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Results for “Systemic inflammation”

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At least 235 records · Page 13Linked to original sources

PubMed2005

Low-grade systemic inflammation, hypoadiponectinemia and a high concentration of leptin are present in very young obese children, and correlate with metabolic syndrome.

OBJECTIVE: To determine the concentration levels of C-reactive protein (CRP), leptin and adiponectin in obese pre-pubertal children, and their possible relation with metabolic syndrome, fibrinogen and plasminogen activator inhibitor-1. METHODS: A study was carried out in 51 obese children (aged 6 to 9 years) and the same number of non-obese children (control group), matched by age and sex. (Cross-sectional study of obese children). Body mass index (BMI), waist/hip ratio (WHR) and blood pressure were determined for each child. Serum CRP, leptin, adiponectin, glucose, insulin, lipid profile, plasminogen activator inhibitor-1 (PAI-1) and fibrinogen were all measured. RESULTS: The levels of CRP serum (1.67+/-0.222 vs 0.92+/-0.16 mg/l) and leptin (15.56+/-1.27 vs 4.68+/-0.62 ng/ml) were significantly higher in obese children. The adiponectin level was significantly higher in non-obese children (11.58+/-0.63 vs 9.64+/-0.49 microg/dl). In the obese group, log. CRP showed a positive correlation with BMI, insulin, homeostasis model assessment (HOMA), triglycerides, alanine aminotransferase (ALT), uric acid, PAI-1, fibrinogen and interleukin 6 (IL-6), and correlated negatively with apolipoprotein A-I and high-density lipoprotein cholesterol (HDL-C). The leptin was positively correlated with BMI, insulin, HOMA, triglycerides and PAI-1 and negatively with Apo A-I and HDL-C. Adiponectin correlated negatively with BMI, insulin, HOMA, and triglycerides. CONCLUSIONS: Low-grade systemic inflammation, elevated leptin concentration and low adiponectin level are described in very young obese children, correlating with a range of variables of metabolic syndrome. Inflammation and adipocytokines can play an important role in the etiopathogeny of metabolic syndrome.

Adiponectin↗

PubMed2001

Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture.

Inosine is a naturally occurring purine formed from the breakdown of adenosine. Here we have evaluated the effects of inosine in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice subjected to CLP were treated with either inosine (100 mg/kg, intraperitoneally) or vehicle 1 h before and 6 h after CLP. After 12 h tumor necrosis factor alpha, interleukin 6 (IL-6), and IL-10 were measured in plasma. Biochemical markers of organ damage, liver NAD+/NADH (indicator of the mitochondrial redox state), plasma nitrate, tissue myeloperoxidase (MPO, indicator of neutrophil accumulation) and malondialdehyde (MDA, indicator of lipid peroxidation), liver and lung chemokines (macrophage inflammatory protein 1alpha [MIP-1alpha] and MIP-2), and ex vivo vascular reactivity in aortic rings were also measured. Mice treated with inosine had significantly lower levels of circulating cytokines. Organ damage was significantly reduced by inosine treatment, which was associated at the tissue level with an increased hepatic NAD+/NADH ratio, decreased MPO activity in the lung, reduced MDA formation in the gut and liver, and decreased MIP-1alpha and MIP-2 in the lung and liver. Furthermore, inosine significantly improved endothelium-dependent relaxant responses of aortic rings. These effects were associated with significant improvement of the survival of CLP mice treated with inosine, an effect that was still observed when inosine treatment was delayed 1 h after CLP, especially when it was associated with appropriate antibiotic treatment. Thus, inosine reduced systemic inflammation, organ damage, tissue dysoxia, and vascular dysfunction, resulting in improved survival in septic shock.

Animals↗

PubMed2005

Paradoxical effect of body mass index on survival in rheumatoid arthritis: role of comorbidity and systemic inflammation.

