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At least 595 records · Page 33Linked to original sources
PubMed2005

Blockade of tissue factor-factor X binding attenuates sepsis-induced respiratory and renal failure.

Tissue factor expression in sepsis activates coagulation in the lung, which potentiates inflammation and leads to fibrin deposition. We hypothesized that blockade of factor X binding to the tissue factor-factor VIIa complex would prevent sepsis-induced damage to the lungs and other organs. Acute lung injury was produced in 15 adult baboons primed with killed Escherichia coli [1 x 10(9) colony-forming units (CFU)/kg], and then 12 h later, they were given 1 x 10(10) CFU/kg live E. coli by infusion. Two hours after live E. coli, animals received antibiotics with or without monoclonal antibody to tissue factor intravenously to block tissue factor-factor X binding. The animals were monitored physiologically for 34 h before being killed and their tissue harvested. The antibody treatment attenuated abnormalities in gas exchange and lung compliance, preserved renal function, and prevented tissue neutrophil influx and bowel edema relative to antibiotics alone (all P < 0.05). It also attenuated fibrinogen depletion (P < 0.01) and decreased proinflammatory cytokines, e.g., IL-6 and -8 (P < 0.01), in systemic and alveolar compartments. Similar protective effects of the antibody on IL-6 and -8 expression and permeability were found in lipopolysaccharide-stimulated endothelial cells. Blockade of factor X binding to the tissue factor-factor VIIa complex attenuates lung and organ injuries in established E. coli sepsis by attenuating the neutrophilic response and inflammatory pathways.

Animals↗
PubMed2002

Primary inflammation in human cystic fibrosis small airways.

Most cystic fibrosis (CF) patients die of lung failure, due to the combined effects of bacterial infection, neutrophil-mediated inflammation, and airway obstruction by hyperviscous mucus. To this day, it remains unclear where and how this pathological vicious circle is initiated in vivo. In particular, it has proven difficult to investigate whether inflammatory pathways are dysregulated in CF airways independently of infection. Also, the relative involvement of large (tracheobronchial) vs. small (bronchiolar) airways in CF pathophysiology is still unclear. To help address these issues, we used an in vivo model based on the maturation of human fetal CF and non-CF small airways in severe combined immunodeficiency mice. We show that uninfected mature CF small airway grafts, but not matched non-CF controls, undergo time-dependent neutrophil-mediated inflammation, leading to progressive lung tissue destruction. This model of mature human small airways provides the first clear-cut evidence that, in CF, inflammation may arise at least partly from a primary defect in the regulation of neutrophil recruitment, independently of infection.

Animals↗
PubMed2000

Acid aspiration increases sensitivity to increased ambient oxygen concentrations.

Previously we have demonstrated that prolonged exposure to 100% ambient oxygen leads to a marked loss in functional lung volume and lung compliance, hypoxemia, and surfactant system abnormalities similar to acute respiratory distress syndrome (ARDS). However, 50% oxygen administration is believed to be safe in most clinical settings. In the present study, we have evaluated the effects of a 24-h exposure to 50% oxygen in rabbits immediately following experimental gastric acid aspiration. Mild hypoxemia, but no changes in mortality, lung volume, lung compliance, surfactant metabolism, or edema formation occurred after 24 h of normoxia postacid aspiration. Conversely, a relatively short (24-h) exposure to 50% oxygen after acid aspiration results in increased pulmonary edema, physical signs of respiratory distress, and mortality, as well as decreased arterial oxygenation, lung volume, lung compliance, and type II alveolar cell surfactant synthesis. These results suggest that acid aspiration alters the "set point" for oxygen toxicity, possibly by "priming" cells through activation of inflammatory pathways. This pathogenic mechanism may contribute to the progression of aspiration pneumonia to ARDS.

Air↗
PubMed2004

Tissue factor in the myocardium: evidence of roles in haemostasis and inflammation.

The interaction between cell-surface tissue factor (TF) and the plasma coagulation factor VII (FVII) initiates the coagulation network that leads to the generation of thrombin and the formation of a fibrin clot. Thrombin also activates cellular protease activated receptors (PARs) through which it activates components of the inflammatory pathway. TF is expressed constitutively by cardiomyocytes and evidence from mice transgenic for a human TF mini-gene that express very low levels of human TF suggests that the TF-FVII interaction is critical for haemostasis within the heart. Pathological contact between TF and FVII may occur in the heart during ischaemia-reperfusion (I-R) injury and this may lead to activation of coagulation and thrombin generation. Evidence from animal models now suggests that thrombin is an important mediator of inflammation in I-R injury. The coagulation pathway therefore represents a novel therapeutic target for intervention in the prevention of I-R injury.

