Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High levels of free heme are found in pathological states of increased hemolysis, such as sickle cell disease, malaria, and ischemia reperfusion. The hemolytic events are often associated with an inflammatory response that usually turns into chronic inflammation. We recently reported that heme is a proinflammatory molecule, able to induce neutrophil migration, reactive oxygen species generation, and IL-8 expression. In this study, we show that heme (1-50 microM) delays human neutrophil spontaneous apoptosis in vitro. This effect requires heme oxygenase activity, and depends on reactive oxygen species production and on de novo protein synthesis. Inhibition of ERK and PI3K pathways abolished heme-protective effects upon human neutrophils, suggesting the involvement of the Ras/Raf/MAPK and PI3K pathway on this effect. Confirming the involvement of these pathways in the modulation of the antiapoptotic effect, heme induces Akt phosphorylation and ERK-2 nuclear translocation in neutrophils. Futhermore, inhibition of NF-kappa B translocation reversed heme antiapoptotic effect. NF-kappa B (p65 subunit) nuclear translocation and I kappa B degradation were also observed in heme-treated cells, indicating that free heme may regulate neutrophil life span modulating signaling pathways involved in cell survival. Our data suggest that free heme associated with hemolytic episodes might play an important role in the development of chronic inflammation by interfering with the longevity of neutrophils.
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PMID:Heme inhibits human neutrophil apoptosis: involvement of phosphoinositide 3-kinase, MAPK, and NF-kappaB. 1526 37

Ischemia and systemic infection are implicated in the etiology of periventricular white matter injury, a major cause of adverse motor and cognitive outcome in preterm infants. Cytokines are signaling proteins that can be produced as part of the inflammatory response to both ischemia and infection. The aim of this study was to relate cerebrospinal fluid (CSF) concentrations of IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) to magnetic resonance-defined white matter injury in preterm infants. Relationships between CSF and plasma cytokine concentrations were also examined. Preterm infants (<or=32 wk) and more mature infants from The Royal Women's Hospital, Melbourne, Australia, and Christchurch Women's Hospital, Christchurch, New Zealand, were eligible for study if they required a clinically indicated lumbar puncture. Plasma samples were obtained in a subgroup of Christchurch infants. Preterm infants underwent advanced quantitative volumetric magnetic resonance imaging using a 1.5-Tesla scanner at term equivalent. One hundred forty-six infants were enrolled and 190 CSF and 42 plasma samples obtained. There was no significant correlation between paired CSF and plasma concentrations for any cytokine. In comparing plasma and CSF concentrations, levels of IL-8 were significantly higher in CSF than plasma. Preterm infants with MRI-defined cerebral white matter injury had higher levels of IL-6, IL-10, and TNF-alpha in the CSF than infants without such injury. Plasma cytokine concentrations may not reflect CSF cytokine levels or inflammatory events within the brain. Elevated CSF levels of cytokines in infants with white matter injury suggest an altered inflammatory balance.
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PMID:The relationship of CSF and plasma cytokine levels to cerebral white matter injury in the premature newborn. 1558 89

Inflammatory processes play a crucial role in the pathogenesis of atherosclerosis and other vascular disorders. We hypothesized that ischemia of the ductus arteriosus might initiate an active inflammatory response that could play a role in ductus remodeling and permanent closure. To test this hypothesis, we studied effects of postnatal ductus construction on inflammatory processes and remodeling in late-gestation fetal and newborn baboons, and preterm newborn baboons. After postnatal ductus constriction, the expression of several genes known to be essential for atherosclerotic remodeling [vascular cell adhesion molecule (VCAM)-1, E-selectin, IL-8, macrophage colony stimulating factor-1, CD154, interferon-gamma, IL-6, and tumor necrosis factor-alpha] was increased in the ductus wall. We were unable to detect intercellular adhesion molecule (ICAM)-1, ICAM-2, P-selectin, monocyte chemoattractant protein-1, or IL-1 by either real-time PCR or immunohistochemistry. VCAM-1, which is newly expressed by luminal cells of the closed ductus, is an important ligand for the mononuclear cell adhesion receptor VLA4. After postnatal constriction, VLA4+ monocytes/macrophages (CD68+ and CD14+) and, to a lesser extent, T-lymphocytes adhered to the ductus wall. Neutrophils and platelets were not observed. The extent of postnatal neointimal remodeling (both endothelial cell layering and subendothelial space thickening) was associated with the degree of mononuclear cell adhesion. Similarly, the extent of vasa vasorum ingrowth correlated with the invasion of CD68+ cells, from the adventitia into the muscle media. Based on these data, we conclude that the inflammatory response following postnatal ductus constriction may be as necessary for ductus remodeling as it is for atherosclerotic remodeling.
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PMID:The role of monocyte-derived cells and inflammation in baboon ductus arteriosus remodeling. 1561 59

