The pathology of Kawasaki disease aortitis: a study of 37 cases.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis syndrome that occurs most frequently in children. Most clinical and pathological studies have focused on its coronary artery lesions. To date, no detailed studies of the aorta have been conducted. We studied KD autopsy cases with the aims of clarifying the time-course of changes in aortic lesions, the differences in the inflammatory cells and degree of inflammation at various aortic sites, and the progression of the inflammation. MATERIALS AND METHODS: The study materials were aortic specimens taken from 37 KD autopsy cases (acute phase: 19; remote phase: 18). Twenty-seven of the cases also had coronary aneurysms. We chose 3 aortic sites, i.e., the thoracic aorta, aortic root and aortic bifurcation, and we histologically observed and compared those sites in regard to the changes with time, the kinds of infiltrating cells and the number of inflammatory cells. We also observed the relationship between the vasa vasorum and inflammatory cell localization in the tunica media, and examined the progression of inflammation in the tunica media. RESULTS: Destruction of the vascular architecture was not seen in any of the 37 cases, but inflammatory cell infiltration was observed in 90% of the acute-phase cases. The inflammatory cell infiltration involved the tunica intima and tunica adventitia of the aorta on the 6th disease-day, and all layers of the aorta on the 13th disease-day; the infiltration peaked on the 18th disease-day. The infiltration gradually disappeared thereafter, and no significant infiltration was seen in the remote phase. The infiltrating inflammatory cells consisted mainly of CD163-positive macrophages. Comparison of the 3 sites of the aorta showed that the inflammatory cell infiltration was more severe in the aortic root and aortic bifurcation than in the thoracic aorta. The progression of inflammation to the aortic tunica media from the adventitia showed 2 patterns: 1 in which macrophages were aggregated around the vasa vasorum; and a second in which there was no such aggregation around the vasa vasorum, but there was diffuse inflammatory cell infiltration of the tunica media. In addition to this, there were findings of direct infiltration of cells from the tunica intima into the tunica media. CONCLUSION: Inflammation in KD occurs in the aorta. The changes with time and the kinds of infiltrating cells were the same as reported to date for coronary arteries in KD. There were differences in the degree of inflammation among the 3 aortic sites. It can be thought that the inflammation from the adventitia to the media progresses via the vas vasorum, and also, there is a possibility of spreading directly. From the intima to the media, inflammation spreads directly. However, formation of aneurysms and destruction of the vascular architecture of the aorta were absent in this study, unlike in coronary arteries.

Immune cells and vasa vasorum in the tunica media of atherosclerotic coronary arteries.

In coronary artery disease (CAD), the disruption of the tunica media immune privilege manifests as increased leukocyte infiltration and the formation of vasa vasorum. We aimed to characterize the immune privilege status of the tunica media in human coronary arteries (CAs) with atherosclerotic plaques, by comparing the abundance and composition of immune-cell infiltrates within the individual arterial-wall layers, and by evaluating vasa vasorum neovascularization of the tunica media. The tissue samples were obtained from 36 symptomatic patients with diffuse CAD (aged 60-72 years) who underwent coronary endarterectomy. T and B cells, macrophages and endothelial cells in the CAs were detected by immunohistochemistry. Morphological analysis of CAs showed significant atherosclerotic changes in all specimens. In the media, we observed damage and loss of smooth muscle cells, destruction of the extracellular matrix architecture, and fibrosis. There were 43.3% of immune cells in the intima, 50% in the adventitia, and 6.7% in the media. In the media, 51.1% of the immune cells were T cells (p ˂ 0.001 compared to B cells and macrophages; ANOVA, Scheffe post hoc analysis), 23.5% were B cells, and 25.4% were macrophages. The number of vasa vasorum in the media was 1 in 38.9% of CAs, 2-3 in 36.1%, and ≥4 in 25% of CAs. Our results indicate that, in atherosclerotic CAs, the immune privilege of the media is disrupted by the infiltration of T and B cells, macrophages, and the presence of vasa vasorum.

Immunophenotypic analysis of the chronological events of tissue repair in aortic medial dissections.

