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

Sequestration of neutrophils and release of histotoxic mediators are considered important for the development of pathologic alterations of the lung defined as adult respiratory distress syndrome. Mechanisms of inflammatory lung injury caused by abdominal sepsis were investigated using the colon ascendens stent peritonitis (CASP) model that closely mimics the human disease. In the CASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending colon, generating a septic focus. In contrast to the cecal ligation and puncture model of peritonitis, survival of mice following CASP surgery is dependent on IFN-gamma, but independent of tumor necrosis factor (TNF). Here we show that the systemic inflammation induced by CASP surgery results in a rapid and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung. Activation of circulating granulocytes was characterized by increased production of serine proteinases and reactive oxygen metabolites, as well as elevated expression of cell surface Mac-1. Expression of MIP-2, KC, MIP-1alpha and E-selectin mRNA in lung was strongly increased within 3 h following CASP surgery, whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed. In contrast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not detectable after CASP surgery. Importantly, recruitment of leukocytes to the lung was normal in lipopolysaccharide-resistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.
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PMID:Mechanisms of acute inflammatory lung injury induced by abdominal sepsis. 1006 20

The host response to Gram-negative LPS is characterized by an influx of inflammatory cells into host tissues, which is mediated, in part, by localized production of chemokines. The expression and function of chemokines in vivo appears to be highly selective, though the molecular mechanisms responsible are not well understood. All CXC (IFN-gamma-inducible protein (IP-10), macrophage inflammatory protein (MIP)-2, and KC) and CC (JE/monocyte chemoattractant protein (MCP)-1, MCP-5, MIP-1alpha, MIP-1beta, and RANTES) chemokine genes evaluated were sensitive to stimulation by LPS in vitro and in vivo. While IL-10 suppressed the expression of all LPS-induced chemokine genes evaluated in vitro, treatment with IFN-gamma selectively induced IP-10 and MCP-5 mRNAs, but inhibited LPS-induced MIP-2, KC, JE/MCP-1, MIP-1alpha, and MIP-1beta mRNA and/or protein. Like the response to IFN-gamma, LPS-mediated induction of IP-10 and MCP-5 was Stat1 dependent. Interestingly, only the IFN-gamma-mediated suppression of LPS-induced KC gene expression was IFN regulatory factor-2 dependent. Treatment of mice with LPS in vivo also induced high levels of chemokine mRNA in the liver and lung, with a concomitant increase in circulating protein. Hepatic expression of MIP-1alpha, MIP-1beta, RANTES, and MCP-5 mRNAs were dramatically reduced in Kupffer cell-depleted mice, while IP-10, KC, MIP-2, and MCP-1 were unaffected or enhanced. These findings indicate that selective regulation of chemokine expression in vivo may result from differential response of macrophages to pro- and antiinflammatory stimuli and to cell type-specific patterns of stimulus sensitivity. Moreover, the data suggest that individual chemokine genes are differentially regulated in response to LPS, suggesting unique roles during the sepsis cascade.
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PMID:Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo. 1041 57

Abdominal sepsis and septic shock are still major causes of mortality in intensive care units (ICU). Acute renal failure (ARF) is one of the hallmarks encountered in septic shock. The pathophysiological alterations leading to ARF are poorly understood. A novel murine model of polymicrobial sepsis (colon ascendens stent peritonitis [CASP]) was used to investigate functional renal parameters, renal chemokine transcription levels, and recruitment of inflammatory leukocytes in septic ARF. CASP was induced by inserting a 14-gauge stent into the colon ascendens of C57BL/6 mice, generating a septic focus resulting in polymicrobial sepsis. Mice were monitored for urine output and serum azotemia. Kidneys were harvested for analysis of leukocyte infiltration by immunohistochemistry and chemokine gene expression by RNase protection assay (3, 6, 12, and 18 h). CASP, but not sham-CASP, resulted in anuria immediately after surgery and in elevated serum creatinine and BUN detected 18 h after CASP surgery, confirming acute renal failure. Progressive induction of chemokine gene expression was observed for IP-10, MIP-2, MIP-1alpha, MIP-1beta, MCP-1, and RANTES peaking at 12 h with subsequent decrease. Immunohistochemistry revealed an accumulation of neutrophils and monocytes which had adhered to the renal vascular endothelium. Thus, acute renal failure in sepsis is accompanied by a marked upregulation of chemokines of the CC and CXC group within the kidney.
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PMID:Massive chemokine transcription in acute renal failure due to polymicrobial sepsis. 1094 65