Endothelial cells play a key role in ischemia reperfusion injury. We investigated the effects of lidocaine on activated human umbilical vein endothelial cell (HUVEC) interleukin (IL)-1beta, IL-6, and IL-8 concentrations and intercellular adhesion molecule-1 (ICAM-1) expression. HUVECs were pretreated with different concentrations of lidocaine (0 to 0.5 mg/mL) for 60 min, thereafter tumor necrosis factor-alpha was added at a concentration of 2.5 ng/mL and the cells incubated for 4 h. Supernatants were harvested, and cytokine concentrations were analyzed by enzyme-linked immunosorbent assay. Endothelial ICAM-1 expression was analyzed by using flow cytometry. Differences were assessed using analysis of variance and post hoc unpaired Student's t-test where appropriate. Lidocaine (0.5 mg/mL) decreased IL-1beta (1.89 +/- 0.11 versus 4.16 +/- 1.27 pg/mL; P = 0.009), IL-6 (65.5 +/- 5.14 versus 162 +/- 11.5 pg/mL; P < 0.001), and IL-8 (3869 +/- 785 versus 14,961 +/- 406 pg/mL; P < 0.001) concentrations compared with the control. IL-1beta, IL-6, and IL-8 concentrations in HUVECs treated with clinically relevant plasma concentrations of lidocaine (0.005 mg/mL) were similar to control. ICAM-1 expression on lidocaine-treated (0.05 mg/mL) HUVECs was less than on controls (198 +/- 52.7 versus 298 +/- 50.3; Mean Channel Fluorescence; P < 0.001). Activated endothelial IL-1beta, IL-6, and IL-8 concentrations and ICAM-1 expression are attenuated only by lidocaine at concentrations larger than clinically relevant concentrations.
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PMID:Activated endothelial interleukin-1beta, -6, and -8 concentrations and intercellular adhesion molecule-1 expression are attenuated by lidocaine. 1567 67

Myocardial infarction is associated with an inflammatory response leading to leukocyte recruitment, healing and formation of a scar. Members of the chemokine superfamily are rapidly induced in the infarcted myocardium and may critically regulate the post-infarction inflammatory response. CXCL8/Interleukin (IL)-8 is upregulated in the infarcted area and may induce neutrophil infiltration. In addition, mononuclear cell chemoattractants, such as the CC chemokines CCL2/Monocyte Chemoattractant Protein (MCP)-1, CCL3/Macrophage Inflammatory Protein (MIP)1alpha, and CCL4/MIP-1beta are expressed in the ischemic area, and may regulate monocyte and lymphocyte recruitment. However, chemokines may have additional effects on healing infarcts beyond their leukotactic properties. The CXC chemokine CXCL10/Interferon-y inducible Protein (IP)-10, a potent angiostatic factor with antifibrotic properties, is induced in the infarct and may prevent premature angiogenesis and fibrous tissue deposition, until the infarct is debrided and provisional matrix necessary to support granulation tissue ingrowth is formed. Chemokine induction in the infarct is transient, suggesting that inhibitory mediators (such as transforming growth Factor (TGF)-beta) may be activated suppressing chemokine synthesis and leading to resolution of inflammation and transition to fibrosis. Brief repetitive ischemia in mice also results in chemokine upregulation followed by suppression of chemokine synthesis and interstitial fibrosis, in the absence of myocardial infarction. Chemokine expression may play a role in the pathogenesis of non-infarctive ischemic cardiomyopathy, where early ischemia-induced chemokine expression may be followed by activation of inhibitory mediators that suppress inflammation, but induce fibrosis.
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PMID:Chemokines in the ischemic myocardium: from inflammation to fibrosis. 1569 6

This study investigated the role of heme oxygenase (HO)-1 in the cardiac tissue injury of acute ischemia/reperfusion (I/R) in diabetic streptozotocin (STZ)-induced hyperglycemic rats. The effects of 1) hemin, an inducer of HO expression and activity, and 2) zinc protoporphyrin IX (ZnPP-IX), an inhibitor of HO activity, have also been investigated on the tissue injury by I/R and some mediators released in these circumstances. STZ hyperglycemic rats had impaired levels of HO-1 within the cardiac tissue and increased myocardial infarct size (IS) following I/R, as compared with the nondiabetic rats. In these rats, administration of hemin 4 mg/kg 18 h before I/R increases the levels of HO-1 within the tissue. However, the values of HO-1 assayed in these circumstances were significantly lower (P < 0.01) than those assayed in nondiabetic animals subjected to the same procedures; IS was much more extended (P < 0.01) than in the parent nondiabetic group. STZ hyperglycemic rats also predisposed the heart to produce high levels of the cytokines interleukin (IL)-1beta and CXCL8. Subsequent I/R further increased (P < 0.01) the cytokine production, an effect partly prevented by hemin treatment. This recovered the huge number of infiltrated polymorphonuclear (PMN) leukocytes within the cardiac tissue associated with the STZ hyperglycemic state and I/R damage.
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PMID:Hyperglycemia in streptozotocin-induced diabetic rat increases infarct size associated with low levels of myocardial HO-1 during ischemia/reperfusion. 1573 59