BACKGROUND: Despite high cardiovascular mortality in rheumatoid arthritis (RA), few studies of body mass index (BMI) and obesity as risk factors for death in RA have been published. METHODS: We estimated the effect of BMI on survival in a cohort of 779 patients with RA adjusting for comorbidity, RA disease severity, erythrocyte sedimentation rate (ESR), and other potential confounders. RESULTS: The cohort accrued 123 deaths in 3460 person-years (3.6 deaths per 100 person-years; 95% confidence interval [CI], 3.0-4.2). The BMI was inversely associated with mortality. Patients with BMIs of 30 or higher had the lowest mortality, 1.7 deaths per 100 person-years (95% CI, 1.1-2.5). Mortality was higher in each lower BMI category, reaching its highest rate among patients with BMIs lower than 20 with 15.0 deaths per 100 person-years (95% CI, 9.9-23.0). The survival advantage of high BMI was independent of RA onset age, RA duration, sex, ethnic group, socioeconomic status, smoking status, and use of methotrexate but was lost on adjusting for comorbidity and RA severity. We observed an interaction between BMI and ESR, where the BMI protective influence occurred only if the ESR was low. The BMI x ESR interaction was independent of all covariates, including comorbidity and RA severity. CONCLUSIONS: Body mass has a paradoxical effect on mortality in RA. Patients with high BMI have lower mortality than thinner patients. This effect is mediated in part by comorbidity. The effect of body mass on survival seems to be modified by the level of systemic inflammation.

Adult↗

PubMed2006

Loss of cortical bone from the metacarpal diaphysis in patients with rheumatoid arthritis: independent effects of systemic inflammation and glucocorticoids.

OBJECTIVE: To identify factors associated with the loss of cortical diaphyseal bone over time in patients with rheumatoid arthritis (RA). METHODS: We measured the combined cortical thickness (CCT) of the second metacarpal bone from digitized hand radiographs in an RA cohort. We estimated the rate of loss of CCT, and tested the effect of factors that could accelerate the rate. RESULTS: We studied 649 patients, who had 2990 hand radiographs. The median interval between the first and last followup radiograph was 2 years (range 0 to 23 yrs). The mean CCT at baseline was 4.04 mm (standard deviation 1.18). CCT loss was greatest during the earliest observation stages, following a square-root function of time at a rate of 0.393 mm/year(1/2) (95% CI 0.360, 0.423). Patients with a mean erythrocyte sedimentation rate (ESR) < 30 mm/h lost CCT at a rate of 0.303 mm/year(1/2) (95% CI 0.247, 0.358); those with a mean ESR > 30 and < or = 60 mm/h lost CCT at 0.395 mm/year(1/2) (95% CI 0.345, 0.446); and those with ESR > 60 mm/h lost CCT at 0.554 mm/year(1/2) (95% CI 0.480, 0.628). Patients who received a cumulative dose of glucocorticoids > or = 11.7 g lost CCT at 0.659 mm/year(1/2) (95% CI 0.577, 0.742), compared to 0.361 mm/year(1/2) (0.323, 0.401) in patients who did not receive glucocorticoids. In a multivariable model, the effect of the ESR and cumulative glucocorticoids was independent of age at RA onset, RA duration, sex, ethnic group, body mass index, presence of rheumatoid nodules, rheumatoid factor, and the HLA-DRB1 shared epitope. CONCLUSION: Early rapid loss of cortical diaphyseal bone occurs in patients with RA, followed by gradual slowing. Systemic inflammation and glucocorticoids seem to accelerate bone loss independently of other risk factors. Cortical diaphyseal bone may be an important target of the disease process in RA.

Arthritis, Rheumatoid↗

PubMed1989

Protracted anemia associated with chronic, relapsing systemic inflammation induced by arthropathic peptidoglycan-polysaccharide polymers in rats.

Mild hypoproliferative anemia with abnormal iron metabolism frequently accompanies chronic inflammation and infection in humans. To determine whether anemia is associated with chronic relapsing arthritis induced by bacterial cell wall polymers, serial determinations of the hematocrit were measured in rats injected intraperitoneally with sonicated peptidoglycan-polysaccharide fragments from group A streptococci. Acute anemia peaked 5 to 10 days after injection, and chronic, spontaneously relapsing anemia persisted for 309 days. 51Cr labeling demonstrated decreased erythrocyte survival, i.e., a half-life of 8.4 days in cell wall-injected rats versus 11.8 days in controls. Erythrocytes were mildly microcytic, and leukocyte counts were elevated during early spontaneous reactivation of arthritis, 15 days after injection of peptidoglycan-polysaccharide. Bone marrow myeloid/erythroid precursor ratios were elevated in arthritic rats (P less than 0.0001). Purified peptidoglycan produced an acute anemia lasting 10 days, while injection of group A streptococcal polysaccharide and mutanolysin-digested cell wall did not affect the hematocrit. The minimal effective dose of peptidoglycan-polysaccharide was 5 micrograms of rhamnose per g (body weight). Serum iron and transferrin levels were decreased in cell wall-injected rats (P less than 0.005) and were closely correlated with hematocrit values and joint inflammatory scores. Stainable iron was increased in the liver, spleen, and mesenteric lymph nodes and unchanged in the bone marrow of cell wall-injected rats. Anemia accompanying chronic, relapsing systemic inflammation induced by peptidoglycan-polysaccharide polymers appears to be an excellent animal model of the anemia of chronic disease.