The loss of CXCR2 expression by neutrophils is a well-described, but poorly understood, consequence of clinical sepsis. To address the potential impact of this CXCR2 deficit during the septic response, we examined the role of CXCR2 in a murine model of septic peritonitis provoked by cecal ligation and puncture (CLP). CLP-induced mouse mortality was significantly attenuated with i.v. or i.p. administration of an affinity-purified murine CXCR2-specific polyclonal Ab. Mouse survival required Ab administration before and every 2 days following CLP. Furthermore, mice deficient in CXCR2 (CXCR2(-/-)) were significantly protected against CLP-induced mortality compared with control (CXCR2(+/+)) mice. The anti-CXCR2 Ab treatment delayed, but did not completely inhibit, the recruitment of leukocytes, specifically neutrophils, into the peritoneal cavity. Peritoneal macrophages from anti-CXCR2 Ab-treated mice exhibited markedly increased RNA and protein levels of several key proinflammatory cytokines and chemokines. Specifically, isolated preparations of these cells released approximately 11-fold more CXCL10 protein compared with peritoneal macrophages from control-treated or naive mice. CXCR2(-/-) mice had higher resting and CLP-induced levels of peritoneal CXCL10 compared with CXCR2(+/+) mice. Administration of a neutralizing, affinity-purified, murine CXCL10-specific polyclonal Ab before CLP in wild-type mice and every 2 days after surgery significantly increased mortality compared with control Ab-treated mice. Anti-CXCL10 treatment in CXCR2(-/-) mice negated the protective effect associated with the absence of CXCR2. In summary, these data demonstrate that the absence of CXCR2 protects mice from septic injury potentially by delaying inflammatory cell recruitment and enhancing CXCL10 expression in the peritoneum.
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PMID:Immunomodulatory role of CXCR2 during experimental septic peritonitis. 1450 Jun 78

Chemokines represent a superfamily of chemotactic cytokines involved in recruitment, activation and adhesion of a variety of leukocyte types to inflammatory foci. We cloned and sequenced the cDNA of a CXC chemokine that is most similar to CXCL10 from channel catfish and blue catfish. Sequence analysis of PCR amplicons from a single F1 hybrid catfish indicated that channel catfish and blue catfish may have a multigene family for the CXC chemokine. The catfish CXC chemokine was expressed in a wide range of tissues including head kidney, spleen, liver, gill, skin, stomach, and intestine, but not in the muscle. Fish challenged with intracellular bacterium Edwardsiella ictaluri, the causative agent of enteric septicemia of catfish (ESC), showed dramatically elevated levels of the CXC chemokine expression, as quantified with real time RT-PCR. Differential expression profiles were observed between resistant and susceptible channel catfish strains and blue catfish. Blue catfish were characterized by only modest induction in comparison to the drastic elevation of the CXC chemokine in channel catfish.
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PMID:Sequence analysis and expression of a CXC chemokine in resistant and susceptible catfish after infection of Edwardsiella ictaluri. 1504 45

To study the contribution of inflammatory mediators to the pathogenesis of yellow fever (YF), the serum levels of several cytokines and chemokines were measured in 7 patients with fatal YF (f-YF), 11 patients with nonfatal hemorrhagic YF (nf/h-YF), and 18 patients with nonfatal nonhemorrhagic YF (nf/nh-YF). The levels of interleukin (IL)-6, monocyte chemoattractant protein-1, interferon-inducible protein (IP)-10, tumor necrosis factor- alpha , and IL-1 receptor antagonist (IL-1RA) were all statistically significantly higher in the patients with f-YF than in those with nf/nh-YF. In patients with nf/h-YF, only levels of IP-10 and IL-1RA were significantly elevated. The high levels of pro- and anti-inflammatory cytokines and chemokines in serum from patients with f-YF are reminiscent of those seen in patients with bacterial sepsis. This finding has implications for the understanding of the pathophysiology of YF and the development of therapeutic strategies.
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PMID:Activation of the cytokine network and unfavorable outcome in patients with yellow fever. 1549 39

