Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxpentifylline (pentoxifylline), which is known to have pharmacological effects in animal models of respiratory distress syndrome, multiorgan failure, and shock, was tested in human beings after injection of endotoxin. Of ten healthy volunteers, nine met the inclusion criterion of a rise in body temperature of at least 1.0 degrees C after 100 ng endotoxin (Salmonella abortus equi) as a bolus injection. Serum levels of tumour necrosis factor alpha (TNF) and interleukin-6 (IL-6) were both significantly higher than baseline levels 2 h and 3 h after endotoxin injection. 3 weeks later the nine volunteers were again injected with 100 ng endotoxin and oxpentifylline (500 mg over 4 h) was also infused. There was no rise in TNF levels, though IL-6 levels rose in parallel with body temperature. These data suggest that oxpentifylline blocks the endotoxin-induced synthesis of TNF in man and, therefore, could possibly have beneficial effects in clinical endotoxaemia.
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PMID:Oxpentifylline in endotoxaemia. 196 55

To investigate the implication of extracellular matrix proteinases in acute respiratory distress syndrome (ARDS), we determined 92 kD gelatinase (92 G'ase) and its natural antagonist, the tissue inhibitor of metalloproteinases-1 (TIMP) in bronchoalveolar lavage fluid (BALF) and plasma of 33 intensive care unit (ICU) patients presenting with trauma or septic shock. Eleven of these patients developed short-course ARDS, nine developed prolonged ARDS, and 13 did not progress to ARDS. Ten non-ICU patients served as controls. During the early phase of disease, 92 G'ase in BALF of ICU patients was higher than in controls, but plasma levels were not different. TIMP was increased in BALF and plasma in ARDS as compared with those of patients at risk. The 92 G'ase/TIMP ratio in BALF remained elevated in late phases of prolonged ARDS. The high intrapulmonary levels of 92 G'ase in patients at risk and with ARDS may reflect increased turnover of extracellular matrix in acute lung injury. Increased TIMP may interfere with tissue repair and fibrosis by its inhibition of 92 G'ase. Interleukin-6 (IL-6) could be involved in enhanced local synthesis of TIMP. The balance between 92 G'ase and TIMP may play an important role in lung remodeling, which is characteristic of ARDS.
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PMID:Matrix metalloproteinases and TIMP in acute respiratory distress syndrome. 875 5

Although the pathogenesis of the acute respiratory distress syndrome (ARDS) is complex and poorly understood, several observations point to an important role of interactions between polymorphonuclear neutrophils (PMN) and cytokines in this process. We therefore studied certain parameters involved in PMN transendothelial migration (adhesion molecule expression and cytoskeletal organization) in patients with ARDS (n = 14) in comparison with other ventilated patients (n = 15). We found that in the basal state, both whole-blood PMN and alveolar PMN obtained by bronchoalveolar lavage (BAL) were activated, as shown by decreased L-selectin CD62L and increased beta 2 integrin CD11b expression, as well as decreased F-actin content. The degree of PMN activation increased with the degree of lung injury and with the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-8 (IL-8). Moreover, the capacity of ex vivo stimulation of alveolar PMN by a bacterial peptide was low in ARDS and could partly account for the high susceptibility of these patients to lung infection. Therefore, ARDS-associated lung injury could be caused, at least in part, by inappropriate adhesion and transendothelial migration of proinflammatory cytokine-primed PMN.
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PMID:Interactions between neutrophils and cytokines in blood and alveolar spaces during ARDS. 881 May 92

The aim of this study was to investigate whether bronchoalveolar lavage (BAL) and serum levels of proinflammatory cytokines discriminate between different entities of patients with acute respiratory failure. BAL and circulating concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) were measured in 74 mechanically-ventilated patients and 17 healthy controls. Patients were classified as cardiogenic pulmonary oedema (CPO), acute respiratory distress syndrome (ARDS), primary severe pneumonia (PN) and a combined group (PN+ARDS). In all patients with ARDS and/or PN, markedly elevated BAL levels of IL-6 and IL-8 were detected, which were significantly greater than levels in CPO and healthy controls. Absolute quantities and time-course of these cytokines did not differentiate between the absence and presence of lung infection, or different categories of PN. Similarly, circulating IL-6 levels were comparably elevated in patients with ARDS and/or PN, whereas circulating IL-8 concentrations were inconsistently increased. TNF-alpha was rarely detected in BAL samples, but increased serum concentrations were measured in ARDS and/or PN patients. Bronchoalveolar lavage levels of interleukin-6 and interleukin-8, but not tumour necrosis factor-alpha, and serum concentrations of interleukin-6 are consistently elevated in acute respiratory distress syndrome and/or severe pneumonia, discriminating these entities from cardiogenic pulmonary oedema. Alveolar and systemic cytokine profiles do not differentiate between acute respiratory distress syndrome in the absence of lung infection and states of severe primary or secondary pneumonia, which evidently present with comparable local and systemic inflammatory sequelae.
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PMID:Bronchoalveolar and systemic cytokine profiles in patients with ARDS, severe pneumonia and cardiogenic pulmonary oedema. 888 Jan 3