Anemia↗

PubMed2005

Higher circulating hsCRP levels are associated with lower bone mineral density in healthy pre- and postmenopausal women: evidence for a link between systemic inflammation and osteoporosis.

Factors involved in inflammation are linked with those critical for bone remodeling. We examined the association between serum high sensitivity C-reactive protein (hsCRP) levels and bone mineral density (BMD) in healthy women. Serum concentrations of hsCRP and total alkaline phosphatase (ALP) were measured in premenopausal ( n =3,662) and postmenopausal ( n =1,031) women aged 30 years or older. BMD was measured at the femoral neck and lumbar spine using dual energy X-ray absorptiometry. According to the WHO definition, osteopenia was diagnosed at -2.5< T -score < -1.0 SD, and osteoporosis was diagnosed at T -score < or = -2.5 SD at any sites. Compared with normal subjects, log-transformed serum hsCRP levels were higher in osteopenic and osteoporotic subjects (all, P < 0.001) with linearity ( P for trend <0.001), after adjustment for age, BMI and menopausal status. Menopausal status did not have a significant interaction on the association ( P =0.457). In both premenopausal and postmenopausal women, serum total ALP levels were higher in the subjects with higher hsCRP quintiles than those with the lowest quintile (all, P for trend < 0.001). Multivariate-adjusted odds ratio (OR) for osteoporosis and osteopenia were 1.35 (95% CI, 1.08 to 1.68) in the highest hsCRP quintile of premenopausal women, and OR for osteoporosis was 1.54 (95% CI, 1.10 to 2.53) in the highest hsCRP quintile of postmenopausal women. These findings suggest that subclinical systemic inflammation may be associated with bone turnover rate and bone mass in healthy women.

Absorptiometry, Photon↗

PubMed2003

Fas-mediated neutrophil apoptosis and associated A1 protein expression during systemic inflammation are regulated independently of both tumor necrosis factor receptors.

TNFR-1 (p55) and Fas share a death domain which is critical for apoptosis signaling whereas TNFR-p55 and TNFR-2 (p75) can activate NF-kappaB leading to anti-apoptotic proteins expression such as A1. The purpose of this study was to elucidate the role(s) of TNFR-p55 and TNFR-p75 in Fas-mediated neutrophil apoptosis and A1 expression in a mouse model of endotoxemia. Gene knockout (KO) (p55-/-, p75-/-, p55(-/-)/p75(-/-)) or wild type (WT) mice were injected i.p. with saline or LPS (4 microg/g) followed by collecting peripheral blood after 24 h. Neutrophil apoptosis was assessed by propidium iodide staining using two-color flow cytometry with granulocyte-specific Gr1-FITC after 6-h whole blood culture with or without Fas agonist Jo2 (300 ng/ml) in the presence or absence of cycloheximide (CHX, 30 microg/ml). Membrane-associated receptors (Fas, TNFR-p55 and TNFR-p75) and cytoplasmic A1 expression of freshly isolated neutrophils were assessed by one-color flow cytometry and western blotting respectively. Compared with the group-WT/Sal, Jo2 induced apoptosis only in the presence of CHX (J+C). J+C-induced apoptosis was significantly lower in the group-p55(-/-)/Sal and p55(-/-)/p75(-/-)/Sal but not in the group-p75(-/-)/Sal. J+C-induced apoptosis was inhibited similarly in all the LPS-injected WT and KO mice. Strong A1 expression was also induced similarly in all the LPS-injected WT and KO mice. Fas and TNFR-p55 expression was normal and TNFR-p75 was significantly increased in all the LPS-injected WT and KO mice although absence of the appropriate surface receptors was confirmed in the KO mice. We conclude that p55 normally plays a proapoptotic role, but p75 appears to play a minimal role in Fas-mediated neutrophil apoptosis. During endotoxin-induced systemic inflammation, both TNFR-p55 and TNFR-p75 appear to be of minimal importance for modulation of Fas-mediated apoptosis and associated A1 protein expression despite normal Fas/TNFR-p55 and increased TNFR-p75 expression in neutrophils.