Acute medial dissection of aorta can occur in the context of a sudden and unexpected death. For medico-legal reasons it is important to estimate as accurately the histological age of dissections. We evaluated the additional value of a systematic application of immunohistochemistry, compared with conventional histology only, in determining chronological steps of injury and repair. Thirty two paraffin embedded specimens of aortic dissection were retrospectively allocated to one of four defined stages: acute (I), subacute (II), early organizing (III) and scarring (IV) using Hematoxylin and Eosin and Elastica van Gieson stained sections. Subsequent immunohistochemically staining was performed with the following markers: (myeloperoxidase (neutrophils), citrullinated-Histone 3 (neutrophil extracellular traps), CD68 (macrophages), CD3 (T-cells), CD31 and CD34 (endothelial cells), and smooth muscle actin. Immune stained sections were scored semi-quantitatively. Histologically, five cases were identified as stage I, 16 as II, 7 as III and 4 as IV. Additional immunostaining for smooth muscle cells and endothelial cells altered the classification in 25% of cases (all in groups II and III). Immunostaining and semi-quantitative grading of involvement of neutrophils, macrophages and NETs also provided specific distribution patterns over the 4 age categories, including unexpected involvement of the peri adventitial fat tissue. In conclusion, it appears that semi-quantitative immunohistochemistry of resident vascular wall cells, inflammatory cells and NETS represents a useful adjunct in detailed histopathological grading of the chronological age of aortic dissections.

Inflammatory and immune responses in the arterial media.

Inflammatory arterial diseases differentially affect the compartments of the vessel wall. The intima and adventitia are commonly involved by the disease process, with luminal and microvascular endothelial cells playing a critical role in the recruitment and activation of leukocytes. In contrast, the avascular media is often spared by immune-mediated disorders. Surprisingly, vascular smooth muscle cells (VSMCs), the predominant and often exclusive cell type of the media, are capable of robust proinflammatory responses to diverse stressors. The multiple cytokines and chemokines produced within the media can profoundly affect macrophage and T cell function, thus amplifying and shaping innate and adaptive immune responses. On the other hand, VSMCs and the extracellular matrix that they produce also display significant anti-inflammatory properties. The balance between the pro- and anti-inflammatory effects of VSMCs and their extracellular matrix versus the strength of the inciting immunologic events determines the pattern of medial pathology. Limitations on the extent of medial infiltration and injury, defined as medial immunoprivilege, are typically seen in arteriosclerotic diseases, such as atherosclerosis and transplant vasculopathy. Conversely, breakdown of medial immunoprivilege that manifests as more intense leukocytic infiltrates, loss of VSMCs, and destruction of the extracellular matrix architecture is a general feature of certain aneurysmal diseases and vasculitides. In this review, we consider the inflammatory and immune functions of VSMCs and how they may lead to medial immunoprivilege or medial inflammation in arterial diseases.

Effects of micro-amounts of Porphyromonas gingivalis lipopolysaccharide on rabbit inflammatory immune response and development of atherosclerosis.

BACKGROUND AND OBJECTIVE: Porphyromonas gingivalis (Pg) lipopolysaccharide is associated with the immune response and atherosclerosis. This study aimed to evaluate the effects of micro-amounts of Pg-lipopolysaccharide on rabbit inflammatory immune response and the development of atherosclerosis. MATERIAL AND METHODS: Twenty-four New Zealand white rabbits were randomly divided into four groups (n = 6). Group A was fed a regular diet and normal saline. Group B was supplied with a high-fat diet and normal saline. Group C was treated with a normal diet and Pg-lipopolysaccharide. Group D was given a high-fat diet and Pg-lipopolysaccharide. After 14 wk, the rabbits were killed to determine the changes in pathological indices. RESULTS: The serum lipid levels of groups B and D were significantly higher than that of group A (p < 0.01), and that of group C was higher (p < 0.05). Serum interleukin-6, monocyte chemoattractant protein-1 and tumor necrosis factor-α levels were significantly elevated by individual high-fat diets or Pg-lipopolysaccharide stimulation (p < 0.05). Groups A and C did not undergo evident aortic pathological damages, while foam cells appeared in the other two groups. Real-time polymerase chain reaction detection showed that toll-like receptor-2, interleukin-6, matrix metalloproteinase-9 and monocyte chemoattractant protein-1 were highly expressed in groups B and D (p < 0.05), and toll-like receptor-4, C-reactive protein and tumor necrosis factor-α levels were higher than those of group A (p < 0.05). Western blotting showed that transcription factor NF-κB p65 was expressed more highly in the three experimental groups than in group A (t = 9.26, p < 0.01). CONCLUSION: Micro-amounts of Pg-lipopolysaccharide induced the high expressions of inflammatory factors and mediated the inflammatory response. Pg-lipopolysaccharide elevated the blood lipid level less significantly than the high-fat diet did, but it may promote atherosclerosis.

