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)

The role of neutrophils in the immune response has long been regarded as mainly phagocytic, but recent publications have indicated the production of several cytokines by polymorphonuclear leucocytes (PMN). The results of the individual reports, however, vary considerably. In this study, we established a cytokine profile of pure human neutrophils and demonstrated that minor contamination of peripheral blood mononuclear cells (PBMCs) in PMN preparations can lead to false-positive results. In our hands, peripheral blood PMN fail to produce the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha). Instead, they secrete large amounts of the chemokine IL-8 and the anti-inflammatory IL-1 receptor antagonist (IL-1ra). Additionally, PMN preparations of a high purity show production of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and growth-related oncogene-alpha (GRO-alpha), as well as macrophage colony-stimulating factor (M-CSF). The neutrophil therefore represents a novelty by producing the antagonist of IL-1beta (i.e. IL-1ra) in the absence of IL-1beta itself. To support our results, we differentiated stem cells from human cord blood into PMN and monocytes, respectively. These in vitro-differentiated PMN showed the same cytokine profile as peripheral blood PMN lacking IL-1beta, while differentiated monocytes produced the expected IL-1beta in addition to IL-1ra. The clear anti-inflammatory nature of their cytokine profile enables PMN to antagonize pro-inflammatory signals in experimental conditions. It is therefore possible that PMN play a key role in immune regulation by counteracting a dysregulation of the inflammatory process. Clinical studies, in which administration of recombinant G-CSF had a favourable effect on the outcome of severe infections and even sepsis without worsening inflammation, could thus be explained by our results.
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PMID:Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators. 1706 11

Severe injury deranges immune function and increases the risk of sepsis and multiple organ failure. Kupffer cells play a major role in mediating posttraumatic immune responses, in part via different Toll-like receptors (TLR). Although mitogen-activated protein kinases (MAPK) are key elements in the TLR signaling pathway, it remains unclear whether the activation of different MAPK are TLR specific. Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP approximately 35 mm Hg for 90 min), and resuscitation. Kupffer cells were isolated 2 h thereafter, lysed and immunoblotted with antibodies to p38, ERK1/2, or JNK proteins. In addition, cells were preincubated with specific inhibitors of p38, ERK1/2, or JNK MAPK followed by stimulation with the TLR2 agonist, zymosan; the TLR4 agonist, LPS; or the TLR9 agonist, CpG DNA. Cytokine (TNF-alpha, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and KC) production was determined by cytometric bead array after 24 h in culture. MAPK activity as well as TNF-alpha, MCP-1, and KC production by Kupffer cells were significantly increased following trauma-hemorrhage. TLR4 activation by LPS stimulation increased the levels of all measured cytokines. CpG-stimulated TLR9 signaling increased TNF-alpha and IL-6 levels; however, it had no effect on chemokine production. Selective MAPK inhibition demonstrated that chemokine production was mediated via p38 and JNK MAPK activation in TLR2, -4, and -9 signaling. In contrast, TNF-alpha and IL-6 production was differentially regulated by MAPK depending on the TLR pathway stimulated. Thus, Kupffer cell TLR signaling employs different MAPK pathways in eliciting cytokine and chemokine responses following trauma-hemorrhage.
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PMID:The role of MAPK in Kupffer cell toll-like receptor (TLR) 2-, TLR4-, and TLR9-mediated signaling following trauma-hemorrhage. 1711 77

Very low birth weight (VLBW) infants with suspected late-onset infection requiring sepsis screening were enrolled in a prospective study to evaluate the diagnostic utilities of a comprehensive panel of key chemokines and cytokines, both individually and in combination, to identify diagnostic markers for early recognition of bacterial sepsis and necrotizing enterocolitis (NEC). Plasma chemokines interleukin (IL)-8, interferon-gamma-inducible protein 10 (IP-10), monokine induced by interferon-gamma (MIG), monocyte chemoattractant protein 1 (MCP-1), growth-related oncogene-alpha (GRO-alpha), and regulated upon activation of normal T cell expressed and secreted (RANTES) and cytokines IL-1beta, IL-6, IL-10, IL-12p70, and tumor necrosis factor alpha (TNF-alpha) were measured at the onset of sepsis (0 h) and 24 h later. Of 155 suspected infection episodes, 44 were classified as infected. Concentrations of all studied inflammatory mediators (except IL-1beta and RANTES) were significantly higher in the infected than in the noninfected group at 0 h, but the levels decreased precipitously by 24 h. IP-10 with a plasma cutoff concentration > or = 1250 pg/mL could identify all septicemic and NEC cases and had the highest overall sensitivity (93%) and specificity (89%) at 0 h. We conclude that preterm infants have the ability to induce a robust chemokine and cytokine response during sepsis, and IP-10 is a sensitive early marker of infection.
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PMID:IP-10 is an early diagnostic marker for identification of late-onset bacterial infection in preterm infants. 1721 Nov 48