Animals↗

PubMed2005

Platelet-activating factor acetylhydrolase activity indicates angiographic coronary artery disease independently of systemic inflammation and other risk factors: the Ludwigshafen Risk and Cardiovascular Health Study.

BACKGROUND: Platelet-activating factor acetylhydrolase (PAF-AH), also denoted as lipoprotein-associated phospholipase A2, is a lipoprotein-bound enzyme that is possibly involved in inflammation and atherosclerosis. This study investigates the relationship of PAF-AH activity to angiographic coronary artery disease (CAD), the use of cardiovascular drugs, and other established risk factors. METHODS AND RESULTS: PAF-AH activity, lipoproteins, sensitive C-reactive protein (sCRP), fibrinogen, serum amyloid A, and white blood cell count were determined in 2454 subjects with angiographically confirmed CAD and in 694 control subjects. PAF-AH activity was highly correlated with LDL cholesterol (r=0.517), apolipoprotein B (r=0.644), and non-HDL cholesterol (r=0.648) but not with sCRP or fibrinogen. PAF-AH activity was lower in women than in men and was affected by the intake of lipid-lowering drugs (-12%; P<0.001), aspirin (-6%; P<0.001), beta-blockers (-6%; P<0.001), and digitalis (+7%; P<0.001). Unlike sCRP, fibrinogen, and serum amyloid A, PAF-AH activity was not elevated in unstable angina, non-ST-elevation myocardial infarction, or ST-elevation myocardial infarction. When nonusers of lipid-lowering drugs were examined, PAF-AH activity was associated with the severity of CAD and the number of coronary vessels with significant stenoses. In individuals not taking lipid-lowering drugs and after adjustment for use of aspirin, beta-blocker, and digitalis, the odds ratio for CAD associated with increasing PAF-AH activity was 1.39 (95% CI 1.26 to 1.54, P<0.001), a finding that was robust against further adjustments. CONCLUSIONS: PAF-AH activity is not an indicator of the systemic inflammation that accompanies acute coronary syndromes. PAF-AH activity is affected by a number of cardiovascular drugs; however, after such medication use was accounted for, PAF-AH activity was associated with angiographic CAD, complementary to sCRP and independently of established risk factors such as LDL cholesterol.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1997

Association of autonomic nervous hyperreflexia and systemic inflammation in patients with Crohn's disease and ulcerative colitis.

The autonomic nervous system modulates gastrointestinal motility, secretion and mucosal immunity. Its dysfunction may be of pathogenetic importance in inflammatory bowel disease (IBD). This study aimed at investigating the autonomic nervous function in patients with IBD. Forty-seven patients with IBD, 28 with Crohn's disease (CD) and 19 with ulcerative colitis (UC), were investigated by means of 5 cardiovascular and 2 pupillary standardized autonomic nervous function tests. In CD and UC, cardiovascular autonomic neuropathy was very rare (0%, 5%), whereas pupillary autonomic neuropathy was more prevalent (21%, 21%). In contrast to autonomic neuropathy, overall cardiovascular (CD: 29%, UC: 26%) and pupillary autonomic hyperreflexia (46%, 37%) were found more often. Patients with CD and UC demonstrated elevated percentiles in the respiratory sinus arrhythmia test as compared to controls (RSA: 82.3 +/- 3.9%, 80.0 +/- 5.9%, controls: 50.0% +/- 1.5%, p < 0.0001). CD patients with, as compared to patients without, RSA hyperreflexia had significantly higher CDAIs (p < 0.001), increased erythrocyte sedimentation rates (p < 0.005) and more often extraintestinal disease manifestations (p < 0.001). UC patients with, as compared to patients without, pupillary latency time hyperreflexia had lower hemoglobin (p < 0.05), lower albumin (p < 0.01) and increased erythrocyte sedimentation rates (p < 0.05). Autonomic hyperreflexia was significantly associated with more severe inflammation and systemic disease in IBD. Hyperreflexia may be a response to inflammation or a pathogenetic element that drives mucosal inflammation.