Animals↗
PubMed2005

Host-environment interactions: their impact on progression from gastric inflammation to carcinogenesis and on development of new approaches to prevent and treat gastric cancer.

Revelation of the connection between Helicobacter pylori infection and gastric adenocarcinoma has prompted new investigations pertaining to its basic and clinical aspects. H. pylori-induced persistent and uncontrolled gastric inflammation nearly always precedes the development of cancer and is instrumental in initiating a multistep process leading to carcinogenesis. Despite initial optimism about the potential of combination anti-H. pylori therapy to ultimately eradicate gastric adenocarcinoma, recent investigations suggest its use should be targeted and tailored to a selected patient group considering the multifaceted role of H. pylori in disease and the disease heterogeneity of gastric adenocarcinoma. The clinical spectrum of H. pylori infection ranges from asymptomatic gastritis and peptic ulcer to gastric malignancies. The occurrence of one versus another is the result of differences in the magnitude of gastritis, and the current disease paradigm suggests gastric inflammation is common to all H. pylori-associated gastroduodenal diseases. Therefore, the host inflammatory responses to environmental triggers, rather than to bacteria or environmental factors per se, would dictate the variable outcomes of H. pylori infection. Putative factors that are expected to play an important role in stimulating inflammatory pathways and modulating the cross-talk between host and environment are age at the time of infection, environmental cofactors, H. pylori virulence, and host genetics. Elucidation of the intimate relationship between host-environment interaction and gastric inflammation, although currently a formidable task, is essential in the development of new prevention and treatment strategies. Such knowledge might provide clues that allow more accurate prediction of variable outcomes of gastric inflammation and appropriate adjustment of treatment strategies, and might open up novel areas for studying gastric carcinogenesis. The evolving new technologies, such as microarray, proteomic, and functional genomic analyses, promise to shed new light on the immense complexity of the presumed host-environment interactions and will reveal more useful markers for the diagnosis and prognosis of gastric adenocarcinoma.

Adenocarcinoma↗
PubMed1979

Immune-mediated inflammation in the lumen of the bovine mammary gland.

Two groups of cows were sensitized to ovalbumin (OA) during lactation by a subcutaneous injection of OA either in Freund's complete or incomplet adjuvant; two groups of animals injected with the respective adjuvants only served as controls. Intraluminal infusion of microgram quantities of OA in uninflamed mammary glands elicited inflammation, i.e., release of leukocytes into the milk, only in the animals previously sensitized to OA. This indicates that an antigen-specific inflammatory pathway can be established in the mammary gland by parenteral sensitization. Immune-mediated release of leukocytes into the milk could not be reproduced by infusing complement fixing. OA-anti-OA complexes into the lumen of uninflamed glands of unsensitized cows.

Animals↗
PubMed1996

Regulation of mRNA levels of TNF-alpha and the alpha chain of the high-affinity receptor for IgE in mast cells by IFN-gamma and alpha/beta.

Rat mast cell lines (hybrid rat mast cells, HRMC, and rat cultured mast cells, RCMC) and mast cells from the rat body cavity were used to test the hypothesis that IFN-alpha/beta and IFN-gamma inhibit tumor necrosis factor alpha (TNF-alpha)-mediated cytotoxicity by depressing the steady-state levels of mRNA for TNF-alpha. In vitro treatment of mast cells with IFN-gamma and IFN-alpha/beta depressed mRNA levels. By contrast, IFN pretreatment of mast cell lines induced an increase in levels of mRNA for the IFN-inducible gene, 2'5'-oligoadenylate synthetase and also for high-affinity IgE-receptor-alpha. The IFN-mediated regulation of mast cells may be an important mechanism in the control of inflammatory pathways characterized by Th1- and Th2-type responses.

Animals↗
PubMed2005

Myeloperoxidase and cardiovascular disease.

Myeloperoxidase (MPO) is a leukocyte-derived enzyme that catalyzes the formation of a number of reactive oxidant species. In addition to being an integral component of the innate immune response, evidence has emerged that MPO-derived oxidants contribute to tissue damage during inflammation. MPO-catalyzed reactions have been attributed to potentially proatherogenic biological activities throughout the evolution of cardiovascular disease, including during initiation, propagation, and acute complication phases of the atherosclerotic process. As a result, MPO and its downstream inflammatory pathways represent attractive targets for both prognostication and therapeutic intervention in the prophylaxis of atherosclerotic cardiovascular disease.