We evaluated the effect of interleukin-6 (IL-6) on the production of prostacyclin (PGI2) by cultured human pulmonary artery smooth muscle cells (HPASMC). Incubation of these cells for up to 48 h with IL-6 led to a dose- and time-dependent decrease in the concentration of PGI2 in the culture medium. The incubation of HPASMC with 10 micrograms/ml of lipopolysaccharide (LPS), 200 U/ml of IL-1 beta, or 500 U/ml of TNF alpha for 24 hr significantly increased the concentration of PGI2 in the medium. However, the addition of IL-6 to a medium containing LPS, IL-1 beta, or TNF alpha significantly inhibited the stimulatory effect of those substances on PGI2 production. Such inhibition was closely related to the concentration of IL-6. IL-6 may counteract the roles of LPS and of other cytokines on the regulation of pulmonary vascular tension in endotoxin- and cytokine-mediated disorders such as sepsis and the acute respiratory distress syndrome (ARDS).
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PMID:Inhibitory effects of interleukin-6 on release of PGI2 by cultured human pulmonary artery smooth muscle cells. 888 Aug 95

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

Endotoxin causes acute lung injury resembling acute respiratory distress syndrome. Elastase, as well as reactive oxygen species released from activated neutrophils, are thought to play pivotal roles in the pathogenesis of this lung injury. This study investigated whether ONO-5046, a specific elastase inhibitor, can attenuate acute lung injury induced by endotoxin in rabbits. Thirty-two male anesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 for each group): infusion of saline without ONO-5046 treatment (Group S-S), infusion of saline with ONO-5046 (Group S-O), infusion of Escherichia coli endotoxin (100 micrograms/kg over 60 min) without ONO-5046 (Group E-S), and infusion of endotoxin with ONO-5046 (Group E-O). Fifteen minutes before the infusion of endotoxin (Groups E-O and E-S) or saline (Groups S-S and S-O), the animals received a bolus injection of ONO-5046 (10 mg/kg) followed by continuous infusion (10 mg.kg-1.h-1: Groups S-O and E-O) or saline (Groups S-S and E-S). The lungs of the rabbits were ventilated with 40% oxygen. Hemodynamics, peripheral leukocyte and platelet counts, and PaO2 were recorded during the ventilation period (6 h). Lung mechanics, cell fraction of the bronchoalveolar lavage fluid (BALF), activated complement, cytokines, and arachidonic acid metabolite concentrations in the BALF were measured at 6 h. The wet- to dry (W/D)-weight ratio of the lung and albumin concentrations in BALF were analyzed as indices of pulmonary edema. Endotoxin decreased lung compliance and PaO2, and increased the W/D weight ratio, neutrophil counts, and albumin concentration in the BALF. Concentrations of activated complement C5a, interleukin-6, interleukin-8, and thromboxane B2 in the BALF were increased by the infusion of endotoxin. ONO-5046 treatment attenuated these changes. Endotoxin caused extensive morphologic lung damage, which was lessened by ONO-5046. In conclusion, intravenous ONO-5046 pretreatment attenuated endotoxin-induced lung injury in rabbits. This beneficial effect of ONO-5046 may be due, in part, to a reduction in the levels of mediators that activate neutrophils, in addition to the direct inhibitory effect on elastase.
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PMID:ONO-5046, an elastase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits. 914 38

Interleukin-6 (IL-6) is a cytokine produced in response to a variety of inflammatory stimuli. Although IL-6 is often observed in increased amounts in acute respiratory distress syndrome, its role in the development of lung injury is unclear. The role of IL-6 was studied in the rat model of lung injury induced by the intra-alveolar deposition of IgG immune complexes. IL-6 induction, as determined by Northern blot analysis and bioactivity, was found as a function of time during the course of development of injury. Recombinant IL-6 instilled intratracheally at commencement of injury led to substantial reductions in lung vascular permeability, neutrophil accumulation, and levels of tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 in bronchoalveolar lavage fluids. Conversely, blocking of intrinsic IL-6 by a neutralizing antibody resulted in increases in lung vascular permeability, neutrophil content, and TNF-alpha levels in bronchoalveolar lavage fluids. Rat alveolar macrophages stimulated in vitro with lipopolysaccharide in the presence of IL-6 showed a significant reduction in TNF-alpha expression. Together, these findings suggest that IL-6 acts as an intrinsic regulator of lung inflammatory injury after deposition of IgG immune complexes and that the protective effects of exogenously administered IL-6 may be in part linked to suppressed TNF-alpha production.
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PMID:Regulatory effects of interleukin-6 in immunoglobulin G immune-complex-induced lung injury. 921 45