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

Chemokines are best known for their vital role in leukocyte chemotaxis, as part of the larger inflammatory response. Expression analysis and functional characterization of chemokines in mammalian species have often overlooked the role of these proteins under homeostatic conditions. Recent investigations of chemokine diversity in teleost fish have also centered on the immune-related functions of chemotactic cytokines, such as CXCL8 and CXCL10. While a disease-based approach to chemokines is essential to the development of remediative therapies for both human and animal infections, it may be a poor measure of the overall complexity of chemokine functions. As part of a larger effort to assess the conservation of chemokine diversity in teleost fish, we report here the identification of three novel, constitutively expressed CXC chemokines from channel catfish (Ictalurus punctatus). Phylogenetic analyses indicated that two of the three CXC chemokines were orthologues for mammalian CXCL12 and CXCL14, respectively. Whereas a clear orthology could not yet be established for the third CXC chemokine, it shared highest amino acid identity with mammalian CXCL2. All three CXC chemokines show expression in a wide range of tissues, and early expression during development was observed for CXCL12. The expression of this new set of catfish CXC chemokines was not induced during challenge by infection of Edwardsiella ictaluri, the causative agent of the fish pathogen enteric septicemia of catfish. In contrast to the gene duplication of CXCL12 in carp and zebrafish, Southern blot analysis indicated that all three catfish CXC chemokines exist as single copy genes in the catfish genome suggesting that gene duplication of CXC chemokines in specific teleost fish was a recent evolutionary event.
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PMID:Constitutive expression of three novel catfish CXC chemokines: homeostatic chemokines in teleost fish. 1595 Jul 31

Gender-based differences in the incidence and severity of bacterial sepsis render males more susceptible to septic shock than females. However, the mechanisms that underlie this sexual dimorphism remain unclear. In the present study we confirm that males produce significantly higher levels of the inflammatory cytokine IL-6 and the acute phase protein LPS-binding protein (LBP) than females following in vivo lipopolysaccharide (LPS) exposure. It has also been verified that LPS-challenged male-derived macrophages produce higher levels of IL-1beta and lower levels of PGE(2) than similarly treated female-derived cells. Importantly, we demonstrated that male-derived macrophages produce significantly higher levels of the inflammatory chemokine IP-10 following LPS challenge than their female counterparts. It has been demonstrated further that, although resting macrophage levels of mRNA encoding Toll-like receptor 4 (TLR4) and its co-receptor CD14, are not significantly different between genders, male-derived macrophages constitutively express higher levels of these proteins on their cell surface. Elevated circulating levels of LBP and constitutively higher cell surface expression of TLR4 and CD14 on macrophages in males could result in the observed sexual dimorphism in LPS-induced inflammatory mediator production and the greater susceptibility of males to bacterial sepsis.
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PMID:Sexual dimorphism in expression of receptors for bacterial lipopolysaccharides in murine macrophages: a possible mechanism for gender-based differences in endotoxic shock susceptibility. 1657 44

Microdialysis emerges as a useful tool to evaluate tissue inflammation in a number of clinical conditions, like sepsis and transplant rejection, but systematic methodological studies are missing. This study was undertaken to determine the recovery of relevant inflammatory mediators using the microdialysis system, comparing microdialysis membranes with two different molecular weight cut-offs at different flow rates. Twenty and 100 kDa pore sizes CMA microdialysis catheters were investigated using velocities of 0.3, 1.0 and 5.0 microl/min. Reference preparations for cytokines [tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and IL-10; m.w. 17-28 kDa] and chemokines (IL-8, MCP-1, IP-10 and MIG; m.w. 7-11 kDa) were prepared from plasma after incubating human whole blood with lipopolysaccharide. Reference preparation for complement anaphylatoxins (C3a, C4a, C5a; m.w. 9-11 kDa) was prepared by incubating human plasma with heat-aggregated immunoglobulin G. The reference preparations were quantified for the respective inflammatory molecules and used as medium for the microdialysis procedure. Through the 20 kDa filter only the four chemokines passed, but with low recovery (3-7%) and limited to the 1.0 microl/min velocity. The recovery with the 100 kDa filter was as follows: IL-1beta = 75%, MCP-1 = 55%, MIG = 50%, IL-8 = 38%, C4a = 28%, IP-10 = 22%, C5a = 20%, C3a = 16%, IL-6 = 11, IL-10 = 8% and TNF-alpha = 4%. The highest recovery for all chemokines and anaphylatoxins were consistently at velocity 1.0 microl/min, whereas IL-1beta and IL-10 recovered most efficiently at 0.3 microl/min. Thus, microdialysis using catheters with a cut-off of 100 kDa is a reliable method to detect inflammation as judged by a defined panel of inflammatory markers. These findings may have important implications for future clinical studies.
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PMID:Microdialysis for monitoring inflammation: efficient recovery of cytokines and anaphylotoxins provided optimal catheter pore size and fluid velocity conditions. 1691 4


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