In rainbow trout (Oncorhynchus mykiss), at least three CXC chemokines and eighteen CC chemokine sequences have been discovered in the past years, although no studies concerning their bioactivity have been performed yet. We have studied the expression of five different CC chemokines that cluster into the group of inducible chemokines (CK5A, CK5B, CK6, CK7A and CK7B) in trout injected with a plasmid coding for the glycoprotein G gene (pMCV1.4-G) of viral haemorrhagic septicemia virus (VHSV). In a previous work, we had demonstrated that a plasmid coding for the CXC chemokine interleukin 8 (IL-8, pIL8+) when co-administered with pMCV1.4-G was able to modulate the expression of induced pro-inflammatory cytokines, therefore, we have also studied the expression of these inducible CC chemokines in fish injected with pMCV1.4-G in the presence of pIL8+, study that will also help establish the relations among the different chemokine groups. All chemokines were induced in the head kidney of fish injected with the DNA vaccine, and the co-administration of pIL8+ together with the vaccine modulated the expression of all CC chemokines studied. In this sense, expression of the inducible CC chemokines was also studied in trout head kidney leucocytes treated with supernatants from EPC cells transfected with pIL8+. In this case, all CC chemokines studied except for CK5B were significantly induced by rainbow trout IL-8.
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PMID:Expression of inducible CC chemokines in rainbow trout (Oncorhynchus mykiss) in response to a viral haemorrhagic septicemia virus (VHSV) DNA vaccine and interleukin 8. 1728 35

Protein C (PC) plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. This study explored the consequences of PC suppression on the kidney in a cecal ligation and puncture model of polymicrobial sepsis. This study shows that a rapid drop in PC after sepsis is strongly associated with an increase in blood urea nitrogen, renal pathology, and expression of known markers of renal injury, including neutrophil gelatinase-associated lipocalin, CXCL1, and CXCL2. The endothelial PC receptor, which is required for the anti-inflammatory and antiapoptotic activity of activated PC (APC), was significantly increased after cecal ligation and puncture as well as in the microvasculature of human kidneys after injury. Treatment of septic animals with APC reduced blood urea nitrogen, renal pathology, and chemokine expression and dramatically reduced the induction of inducible nitric oxide synthase and caspase-3 activation in the kidney. The data demonstrate a clear link between acquired PC deficiency and renal dysfunction in sepsis and suggest a compensatory upregulation of the signaling receptor. Moreover, these data suggest that APC treatment may be effective in reducing inflammatory and apoptotic insult during sepsis-induced acute renal failure.
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PMID:Role of protein C in renal dysfunction after polymicrobial sepsis. 1730 Nov 89