Cardiovascular Diseases↗
PubMed2006

Pioglitazone inhibits in-stent restenosis in atherosclerotic rabbits by targeting transforming growth factor-beta and MCP-1.

OBJECTIVE: Although emerging data from preclinical and clinical studies suggests a reduction of in-stent restenosis with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, the reduction of neointimal growth via anti-inflammatory mechanisms has not been explored. METHODS AND RESULTS: Hypercholesterolemic New Zealand White rabbits (n=45) received bilateral balloon-expandable stents implanted into atherosclerotic iliac arteries. Animals were randomized to oral pioglitazone 3 (low dose) or 10 mg/kg per day (high dose) started on the day of stent implantation; control rabbits received placebo. Tissue harvest was performed 28 days after stenting, and stented segments underwent histology, morphometry, immunostaining for macrophages, and scanning electron microscopy. In selected animals, stented arterial segments were placed in organoid culture for 48 hours, and the conditioned media was assayed for 23 different cytokines. There was a 21% reduction in neointimal area for high-dose pioglitazone treated versus placebo rabbits (P<0.005), which was associated with a significant reduction of neointimal macrophages. Analysis of conditioned media revealed an 82% and 74% reduction in the release of monocyte chemoattractant protein-1 (MCP-1) (P<0.007) and transforming growth factor (TGF)-beta1 (P<0.01), respectively, in stented segments from animals treated with 10 mg/kg per day pioglitazone versus placebo. CONCLUSIONS: Oral pioglitazone suppresses in-stent neointimal growth by limiting local inflammatory pathways and may be useful as an adjunctive therapy in patients undergoing percutaneous interventions.

Administration, Oral↗
PubMed2006

Association between a leukotriene C4 synthase gene promoter polymorphism and coronary artery calcium in young women: the Muscatine Study.

OBJECTIVE: A majority of the recognized risk factors for atherosclerosis and the development of cardiovascular disease have been derived from the study of older populations who have already manifested clinical symptoms. If risk factors can be identified earlier in life, such as genetic variation, preventive measures may be taken before overt symptoms of pathology have manifested, and when treatments may be most effective. METHODS AND RESULTS: In an effort to identify individuals at increased risk for cardiovascular disease, we genotyped 732 members of the Muscatine Study Longitudinal Adult Cohort for candidate genetic markers associated with several pathogenetic processes. We identified age-adjusted increased risks for coronary artery calcium (OR 4.29; 95% CI 1.78, 10.31) and increased mean carotid artery intimal-medial thickness associated with the (-444)A>C promoter polymorphism of Leukotriene C4 Synthase (LTC4S) in women. There were no similar associations in men. CONCLUSIONS: LTC4S plays a key role in the process of inflammation as the rate limiting enzyme in the conversion of arachidonic acid to cysteinyl-leukotrienes, important mediators of inflammatory responses. The (-444)C variant upregulates LTC4S mRNA expression, increasing the synthesis of proinflammatory leukotrienes. Our results support genetic variation modifying inflammatory pathways as an important mechanism in the development of atherosclerosis.

Adult↗
PubMed2002

Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells.

BACKGROUND: Although CD40 signaling participates in atherosclerosis, links between lipid risk factors and this inflammatory pathway remain obscure. Cardiovascular risk reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may involve actions beyond lipid lowering, including reduced inflammation. Therefore, this study analyzed whether oxidized low-density lipoprotein (oxLDL) induces CD40/CD40L expression on cells implicated in atherogenesis and whether statins affect their expression in vitro as well as the expression of soluble CD40L (sCD40L) in vivo. METHODS AND RESULTS: Treatment of human vascular endothelial and smooth muscle cells and mononuclear phagocytes with oxLDL augmented the basal expression of CD40 and CD40L mRNA and protein. In contrast, cerivastatin, atorvastatin, or simvastatin concentration-dependently diminished the constitutive as well as oxLDL- or cytokine-induced expression of the receptor/ligand dyad, an effect reversed by mevalonate. Patients treated with statins had diminished sCD40L plasma levels compared with untreated control patients (8.3+/-3.1 ng/mL [n=11] versus 13.1+/-2.5 ng/mL [n=16], P<0.05), supporting the clinical relevance of the in vitro observations. Platelet-enriched plasma of mice deficient in CD40L showed markedly delayed fibrin clot formation, suggesting a role for the ligand in blood coagulation and supporting the hypothesis that statin-mediated reduction in CD40/CD40L expression might limit thrombosis. CONCLUSIONS: OxLDL may promote expression of CD40 and CD40L in human atheroma. Statins may limit the expression of the CD40 receptor/ligand dyad in two ways, directly as well as through diminished lipoprotein levels. Thus, reduced CD40 signaling may account for some of the statins' antiinflammatory action.