Antiatherosclerotic effects of the novel angiotensin receptor antagonist Fimasartan on plaque progression and stability in a rabbit model: a double-blind placebo-controlled trial.

OBJECTIVES: To evaluate the effect of the novel angiotensin receptor blocker Fimasartan on the development of atherosclerosis and plaque stabilization in an animal model. METHODS: Twenty-four rabbits received an aortic balloon injury from 30 cm to a level just above the aortic valve to the iliac bifurcation using 3 Fr Fogarty catheters on third day of the experiment, followed by a 1% cholesterol diet for 8 weeks. The rabbits were randomized to receive placebo or 3 or 6 mg · kg⁻¹ · d⁻¹ Fimasartan. The study was double blinded. The rabbits started receiving their medications 2 days before the aortic balloon injury and treatment continued. Atherosclerosis burden was determined by calculating the intima-media ratio of the infrarenal portion of the aorta because the bulk of the atherosclerotic burden was limited to the infrarenal region. The frequency of plaque disruption with thrombosis and the proportions of the plaques that were occupied by macrophages, smooth muscle cells, and collagen were determined. RESULTS: Relative to the placebo group, the Fimasartan-treated rabbits had less atherosclerosis [intima-media ratio (mean ± SEM) of 1.14 ± 0.21 vs. 1.51 ± 0.26, P = 0.005], fewer disrupted plaques with thrombi (3 of 16 vs. 5 of 8, P = 0.047), lower proportion of macrophages (17.5% ± 2.5% vs. 26% ± 3.5%, P = 0.03), higher proportion of smooth muscle cells (43.5% ± 8.3% vs. 11.9% ± 2.1%, P = 0.001), and higher proportion of collagen (34.3% ± 6.4% vs. 19.7% ± 2.1%, P = 0.02). CONCLUSIONS: These results show that the newly developed angiotensin receptor blocker, Fimasartan, attenuated atherosclerosis progression and reduced macrophage accumulation in the rabbit aortic plaques.

Changes in vascular function and structure in juvenile idiopathic arthritis.

OBJECTIVE: Chronic inflammatory diseases in adults have been associated with increased cardiovascular risk and impaired vascular function. We aimed to assess the presence of early vascular dysfunction in patients with juvenile idiopathic arthritis (JIA) and investigate the role of inherent inflammatory process of JIA in vascular health. METHODS: Thirty patients with JIA (age range 7-18 years) were compared to 33 age- and sex-matched controls. Endothelial function (brachial artery flow-mediated dilation [FMD]), carotid intima-media thickness (IMT), and arterial stiffness were examined. Endothelial inflammation was assessed by intercellular adhesion molecule 1 (ICAM-1) and P-selectin measurements. RESULTS: Patients with JIA showed decreased FMD compared to controls (P = 0.001), independent of age (P = 0.9 among age subgroups). Baseline differences in erythrocyte sedimentation rate, ICAM-1, and glucose between the 2 groups accounted for the difference in FMD. The presence of systemic JIA was associated with greater IMT compared to patients with oligoarticular disease, polyarticular disease, or controls (P = 0.014, P = 0.069, and P = 0.046, respectively). The difference in IMT between systemic versus oligoarticular/polyarticular JIA was attributed to the following risk factors: age, body mass index, blood pressure, disease activity, and corticosteroids use. There were no differences in arterial stiffness indices between JIA patients and controls or between patients with systemic versus nonsystemic disease. CONCLUSION: Endothelial function is impaired in patients with JIA at a very young age, while IMT is increased only in the presence of systemic JIA. Vascular dysfunction may be partly attributed to the effects of disease-related characteristics (inflammation, disease activity, and medications).

Atherosclerosis and macrovascular involvement in systemic sclerosis: myth or reality.