The CXC chemokine IL-8, which promotes adhesion, activation, and transmigration of polymorphonuclear neutrophils (PMN), has been associated with production of tissue injury in reperfused myocardium. Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric peptide that is a key regulator of genes such as heme oxygenase (HO)-1 expressed under hypoxic conditions. We hypothesized that HO-1 plays an important role in regulating proinflammatory mediator production under conditions of ischemia-reperfusion. HIF-1 was activated in the human microvascular endothelial cell line (HMEC-1) with the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). DMOG significantly attenuated cytokine-induced IL-8 promoter activity and protein secretion and cytokine-induced PMN migration across human microvascular endothelial cell line HMEC-1 monolayers. In vivo studies in a rabbit model of myocardial ischemia-reperfusion showed that rabbits pretreated with a 20 mg/kg DMOG infusion (n = 6) 24 h before study exhibited a 21.58 +/- 1.76% infarct size compared with 35.25 +/- 2.06% in saline-treated ischemia-reperfusion animals (n = 6, change in reduction = 39%; P < 0.001). In DMOG-pretreated (20 mg/kg) animals, plasma IL-8 levels at 3 h after onset of reperfusion were 405 +/- 40 pg/ml vs. 790 +/- 40 pg/ml in saline-treated ischemia-reperfusion animals (P < 0.001). DMOG pretreatment reduced myocardial myeloperoxidase activity, expressed as number of PMN per gram of myocardium, to 1.43 +/- 0.59 vs. 4.86 +/- 1.1 (P = 0.012) in saline-treated ischemia-reperfused hearts. Both in vitro and in vivo DMOG-attenuated IL-8 production was associated with robust HO-1 expression. Thus our data show that HIF-1 activation induces substantial HO-1 expression that is associated with attenuated proinflammatory chemokine production by microvascular endothelium in vitro and in vivo.
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PMID:HIF-1 activation attenuates postischemic myocardial injury: role for heme oxygenase-1 in modulating microvascular chemokine generation. 1601 14

The immune system of higher vertebrates consists of two components: the innate and adaptive immunity. While the adaptive immune system relies on somatically generated and clonally selected antigen receptors, the innate immune system detects the presence of pathogens by their evolutionarily highly conserved, relatively invariant structural motifs. Interestingly, recent data suggest that activation of the innate immune system could play an important role in various diseases without the direct involvement of infectious pathogens. For example, a number of inflammatory cytokines, including TNF (tumor necrosis factor), IL (interleukin)-1beta, IL-6 and IL-8, as well as iNOS (inducible nitric oxide synthase), all components of innate immunity, are also implicated in ischemia/reperfusion injury, and in the abnormal myocardial remodeling characteristic of chronic heart failure. Understanding of the regulation and activation of the innate immune system in diseases not obviously related to an immune response to specific pathogen could provide new therapeutic targets for cardiovascular diseases. Thus, in this review, we provide a general overview of the components of innate immunity with a focus on humoral factors, their role in the response to foreign pathogens, and their potential role in the response to tissue injury (i.e., the "Expanded Self-Non-Self" and the "Danger" theories of immune activation).
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PMID:Innate immunity and the heart. 1585 84

Oxidative stress seems to contribute to cardiopulmonary bypass (CPB)-related postoperative complications. Pediatric patients are particularly prone to these complications. With this in mind, we measured oxidative stress markers in blood plasma of 20 children undergoing elective heart surgery before, during, and up to 48 h after cessation of CPB, along with inflammatory parameters and full analysis of iron status. Ascorbate levels were decreased by approximately 50% (P < 0.001) at the time of aorta cross-clamp removal (or pump switch-off in 4 patients with partial CPB), and associated with corresponding increases in dehydroascorbate (P < 0.001, r = -0.80) and malondialdehyde (P < 0.01, r = -0.59). In contrast to the immediate oxidative response, peak levels of IL-6 and IL-8 were not observed until 3-12 h after CPB cessation. The early loss of ascorbate correlated with duration of CPB (P < 0.002, r = 0.72), plasma hemoglobin after cross-clamp removal (P < 0.001, r = 0.70), and IL-6 and IL-8 levels at 24 and 48 h after CPB (P < 0.01), but not with postoperative lactate levels, strongly suggesting that hemolysis, and not inflammation or ischemia, was the main cause of early oxidative stress. The correlation of ventilation time with early changes in ascorbate (P < 0.02, r = 0.55), plasma hemoglobin (P < 0.01, r = 0.60), and malondialdehyde (P < 0.02, r = 0.54) suggests that hemolysis-induced oxidative stress may be an underlying cause of CPB-associated pulmonary dysfunction. Optimization of surgical procedures or therapeutic intervention that minimize hemolysis (e.g., off-pump surgery) or the resultant oxidative stress (e.g., antioxidant treatment) should be considered as possible strategies to lower the rate of postoperative complications in pediatric CPB.
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PMID:Oxidative stress precedes peak systemic inflammatory response in pediatric patients undergoing cardiopulmonary bypass operation. 1585 50

The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNs chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.
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PMID:2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors. 1597 85


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