Animals↗
PubMed2004

Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine expressed widely by vascular cells. However, scant in vivo evidence supports direct participation of MIF in atherogenesis. Therefore, we investigated whether deficiency of MIF modulates atherosclerotic lesion formation and composition in low-density lipoprotein receptor-deficient (LDLr-/-) mice. METHODS AND RESULTS: MIF-/-LDLr-/- and LDLr-/- mice were generated and consumed an atherogenic diet for 12 or 26 weeks. MIF-/-LDLr-/- mice had significantly reduced abdominal aorta lipid deposition and intimal thickening from aortic arch throughout the abdominal aorta compared with LDLr-/- mice. Marked retardation of atherosclerosis over time in MIF-deficient mice accompanied decreased lesion cell proliferation. At 26 weeks, 20% of MIF-deficient mice developed only early, fatty streak-like lesions, whereas >80% of LDLr-/- mice developed advanced lesions containing calcification and lipid cores. Analysis of smooth muscle cells from mouse aortae demonstrated that MIF deficiency reduced smooth muscle cell proliferation, cysteine protease expression, and elastinolytic and collagenolytic activities. CONCLUSIONS: Deficiency of MIF reduces atherogenesis in LDLr-/- mice. These results provide novel insight into inflammatory pathways operating in atheromata and identify a new potential target for modulating atherogenesis.

Animals↗
PubMed2005

Activation of inflammation and coagulation after infusion of C-reactive protein in humans.

C-reactive protein (CRP) has been postulated to play a causal part in atherosclerosis and its acute complications. We assessed the effects of CRP-infusion on coagulation and inflammatory pathways to determine its role in atherothrombotic disease. Seven male volunteers received an infusion on two occasions, containing 1.25 mg/kg recombinant human CRP (rhCRP) or diluent, respectively. CRP-concentrations rose after rhCRP-infusion from 1.9 (0.3 to 8.5) to 23.9 (20.5 to 28.1) mg/L, and subsequently both inflammation and coagulation were activated. This sequence of events suggests that CRP is not only a well known marker of cardiovascular disease, but is also probably a mediator of atherothrombotic disease.

Adult↗
PubMed2005

Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice.

Peroxisome proliferator-activated receptor (PPAR)-gamma is required for adipogenesis but is also found in the cardiovascular system, where it has been proposed to oppose inflammatory pathways and act as a growth suppressor. PPAR-gamma agonists, thiazolidinediones (TZDs), inhibit cardiomyocyte growth in vitro and in pressure overload models. Paradoxically, TZDs also induce cardiac hypertrophy in animal models. To directly determine the role of cardiomyocyte PPAR-gamma, we have developed a cardiomyocyte-specific PPAR-gamma-knockout (CM-PGKO) mouse model. CM-PGKO mice developed cardiac hypertrophy with preserved systolic cardiac function. Treatment with a TZD, rosiglitazone, induced cardiac hypertrophy in both littermate control mice and CM-PGKO mice and activated distinctly different hypertrophic pathways from CM-PGKO. CM-PGKO mice were found to have increased expression of cardiac embryonic genes (atrial natriuretic peptide and beta-myosin heavy chain) and elevated nuclear factor kappaB activity in the heart, effects not found by rosiglitazone treatment. Rosiglitazone increased cardiac phosphorylation of p38 mitogen-activated protein kinase independent of PPAR-gamma, whereas rosiglitazone induced phosphorylation of extracellular signal-related kinase 1/2 in the heart dependent of PPAR-gamma. Phosphorylation of c-Jun N-terminal kinases was not affected by rosiglitazone or CM-PGKO. Surprisingly, despite hypertrophy, Akt phosphorylation was suppressed in CM-PGKO mouse heart. These data show that cardiomyocyte PPAR-gamma suppresses cardiac growth and embryonic gene expression and inhibits nuclear factor kappaB activity in vivo. Further, rosiglitazone causes cardiac hypertrophy at least partially independent of PPAR-gamma in cardiomyocytes and through different mechanisms from CM-PGKO.

