. Control experiments failed to demonstrate cytotoxicity when HAMVEC were cultured in the presence of IFN-gamma alone, LPS alone, or T cells without LPS. It appears that there is a necessary requirement of both LPS and (presumably activated) T cells or their products (other than IFN-gamma) for enhanced PMN-mediated endothelial cytotoxicity. This phenomenon may also be mediated by increased expression of endothelial adhesion molecules that promote subsequent PMN adhesion.
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PMID:Endotoxin-induced, neutrophil-mediated endothelial cytotoxicity is enhanced by T-lymphocytes. 920 40

Apoptosis (Ao), is a process by which cells undergo a form of non-necrotic cellular suicide, the control of which may have significant impact on host immunoresponsiveness to a septic challenge. The aim of this study was to determine (1) if Ao is evident in granulocytes harvested from the blood or peritoneum of septic animals and to what extent this was associated with cell activation and (2) whether the in vivo administration of the TNF inhibitor (TNFbp) alters this process. To assess the first aim, C3H/HeN male mice were subjected to polymicrobial sepsis [cecal ligation and puncture (CLP)] or sham-CLP (Sham) and sacrificed at 4 or 24 hr following CLP. Blood leukocytes and peritoneal exudate cells were harvested, stained with monoclonal fluorochrome-conjugated antibodies to granulocytes (Gr1), the activation marker ICAM-1, and either the cell cycle dye, 4',6-diamidino-2-phenylindole, or TUNEL assay (to assess the %Ao+), was used for two- and three-color flow cytometric analysis. Peritoneal exudate cells exhibited increased %Ao+ cells at both 4 and 24 hr post-CLP, while blood leukocytes showed a decrease in %Ao+ only at 24 hr. The increase in Ao in the peritoneum was evident only in the Gr1- cell population at 4 hr but was present in both Gr1+ and Gr1- cells at 24 h. Furthermore, the increase in the %Ao+ cells was associated with an increased % of ICAM-1 positive cells. To the extent that TNF affects the 24 hr induction of Ao in peritoneal exudate cells, mice were treated with either 250 micrograms TNFbp/mouse (s.c.) or vehicle control immediately following CLP. The results indicate that administration of TNFbp markedly decreased Gr1+ but not Gr1- cell Ao. Thus, not only does polymicrobial sepsis induce a marked early rise in phagocyte Ao associated with cell activation, but the increase in peritoneal granulocyte Ao, unlike macrophage Ao, is mediated by TNF and/or an agent released by TNF.
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PMID:Factors responsible for peritoneal granulocyte apoptosis during sepsis. 920 49

The intercellular adhesion molecule (ICAM)-1 is expressed constitutively in normal lungs and increased in pulmonary inflammation. Whether increased ICAM-1 expression in the lung contributes to neutrophil sequestration during lung inflammation in sepsis is unclear. We tested this hypothesis in mice after systemic sepsis from cecal ligation and puncture (CLP). ICAM-1 expression in mouse CLP lung tissue was found to increase with time. The time course of lung ICAM-1 up-regulation correlated with increases in lung myeloperoxidase (MPO) activity and neutrophil sequestration by light microscopy. The monoclonal IgG2b rat anti-mouse antibody, an anti-ICAM-1 antibody (YN1/1.7), administered intravenously at doses of 3, 10, or 30 mg/kg, however, did not decrease the lung MPO levels compared with nonimmune rat IgG. In support of these findings, lung MPO content in ICAM-1-deficient mice that underwent CLP was significantly higher than similarly treated ICAM-1-sufficient mice. Our results suggest that neutrophil sequestration in the mouse lung after CLP is not dependent on ICAM-1.
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PMID:Anti-intercellular adhesion molecule-1 antibody and intercellular adhesion molecule-1 gene deficiency do not prevent pulmonary neutrophil recruitment in polymicrobial sepsis. 956 60

We investigated the cellular mechanism by which Bacteroides fragilis promotes the development of intraabdominal abscesses in experimental models of sepsis. B. fragilis, as well as purified capsular polysaccharide complex (CPC) from this organism, adhered to primary murine mesothelial cells (MMCs) in vitro. The binding of CPC to murine peritoneal macrophage stimulated TNF-alpha production, which when transferred to monolayers of MMCs elicited significant ICAM-1 expression by these cells. This response resulted in enhanced polymorphonuclear leukocyte attachment to MMCs that could be inhibited by Abs specific for TNF-alpha or ICAM-1. Mice treated with TNF-alpha- or ICAM-1-specific Abs failed to develop intraabdominal abscesses following challenge with purified CPC. These results illustrated the role of the CPC in promoting adhesion of B. fragilis to the peritoneal wall and coordinating the cellular events leading to the development of abscesses associated with experimental intraabdominal sepsis.
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PMID:Cellular mechanism of intraabdominal abscess formation by Bacteroides fragilis. 959 Feb 49