Antibody-based approaches to pneumococcal disease may hold promise for immunocompromised patients in whom vaccines are less immunogenic and/or in the context of antimicrobial resistance. Antibody-mediated protection against experimental pneumococcal pneumonia has been shown to depend on immunoregulation, but the relationship between antibody and protection against pneumococcal sepsis and immunoregulation has not been examined. Similarly, the requirement for B and T cells for antibody efficacy is not known. In this study, we determined the efficacy of the human pneumococcal capsular polysaccharide serotype 3-specific antibody, A7 (immunoglobulin M [IgM]), in secretory IgM (sIgM)(-/-), CD4(-/-), CD8(-/-), muMT(-/-), and SCID mice and investigated its effect on cytokine and chemokine expression in sera and spleens from mice with intact cellular immunity. A7 is known to be protective against systemic infection with serotype 3 and to require complement for efficacy. Compared to that of an isotype control antibody, A7 administration prolonged the survival of mice of each immunodeficient strain and was associated with a significant reduction in CFU in blood, lung, and spleen samples and a significantly reduced level of keratinocyte-derived chemokine (KC), interleukin-6 (IL-6), and macrophage inflammatory protein-2 (MIP-2) expression in normal and sIgM(-/-) mice. Studies with mice treated with penicillin revealed similar reductions in CFU and similar levels of IL-6, KC, or MIP-2 expression in A7- and penicillin-treated mice. These findings demonstrate that natural IgM and B and T cells are dispensable for A7-mediated protection against experimental pneumococcal sepsis and suggest that the efficacy of antibody-mediated protection depends on immunomodulation. Taken together, our data extend the association between antibody-mediated protection and immunomodulation to protection against systemic pneumococcal infection and to a clinically important serotype often responsible for pneumococcal sepsis.
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PMID:A human monoclonal immunoglobulin M reduces bacteremia and inflammation in a mouse model of systemic pneumococcal infection. 1730 Dec 14

Streptococcus suis capsular type 2 is an important swine pathogen and an agent of zoonosis. Although meningitis is the most common form of disease, septicemia and septic shock are also frequently reported. Despite reports that CD14 is involved in the recognition of encapsulated S. suis by host cells, the mechanisms underlying exacerbated release of pro-inflammatory cytokines, which may have a negative impact on disease outcome, are unclear. Here, we demonstrated that stimulation of human monocytes by whole encapsulated S. suis or its purified cell wall components influences the relative expression of Toll-like receptor (TLR)-2 and CD14 mRNA. Moreover, this stimulation triggered the release of cytokines (tumor necrosis factor-alpha, IL-1beta and IL-6) and chemokines (IL-8 and monocyte chemoattractant protein-1), which was significantly reduced by antibody-mediated blocking of TLR2 but not TLR4. Mouse macrophages deficient in TLR2 also showed impaired cytokine responses to encapsulated bacteria. Given that this response was completely abrogated in myeloid differentiation factor 88 (MyD88)-deficient macrophages, other TLRs might also be involved. Furthermore, we demonstrated that the presence of capsular polysaccharide (CPS)-modulated S. suis interactions with TLRs. In the absence of CPS, uncovered cell wall components induced cytokine and chemokine production via TLR2-dependent as well as -independent pathways, whereas CPS contributes to MCP-1 production in a MyD88-independent manner. Overall, this study contributes to a better understanding of the inflammatory processes induced by an encapsulated pathogen and suggests that the relative expression of CPS, known to be modulated during bacterial invasion and dissemination in the host, might alter interactions with host cells and, consequently, the outcome of the inflammatory response.
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PMID:TLR2-dependent recognition of Streptococcus suis is modulated by the presence of capsular polysaccharide which modifies macrophage responsiveness. 1730

We have demonstrated that volatile anesthetics reduce inflammation after renal ischemia/reperfusion injury in vivo. As hyperactive uncontrolled inflammation can lead to mortality and morbidity during early sepsis, we questioned whether the volatile anesthetic isoflurane could reduce mortality and protect against sepsis induced renal and hepatic dysfunction. Mice were anesthetized with isoflurane or with pentobarbital and subjected to cecal ligation and puncture (CLP) to induce septic peritonitis. Mice were anesthetized for an additional 3 h after CLP with either isoflurane or pentobarbital. Renal and hepatic function was assessed 24 h later and survival after CLP was assessed for 7 days. To determine if isoflurane protects by reducing inflammation, we quantified renal tubular expression of pro-inflammatory (intercellular adhesion molecule 1, tumor necrosis factor alpha [TNF-alpha], and interleukin [IL] 1beta) messenger RNA with reverse transcriptase-polymerase chain reaction. We also measured the plasma levels of the pro-inflammatory cytokines TNF-alpha, keratinocyte-derived chemokine (KC), and IL-6 and an anti-inflammatory cytokine IL-10. Renal cortical apoptosis was also assessed 24 h after CLP. Twenty-four hours after the septic insult, isoflurane-treated mice had significantly improved renal and hepatic function compared with mice anesthetized with pentobarbital. Renal cortices of isoflurane-treated mice had significantly reduced expression of intercellular adhesion molecule 1, TNF-alpha, and IL-1beta messenger RNA and showed less apoptosis. Isoflurane-treated mice had lower plasma levels of TNF-alpha, KC, and IL-6. Isoflurane-anesthetized mice also had significantly prolonged and increased survival compared with pentobarbital-anesthetized mice. Therefore, isoflurane anesthesia conferred significant protection against renal and hepatic dysfunction and death after septic peritonitis and attenuated renal inflammation and apoptosis compared with pentobarbital anesthesia.
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PMID:Isoflurane improves survival and protects against renal and hepatic injury in murine septic peritonitis. 1741 19