Animals↗
PubMed2003

Inflammation and infections as risk factors for ischemic stroke.

BACKGROUND: Inflammatory processes have fundamental roles in stroke in both the etiology of ischemic cerebrovascular disease and the pathophysiology of cerebral ischemia. We summarize clinical data on infection and inflammation as risk or trigger factors for human stroke and investigate current evidence for the hypothesis of a functional interrelation between traditional risk factors, genetic predisposition, and infection/inflammation in stroke pathogenesis. SUMMARY OF REVIEW: Several traditional vascular risk factors are associated with proinflammatory alterations, including leukocyte activation, and predispose cerebral vasculature to thrombogenesis on inflammatory stimulation. Furthermore, accumulation of inflammatory cells, mainly monocytes/macrophages, within the vascular wall starts early during atherogenesis. During later disease stages, their activation can lead to plaque rupture and thrombus formation, increasing stroke risk. Inflammatory markers (eg, leukocytes, fibrinogen, C-reactive protein) are independent predictors of ischemic stroke. Chronic infections (eg, infection with Chlamydia pneumoniae or Helicobacter pylori) were found to increase the risk of stroke; however, study results are at variance, residual confounding is not excluded, and causality is not established at present. In case-control studies, acute infection within the preceding week was a trigger factor for ischemic stroke. Acute and exacerbating chronic infection may act by activating coagulation and chronic infections and may contribute to atherogenesis. Genetic predisposition of the inflammatory host response may be an important codeterminant for atherogenesis and stroke risk. CONCLUSIONS: Inflammation contributes to stroke risk via various interrelated mechanisms. Infectious diseases, traditional risk factors, and genetic susceptibility may cooperate in stimulating inflammatory pathways. Final proof of a causal role of infectious/inflammatory mechanisms in stroke pathogenesis is still lacking and will require interventional studies.

Biomarkers↗
PubMed2005

Elevated tumor necrosis factor-alpha in skeletal muscle after stroke.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine negligibly expressed in normal muscle, is elevated in selected metabolic conditions characterized by muscle wasting and insulin resistance. Inflammation is fundamental to stroke pathogenesis. Stroke patients have gross muscular atrophy and high prevalence of diabetes and insulin resistance. Yet, no previous studies examined TNF-alpha expression in hemiparetic skeletal muscle. This study investigates whether TNF-alpha mRNA levels are elevated in paretic compared with nonparetic leg muscles of chronic ischemic stroke patients and age-matched controls. METHOD: Total RNA extracted from bilateral vastus lateralis muscle biopsies from n=20 hemiparetic stroke patients and n=9 healthy controls was reverse transcribed to cDNA, then TNF-alpha transcripts were amplified by real-time quantitative polymerase chain reaction. TNF-alpha mRNA concentrations were normalized against acidic ribosomal phosphoprotein, housekeeping gene. RESULTS: TNF-alpha mRNA levels were 2.8-fold higher in paretic compared with control leg muscle (6.28+/-1.86 versus 2.28+/-0.67; P<0.03) and 1.6-fold higher in nonparetic leg (3.71+/-1.02; P<0.11) compared with controls. There was a trend for higher TNF-alpha mRNA in paretic compared with nonparetic leg. CONCLUSIONS: Findings demonstrate increased TNF-alpha expression in paretic leg muscle, suggesting inflammatory pathways are accelerated in stroke muscle. Further studies are under way to determine whether intramuscular TNF-alpha contributes to atrophy and metabolic abnormalities after stroke.

Aged↗
PubMed1998

Increased endothelial expression of intercellular adhesion molecule-1 in symptomatic versus asymptomatic human carotid atherosclerotic plaque.