Adolescent↗

PubMed1998

The gut. A key metabolic organ protected by lactoferrin during experimental systemic inflammation in mice.

The gastrointestinal tract may be viewed as an ecologic system in which a balance between the host and bacterial flora exists. Two major host components appear to be involved in maintaining this balance. The first is a non-specific structural barrier provided by the epithelial layer of the gastrointestinal mucosae. The second component involves functional immunological elements found in the mucosal and submucosal compartments, e.g., gut associated lymphoid tissue. When gut integrity is disrupted by invasive pathogens or by trauma, a myriad of pro-inflammatory mediators are released from cells in the gut wall that exert actions in the tissue or gut lumen. One of these mediators is lactoferrin, and iron binding protein found in high concentration in most human exocrine secretions. Despite controversies on its physiological role, evidence is emerging that lactoferrin plays an important role in host defense against toxic metabolites and antigenic components of potential pathogens2-4. This manuscript is intended to provide an overview of work related to lactoferrin's modulatory roles in inflammation, and to present observations from experimental studies on the preservation of intestinal structure and function by lactoferrin during intestinal inflammation. The possibility that lactoferrin limits the autodestructive inflammatory responses presents a new alternative for the future management of systemic inflammation.

Animals↗

PubMed2005

Markers of hemostasis and systemic inflammation in heart disease and atherosclerosis in smokers.

Smoking is a major cause of both chronic obstructive pulmonary disease (COPD) and coronary heart disease, the latter being more common in individuals with COPD. Acute coronary events are usually caused by the development of a platelet-rich thrombus associated with atheromatous plaque rupture or erosion. Levels of systemic biomarkers of inflammation and hemostasis may reflect the presence of atherosclerosis and predisposition to thrombosis, and may allow identification of "vulnerable plaque" and "vulnerable blood" in "vulnerable patients." Hemostasis and inflammation, often viewed as separate processes, are integrated closely, and their response to smoking likely has contributed to the current coronary heart disease epidemic. Coagulation is initiated after exposure of blood to tissue factor present in atheromatous plaques. Fibrinogen and other hemostatic factors important in thrombus formation are influenced by inflammatory stimuli, possibly reflecting both vascular and systemic inflammation. Smokers who develop COPD may have higher basal levels of inflammatory markers, such as fibrinogen, due to lung damage, and respiratory infections to which they are prone may further increase levels, predisposing smokers to coronary events. In summary, smoking predisposes to coronary heart disease and the mechanisms may involve proinflammatory and procoagulant changes. These changes may be more marked in smokers with COPD.

Arteriosclerosis↗

PubMed2004

Selective and antigen-dependent effects of myelin degeneration on central nervous system inflammation.

Damage to myelin sheath or oligodendrocytes may precede or even provoke inflammation of the central nervous system (CNS), but the extent to which these degenerative changes affect inflammation remains largely undefined. To study these processes in more detail, we used CNS antigen-specific T cells in the presence or absence of anti-myelin antibodies to induce experimental autoimmune encephalomyelitis (EAE) in transgenic Lewis rats with low-grade subclinical myelin degeneration and associated microglia cell activation, and in wild-type Lewis rats with an intact CNS. We found that myelin degeneration affects the localization of inflammatory lesions, the numbers of T cells recruited to these lesions, and the severity of the resulting clinical disease. In addition, myelin degeneration and associated microglia cell activation jointly enhance the susceptibility of the CNS to the action of anti-myelin antibodies. Our data show that even subtle alterations of myelin and oligodendrocytes may massively amplify the extent of demyelination and tissue damage, involving different immune effector mechanisms. A similar causal relationship might also operate in human patients with multiple sclerosis, where T cell-mediated inflammation and antibody-mediated demyelination have been documented, and where genetic factors might determine the susceptibility of the target tissue for immune-mediated injury.

Animals↗

PubMed2005

Arterial stiffness is related to systemic inflammation in essential hypertension.