Systemic sclerosis (SSc) is a chronic disease of unknown etiology, characterized by enhanced fibrosis, and microvascular abnormalities. During the past several decades, the death rates due to cardiovascular disease or cerebrovascular disease in SSc patients substantially increased and are currently responsible for 20-30% of mortality. Various autoimmune rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus accelerate atherosclerosis. Although microvascular disease is a hallmark of SSc, an ongoing debate exists regarding the presence and extent of macrovascular diseases and the presence of accelerated atherosclerosis in SSc patients. Despite conflicting results as to intima-media thickness (IMT) in SSc patients, the most recent and largest study has found no difference in either plaque occurrence or IMT. Additionally, abnormal coronary flow reserve in SSc patients appears to be due to microvascular involvement rather than atherosclerosis of the epicardial coronary arteries. Angiographic findings as well as computed tomography studies have generated conflicting reports as to coronary atherosclerosis in SSc. Herein, we review the current knowledge of macrovascular involvement and atherosclerosis in SSc. The differences between SSc and other autoimmune rheumatic diseases in the presence and extent of atherosclerosis need to be further investigated.

Levels of oxidized LDL and advanced glycation end products-modified LDL in circulating immune complexes are strongly associated with increased levels of carotid intima-media thickness and its progression in type 1 diabetes.

OBJECTIVE: High cholesterol levels in circulating immune complexes (IC), surrogate markers of modified LDL, are associated with increased carotid intima-media thickness (IMT) and cardiovascular events in type 1 diabetes. Different modifications of LDL are involved in IC formation, but which of these are predictive of vascular events is not known. Therefore, we measured oxidized LDL (oxLDL), advanced glycation end products-modified LDL (AGE-LDL), and malondialdehyde-modified LDL (MDA-LDL) in IC and determined their relationship with increased carotid IMT and compared the strength of the association with that observed with conventional risk factors. RESEARCH DESIGN AND METHODS: Levels of oxLDL, AGE-LDL, and MDA-LDL were measured in circulating IC isolated from sera of 479 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, collected at baseline. Internal and common carotid IMT were measured 8 and 14 years later by DCCT/EDIC. RESULTS: OxLDL, AGE-LDL, and MDA-LDL levels in circulating IC were significantly correlated with diabetes duration, BMI, and lipid and blood pressure, but not with age. Multivariate logistic regression models indicated that individuals in the highest versus lowest quartile of oxLDL and AGE-LDL in IC had a 6.11-fold [confidence interval (CI) 2.51-14.8] and a 6.4-fold (CI 2.53-16.2) increase in the odds of having high carotid IMT, respectively, after adjusting for conventional risk factors. Parallel analyses resulted in odds ratios of 2.62 (CI 1.24, 5.55) for LDL-C, 1.45 (CI 0.69, 3.03) for diastolic blood pressure, and 2.33 (CI 1.09, 4.99) for A1C. CONCLUSIONS: OxLDL and AGE-LDL in circulating IC were significantly associated with progression and increased levels of carotid IMT in type 1 diabetes.

Immunotherapy for the prevention of myointimal hyperplasia after experimental balloon injury of the rat carotid artery.

We assessed the effect of novel immunotherapeutic heat-killed bacterial (Actinomycetales) preparations on the development of myointimal hyperplasia (MIH) in a rat carotid balloon trauma model and the effect on the immune response by measuring the expression of interferon gamma (IFN-gamma; (Th1) and interleukin 4 (IL-4; Th2). There was a significant reduction (P < .001) in intima/media ratios (mean +/- SEM) in the rats treated by immunomodulation (0.52 +/- 0.03 Gordonia bronchialis, 0.60 +/- 0.03 Rhodococcus coprophilus, 0.43 +/- 0.03 Tsukamurella inchonensis, 0.37 +/- 0.03 Mycobacterium vaccae), in comparison with untreated controls (0.91 +/- 0.05). Postballoon trauma G bronchialis increased messenger RNA (mRNA) IFN-gamma (P < .02) and reduced mRNA IL-4 (P < .05). R coprophilus, T inchonensis, and M vaccae significantly increased production of mRNA IFN-gamma (P < .001). R coprophilus and M vaccae also decreased production of mRNA IL-4 (P < .05, P < .01). Treatment with heat-killed Actinomycetales inhibits MIH through a combination of enhanced Th1 and attenuated Th2 response. Immunomodulation may provide a novel therapeutic option to prevent restenosis.