BACKGROUND AND PURPOSE: The mechanisms that cause carotid atherosclerotic plaque to become symptomatic remain unclear. Evidence suggests that mediators of inflammation are not only instrumental in the formation of plaque but may also be involved in the rapid progression of atheromatous lesions leading to plaque fissuring, endothelial injury, and intraluminal thrombosis. Our goal is to determine whether intercellular adhesion molecule-1 (ICAM-1), a known component of the inflammatory pathway, is preferentially expressed on symptomatic versus asymptomatic carotid plaques. METHODS: Carotid plaques from symptomatic (n = 25) and asymptomatic (n = 17) patients undergoing carotid endarterectomy with lesions involving >60% stenosis were snap-frozen at the time of surgery. Immunofluorescence studies were performed to measure the percentage of luminal endothelial surface that expressed ICAM-1. The relationships of stroke risk factors, white blood cell count, percent stenosis, and soluble ICAM-1 (sICAM-1) plasma levels to endothelial ICAM-1 expression were investigated. RESULTS: An increased expression of ICAM-1 was found in the high-grade regions of symptomatic (29.5%+/-2.4%, mean+/-SEM) versus asymptomatic (15.7%+/-2.7%, mean+/-SEM) plaques (P=0.002) and in the high-grade versus the low-grade region of symptomatic plaques (29.5+/-2.4, mean+/-SEM, versus 8.9+/-1.6; P<0.001). Plasma sICAM-1 levels were not predictive of symptomatic disease, and no significant correlation between risk factor exposure and endothelial ICAM-1 expression was found. CONCLUSIONS: An elevation in ICAM-1 expression in symptomatic versus asymptomatic plaque suggests that mediators of inflammation are involved in the conversion of carotid plaque to a symptomatic state. The data also suggest a differential expression of ICAM-1, with a greater expression found in the high-grade region than in the low-grade region of the plaque specimen.

Adult↗
PubMed2002

Tumor necrosis factor receptor levels are associated with carotid atherosclerosis.

BACKGROUND AND PURPOSE: Recent evidence suggests that atherosclerosis is an inflammatory condition. Serum levels of inflammatory markers may serve as measures of the severity of atherosclerosis and risk of stroke. We sought to determine whether tumor necrosis factor-alpha (TNF-alpha) and TNF receptor levels are associated with carotid plaque thickness. METHODS: The Northern Manhattan Stroke Study is a community-based study of stroke risk factors. For this cross-sectional analysis, inflammatory marker levels, including TNF-alpha and TNF receptors 1 and 2, were measured by immunoassay in stroke-free community subjects undergoing carotid duplex Doppler ultrasound. Maximal carotid plaque thickness (MCPT) was measured for each subject. Analyses were stratified by age < 70 and > or =70 years. Simple and multiple linear regression analyses were used to calculate the association between marker levels and MCPT. Multiple logistic regression was used to calculate odds ratios and 95% CIs for the association of inflammatory markers with MCPT > or =1.5 mm (>75th percentile), after adjustment for demographic and potential medical confounding factors. RESULTS: The mean age of the 279 subjects was 67.6+/-8.5 years; 49% were men; 63% were Hispanic, 17% black, and 17% white. Mean values for TNF-alpha and its receptors were as follows: TNF-alpha, 1.88+/-3.97 ng/mL; TNF receptor 1, 2.21+/-0.99 ng/mL; and TNF receptor 2, 4.85+/-2.23 ng/mL. Mean MCPT was elevated in those in the highest quartiles compared with lowest quartiles of TNF receptor 1 and 2 (1.24 versus 0.79 mm and 1.23 versus 0.80 mm, respectively). Among those aged < 70 years, TNF receptor 1 and 2 were associated with an increase in MCPT (mean difference=0.36 mm, P=0.01 for TNF receptor 1 and mean difference=0.10 mm, P=0.04 for TNF receptor 2). After adjustment for sex, race-ethnicity, hypertension, diabetes mellitus, LDL cholesterol, smoking, and body mass index, associations remained (mean difference=0.36 mm, P=0.001 for TNF receptor 1 and mean difference=0.09 mm, P=0.051 for TNF receptor 2). There was no association for TNF receptors in those aged > or = 70 years old and no association for TNF-alpha in either age group. Among those aged < 70 years, each unit increase in TNF receptor level increased the odds of the participant's having MCPT > or =1.5 mm (adjusted odds ratio=4.7; 95% CI, 1.7 to 15.4 for TNF receptor 1; odds ratio=1.9; 95% CI, 1.3 to 2.9 for TNF receptor 2). CONCLUSIONS: Relative elevation in TNF receptor levels, but not TNF-alpha, is associated with carotid atherosclerosis among individuals aged < 70 years in this multiethnic, urban population. Chronic subclinical infection or inflammation may account for this association, and modification of these inflammatory pathways may provide a novel approach to stroke prevention.

Age Factors↗