The acute phase-reactant high-sensitivity C-reactive protein, a marker of vascular inflammation and an atherosclerotic risk factor, is related to arterial stiffness in healthy subjects and in systemic vasculitis. To explore the relationship between markers of inflammation, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and high-sensitivity C-reactive protein with arterial stiffness, we studied untreated patients (n=78; 56% male; 47+/-1 years of age; mean+/-SEM) with essential hypertension. After overnight fast, augmentation index and pulse wave velocity were assessed noninvasively and related to plasma levels of inflammatory markers measured by ELISA. Pulse wave velocity was significantly related to plasma high-sensitivity C-reactive protein (r=0.31; P<0.001), TNF-alpha, (r=0.30; P<0.001) and IL-6 (r=0.21; P<0.05). There was also a relationship between heart rate-corrected augmentation index to high-sensitivity C-reactive protein (r=0.37; P<0.001), IL-6 (r=0.24; P<0.05), and TNF-alpha (r=0.19, P=0.06). High-sensitivity C-reactive protein was an independent predictor of pulse wave velocity and augmentation index in a multiple stepwise regression model. High-sensitivity C-reactive protein, a marker of systemic inflammation, is independently related to pulse wave velocity, a marker of aortic stiffness, and augmentation index, a manifestation of wave reflection, in essential hypertension.

Arteries↗

PubMed2001

Involvement of the choroid plexus in central nervous system inflammation.

During inflammatory conditions in the central nervous system (CNS), immune cells immigrate into the CNS and can be detected in the CNS parenchyma and in the cerebrospinal fluid (CSF). The most comprehensively investigated model for CNS inflammation is experimental autoimmune encephalomyelitis (EAE), which is considered the prototype model for the human disease multiple sclerosis (MS). In EAE autoagressive CD4(+), T cells gain access to the CNS and initiate the molecular and cellular events leading to edema, inflammation, and demyelination in the CNS. The endothelial blood-brain barrier (BBB) has been considered the obvious place of entry for the circulating immune cells into the CNS. A role of the choroid plexus in the pathogenesis of EAE or MS, i.e., as an alternative entry site for circulating lymphocytes directly into the CSF, has not been seriously considered before. However, during EAE, we observed massive ultrastructural changes within the choroid plexus, which are different from changes observed during hypoxia. Using immunohistochemistry and in situ hybridization, we observed expression of VCAM-1 and ICAM-1 in the choroid plexus and demonstrated their upregulation and also de novo expression of MAdCAM-1 during EAE. Ultrastructural studies revealed polar localization of ICAM-1, VCAM-1, and MAdCAM-1 on the apical surface of choroid plexus epithelial cells and their complete absence on the fenestrated endothelial cells within the choroid plexus parenchyme. Furthermore, ICAM-1, VCAM-1, and MAdCAM-1 expressed in choroid plexus epithelium mediated binding of lymphocytes via their known ligands. In vitro, choroid plexus epithelial cells can be induced to express ICAM-1, VCAM-1, MAdCAM-1, and, additionally, MHC class I and II molecules on their surface. Taken together, our observations imply a previously unappreciated function of the choroid plexus in the immunosurveillance of the CNS.

Animals↗

PubMed2003

Regulation of protease-activated receptor 1 (PAR1) on platelets and responsiveness to thrombin receptor activating peptide (TRAP) during systemic inflammation in humans.

Thrombin is a coagulation protease that activates platelets, endothelial cells, leukocytes and mesenchymal cells. Thrombin signaling is mediated at least in part by protease-activated receptors (PARs). As little is known about the in vivo regulation of PAR1, this study aimed to characterize the effects of systemic thrombin formation during human endotoxemia on the regulation of PAR1 and the associated responsiveness of human platelets to thrombin receptor activating peptide (TRAP). Endotoxin (2 ng/kg) was infused into 40 healthy men to study the regulation of PAR1 in systemic human inflammation. The SPAN12 antibody was used to determine the in vivo regulation of PAR1. To measure whether modulation of the PAR1 receptor may be associated with altered platelet reactivity, whole blood was stimulated with TRAP ex vivo. Thrombin generation was determined by prothrombin (F(1+2)) fragment. F(1+2) levels increased almost 9-fold from 0.5+/-0.1 nmol/L to 4.5+/-1.9 nmol/L at 4 h (p<0.001). PAR1 decreased by approximately 8% (p<0.001) within 2 h after endotoxin infusion and stayed at those levels until 6 h. Concomitantly, TRAP induced P-selectin expression maximally decreased by 18% (p<0.001) at 6 h. In conclusion, PAR1 expression is down-regulated on platelets during systemic thrombin formation induced by inflammation in humans which results in decreased responsiveness to subsequent stimulation of the PAR1 receptor.