The influx of inflammatory mediators and cells into the tracheobronchial effluent of preterm infants with respiratory distress syndrome (RDS) appears to be important in signaling the development of bronchopulmonary dysplasia (BPD). The mechanism that initiates this early inflammatory response is not well understood. The purpose of this study was to test the hypothesis whether increased interleukin-8 (IL-8), a potent chemoattractant for human neutrophils, appears in the airways of preterm infants with RDS in whom BPD develops before the influx of neutrophils. In addition, airway secretions were analyzed for the cytokine interleukin-6 (IL-6) to test the hypothesis whether this pro-inflammatory cytokine is an early marker of inflammation in preterm infants with RDS who progress to BPD. Sixty-five infants less than 32 weeks gestation with RDS were enrolled on the first day of life and 56 infants completed the study, with 31 recovering from RDS (Non-BPD) and 25 infants progressing to BPD. Infants were excluded from enrollment in the presence of maternal chorioamnionitis, infection at birth, or infection within the first week of life. There were no significant differences in birthweight, gestational age, or prolonged rupture of membranes between the two groups. Serial tracheal aspirates (TA) were collected on days 1, 3, 5, and 7 while the infants remained intubated. Significant elevations of TA neutrophil counts were detected in the BPD group on days 5 and 7. Cell-free TA revealed marked elevations of IL-8 in the BPD group compared to the Non-BPD group [median (25th percentile, 75th percentile), ng/ml epithelial lining fluid (ELF)] on day 1 [BPD 485 (195, 840); Non-BPD 63.1 (28.3, 197), P < 0.05] and day 3 [BPD 740 (319, 1310); Non-BPD 111 (54.3, 337); P < 0.05], while on days 5 and 7, the differences were not statistically significant. Interleukin-6 (IL-6) was measured as a marker of acute inflammation and was not different in the two groups on day 1, but was significantly elevated on day 3 [median (25th percentile, 75th percentile), ng/ml ELF; BPD 297 (62.1, 702); Non-BPD 72 (32.8, 266), P < 0.05] and on day 5 [BPD 270 (136, 672); Non-BPD 86.4 (57.8, 138), P < 0.05]. These studies demonstrate that elevation of IL-8 and IL-6 levels precedes the marked neutrophil influx seen in the TA of preterm infants in whom BPD develop. The presence of IL-8 and IL-6 in TA from these infants suggests that these cytokines either initiate the acute inflammatory cascade in the lungs, or they are early markers of the inflammatory process that places preterm infants at high risk for BPD.
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PMID:Elevation of interleukin-8 and interleukin-6 precedes the influx of neutrophils in tracheal aspirates from preterm infants who develop bronchopulmonary dysplasia. 940 66

Hemorrhagic shock (HS) initiates an inflammatory cascade that includes the production of cytokines and recruitment of neutrophils (PMN) and may progress to organ failure, inducing acute respiratory distress syndrome (ARDS). To examine the hypothesis that interleukin-6 (IL-6) contributes to PMN infiltration and lung damage in HS, we examined the lungs of rats subjected to unresuscitated and resuscitated HS for the production of IL-6 and activation of Stat3. Using semiquantitative RT-PCR, we found a striking increase in IL-6 mRNA levels only in resuscitated HS, with peak levels observed 1 h after initiation of resuscitation. Increased IL-6 protein expression was localized to bronchial and alveolar cells. Electrophoretic mobility shift assay of protein extracts from shock lungs exhibited an increase in Stat3 activation with kinetics similar to IL-6 mRNA. In situ DNA binding assay determined Stat3 activation predominantly within alveoli. Intratracheal instillation of IL-6 alone into normal rats resulted in PMN infiltration into lung interstitium and alveoli, marked elevation of bronchoalveolar lavage cellularity, and increased wet-to-dry ratio. These findings indicate that IL-6 production and Stat3 activation occur early in HS and may contribute to PMN-mediated lung injury, including ARDS after HS.
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PMID:Interleukin-6 production in hemorrhagic shock is accompanied by neutrophil recruitment and lung injury. 972 57


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