Treatment of human endothelial cells with cytokines such as tumour necrosis factor-alpha (TNF) or E. coli lipopolysaccharide (LPS) induces the expression of several adhesion molecules and enhances leukocyte adhesion to endothelial cell surface. Interfering with this leukocyte adhesion or adhesion molecules upregulation is an important therapeutic target for the treatment of bacterial sepsis and various inflammatory diseases. In the course of screening marketed European anti-inflammatory herbal drugs for TNF antagonistic activity, a crude ethanolic extract of corn silk (stigma of Zea mays) exhibited significant activity. The extract at concentrations of 9-250 micrograms/ml effectively inhibited the TNF- and LPS-induced adhesiveness of EAhy 926 endothelial cells to monocytic U937 cells. Similar concentration ranges of corn silk extract did also block the TNF and LPS but not the phorbol 12-myristate 13-acetate-induced ICAM-1 expression on EAhy 926 endothelial cell surface. The extract did not alter the production of TNF by LPS-activated macrophages and failed to inhibit the cytotoxic activity of TNF. It is concluded that corn silk possesses important therapeutic potential for TNF- and LPS-mediated leukocyte adhesion and trafficking.
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PMID:Extract of corn silk (stigma of Zea mays) inhibits the tumour necrosis factor-alpha- and bacterial lipopolysaccharide-induced cell adhesion and ICAM-1 expression. 961 11

Fatal Plasmodium falciparum malaria is accompanied by systemic endothelial activation. To study endothelial activation directly during malaria and sepsis in vivo, the expression of cell adhesion molecules on dermal microvascular endothelium was examined in skin biopsies and correlated with plasma levels of soluble (circulating) ICAM-1, E-selectin, and VCAM-1 and the cytokine tumor necrosis factor (TNF)-alpha. Skin biopsies were obtained from 61 cases of severe malaria, 42 cases of uncomplicated malaria, 10 cases of severe systemic sepsis, and 17 uninfected controls. Systemic endothelial activation, represented by the up-regulation of inducible cell adhesion molecules (CAMs) on endothelium and increased levels of soluble CAMs (sCAMs), were seen in both severe and uncomplicated malaria and sepsis when compared with uninfected controls. Plasma levels of sICAM-1, sVCAM-1, and sE-selectin correlated positively with the severity of malaria whereas TNF-alpha was raised nonspecifically in malaria and sepsis. Immunohistochemical evidence of endothelial activation in skin biopsies did not correlate with sCAM levels or disease severity. This indicates a background of systemic endothelial activation, which occurs in both mild and severe malaria and sepsis. The levels of sCAMs in malaria are thus not an accurate reflection of endothelial cell expression of CAMs in a particular vascular bed, and other factors must influence their levels during disease.
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PMID:Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity. 962 52

The role of neutrophils in acute renal failure is controversial. Acute renal failure can clearly occur in the absence of neutrophils. However, recent studies using specific neutrophil markers indicate that neutrophils accumulate in postischemic kidneys. Moreover, reperfusion of ischemic kidneys with neutrophils worsens ischemic injury and causes kidney neutrophil retention. Neutrophil retention is dependent on the state of neutrophil activation and the duration of renal ischemia. This interaction could account for the high frequency of acute renal failure in conditions associated with prolonged prerenal asotemia and neutrophil priming such as the adult respiratory distress syndrome, or sepsis. Neutrophil retention is mediated by interaction of neutrophil integrins and endothelial cell ICAM-1 because maneuvers reducing the expression and/or function of these adhesion molecules is protective in experimental models of ischemia. Nitric oxide is a key modulator of neutrophil worsening of ischemic injury because maneuvers that decrease nitric oxide production worsen and those which increase nitric oxide protect ischemic kidneys from neutrophil effects. The clinical significance of neutrophils may relate to the observation that bioincompatible membranes activate complement, and retard recovery from acute renal failure. In conclusion, neutrophils are an important contributor to ischemic acute renal failure. It remains to be determined whether decreasing neutrophil function accelerates recovery in acute renal failure.
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PMID:The role of neutrophils in acute renal failure. 975 2


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