Adult↗

PubMed2000

Activin A release into the circulation is an early event in systemic inflammation and precedes the release of follistatin.

Recent evidence suggests a role for activin A, and its binding protein, follistatin, in inflammatory pathways. However, whether activin is released systemically during inflammation is not known. In this study, a release of activin A into the circulation occurred in sheep within 1 hour of injection of lipopolysaccharide. This rapid peak in activin A preceded the release of the key inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6. Follistatin release into the circulation occurred some 4 hours after the peak of activin A and continued out to 24 hours from lipopolysaccharide treatment. These data are the first to document a circulatory response of activin A to an inflammatory stimulus, and together with previous findings, suggest that activin A may have both pro- and anti-inflammatory actions in regulating cytokine-driven pathways.

Activins↗

PubMed2003

A synthetic heparin-mimicking polyanionic compound inhibits central nervous system inflammation.

The immunomodulating capacity of heparin led us to test the effect of the synthetic heparin-mimicking and low anticoagulant compound RG-13577 on the course of experimental autoimmune encephalomyelitis (EAE) and central nervous system (CNS) inflammation. EAE was induced in SJL mice by inoculation with whole mouse spinal cord homogenate. RG-13577, delivered intraperitoneally, inhibited the clinical signs of acute EAE and markedly ameliorated inflammation in the spinal cord, primarily by inhibiting heparanase activity in lymphocytes and astrocytes and thus impairing lymphocyte traffic. RG-13577 treatment was effective when started on day of disease induction or day 7 after induction. The low molecular weight heparin, enoxaparin, tested under the same conditions, exerted only a minor insignificant inhibitory effect. RG-13577 also inhibited the tyrosine phosphorylation of several proteins, particularly Erk1 and Erk2 of the MAP kinase signaling pathways associated with inflammation and cell proliferation. RG-13577 blocked the activity of sPLA(2) and inhibited CNS PGE(2) production both in vivo and in vitro.

Animals↗

PubMed2005

Relationships among bacteria, upper airway, lower airway, and systemic inflammation in COPD.

STUDY OBJECTIVE: The upper and lower airways are continuous. While upper airway symptoms are common in COPD patients, with accumulating evidence to suggest increased nasal inflammation, the relationships among upper airway, lower airway, and systemic inflammatory indexes have not been studied. We aimed to confirm that there is heightened nasal inflammation in COPD patients, to test the hypothesis that the degree of upper airway inflammation relates to the degree of lower airway inflammation, and to investigate the underlying associations with bacterial carriage and the systemic inflammatory response. DESIGN: Prospective cohort study. SETTING: Outpatient Department, London Chest Hospital, London, UK. PARTICIPANTS: Forty-seven patients with COPD and 12 control subjects of similar age, sex, and smoking status. MEASUREMENTS: Serum, nasal wash fluid, and sputum samples were obtained from 47 stable patients with COPD for the analysis of inflammatory indexes and bacterial colonization. Nasal wash fluid specimens were obtained from 12 control subjects. RESULTS: COPD patients had an increased nasal interleukin (IL)-8 concentration compared to control subjects (difference, 97.2 pg/mL; p = 0.009). The nasal IL-8 concentration in COPD patients correlated with that in sputum (r = 0.30; p = 0.039). In both the upper and lower airways of patients with COPD, the IL-8 concentration was associated with indexes of bacterial colonization. Patients colonized with a sputum potentially pathogenic microorganism had a higher total nasal bacterial load (difference, 1.5 log cfu/mL; p = 0.016). We did not find significant relationships between the degree of upper or lower airway inflammation, or bacterial carriage, and the systemic inflammatory response. CONCLUSIONS: COPD is associated with an increased nasal concentration of the neutrophil chemoattractant protein IL-8, the degree of which reflects that present in the lower airway. A relationship between lower airway bacterial colonization, postnasal drip, and higher nasal bacterial load may suggest a mechanism underlying this finding. This study is the first to report a correlation between the degree of upper and lower airway inflammation in COPD.

Aged↗