We have shown previously that high concentrations of IL-8 associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 complexes) are present in lung fluids from patients with the acute respiratory distress syndrome (ARDS), and correlate both with the development and outcome of ARDS. We also detected deposition of these complexes in lung tissues from patients with ARDS but not in control tissues. Moreover, we determined that IgG receptors (FcgammaRs) mediate activity of anti-IL-8:IL-8 complexes. In the current study, we generated anti-KC (KC = chemokine (CXC motif) ligand 1 (CXCL1)) autoantibody:KC immune complexes (KC-functional IL-8) in lungs of mice to develop a mouse model of autoimmune complex-induced lung inflammation. Both wild-type (WT) and gamma-chain-deficient mice that lack receptors for immune complexes (FcgammaRs) were studied. First, the mice were immunized with KC to induce anti-KC autoantibodies. Then, KC was administered intratracheally to generate anti-KC:KC complexes in the lung. Presence of anti-KC:KC complexes was associated with development of severe pulmonary inflammation that was, however, dramatically suppressed in gamma-chain-deficient mice. Second, because sepsis is considered the major risk factor for development of ARDS, we evaluated LPS-treated WT as well as gamma-chain-deficient mice for the presence of anti-KC:KC complexes and pulmonary inflammatory responses. We detected complexes between anti-KC autoantibodies and KC in lung lavages and tissues of mice treated with LPS. Moreover, gamma-chain-deficient mice that lack receptors for immune complexes were protected from LPS-induced pulmonary inflammation. Our results suggest that immune complexes containing autoantibodies contribute to development of lung inflammation in LPS-treated mice.
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PMID:Anti-KC autoantibody:KC complexes cause severe lung inflammation in mice via IgG receptors. 1758 13

Mice deficient in tissue inhibitor of metalloproteinase-3 (TIMP-3) develop an emphysema-like phenotype involving increased pulmonary compliance, tissue degradation, and matrix metalloproteinase (MMP) activity. After a septic insult, they develop a further increase in compliance that is thought to be a result of heightened metalloproteinase activity produced by the alveolar macrophage, potentially modeling an emphysemic exacerbation. Therefore, we hypothesized that TIMP-3 null mice lacking alveolar macrophages would not be susceptible to the altered lung function associated with a septic insult. TIMP-3 null and wild-type (WT) mice were depleted of alveolar macrophages before the induction of a septic insult and assessed for alteration in lung mechanics, alveolar structure, metalloproteinase levels, and inflammation. The results showed that TIMP-3 null mice lacking alveolar macrophages were protected from sepsis-induced alterations in lung mechanics, particularly pulmonary compliance, a finding that was supported by changes in alveolar structure. Additionally, changes in lung mechanics involved primarily peripheral tissue vs. central airways as determined using the flexiVent system. From investigation into possible molecules that could cause these alterations, it was found that although several proteases and inflammatory mediators were increased during the septic response, only MMP-7 was attenuated after macrophage depletion. In conclusion, the alveolar macrophage is essential for the TIMP-3 null sepsis-induced compliance alterations. This response may be mediated in part by MMP-7 activity but occurs independently of inflammatory cytokine and/or chemokine concentrations.
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PMID:Contribution of alveolar macrophages to the response of the TIMP-3 null lung during a septic insult. 1839 Dec 26


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