Treatment with telmisartan attenuates graft arteriosclerosis in murine cardiac allografts.

BACKGROUND: Chronic rejection remains the most prominent cause of graft failure after transplantation. Recently, it was reported that telmisartan can function as a partial agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) in addition to a blocker of angiotensin II receptor. We investigated the effect of telmisartan on chronic rejection. METHODS: Hearts from Bm12 mice were transplanted into C57BL/6 mice (Class II mismatch), and allografts were harvested at 8 weeks after transplantation. Recipient mice were fed either control chow or chow containing telmisartan (10 mg/kg/day) from 1 day before transplantation. Proliferation assays of smooth muscle cells (SMCs), which were isolated from the aorta of B/6 mice, was performed. RESULTS: Although severe neo-intimal hyperplasia developed in allografts from control mice fed chow (luminal occlusion 70.9 +/- 6.1%), neo-intimal hyperplasia was significantly attenuated in allografts from mice fed chow containing telmisartan (30.0 +/- 10%, p < 0.001). Expression of interferon (IFN)-gamma and interleukin (IL)-15 mRNAs and matrix metalloproteinase (MMP)-2 in allografts was significantly lower in telmisartan-treated mice than in control mice. Proliferation of smooth muscle cells (SMCs) in response to fetal bovine serum was suppressed significantly by telmisartan (10 micromol/liter). The PPARgamma antagonist blocked telmisartan-induced suppression of SMC proliferation. CONCLUSIONS: Telmisartan attenuates SMC proliferation via PPARgamma activity and suppresses neo-intimal hyperplasia after transplantation. Telmisartan may be useful for suppressing chronic allograft rejection.

IFN-gamma and Fas/FasL pathways cooperate to induce medial cell loss and neointimal lesion formation in allograft vasculopathy.

Using a clinically relevant, fully disparate, allogeneic aortic transplant mouse model of allograft vasculopathy, we have demonstrated that neointimal proliferation is dependent on CD8(+) T cell effector pathways in the presence of therapeutic doses of calcineurin inhibitor (CNI) immunosuppression. CD4(+) T cell pathways are ablated by CNI immunosuppression. In the current study, we examined the relationship between CD8(+) T cell activities, medial SMC loss and neointimal hyperplasia. We demonstrate that at 5-6wk post transplantation in a wild type/wild type transplant CD8(+) T cell infiltration, CD8(+) CTL effector cell mediator expression and medial SMC loss all occur within aortic interposition grafts in the face of CNI immunosuppression. Both IFN-gamma and CTL mediated effector function is required for SMC loss and lesion formation under these conditions. Using strain combinations and reconstitution models, we provide data that blockade of the perforin/granzyme pathway does not prevent lesion formation but that blockade of the Fas/FasL pathway of cytotoxicity dramatically reduces SMC loss and prevents neointimal lesion formation. Both of these blockade strategies are in the face of an active IFN-gamma pathway. These data suggest a cooperative role between Fas/FasL and IFN-gamma mediated effector functions in medial SMC loss and neointimal lesion formation.

Histopathological comparison of vascular wall damage created by external cross-clamp and endoluminal balloon occlusion techniques.

AIM: Almost all cross-clamps utilized in vascular surgery, even atraumatic clamps, have been shown to cause mechanical damage to the vascular wall. In recent years, surgical procedures using an endoluminal balloon technique have been reported as an alternative occlusion strategy. This study discusses the histopathological characteristics and comparison between vascular wall damage secondary to the two occlusion techniques in the early postoperative period. METHODS: Twelve adult rabbits were divided into two experimental groups: the clamp group (N. = 6) and the balloon group (N. = 6). External cross-clamp occlusion was applied to the abdominal aorta for 30 minutes via laparotomy in the clamp group. In the balloon group, occlusion was applied for 30 minutes by inflating the catheter balloon, which was inserted through the iliac artery and advanced into the abdominal aorta. The appropriate aortic segments were subsequently extracted in both groups and tissue samples were examined by light and electron microscopy. Finally, the samples were scored for grade of tissue damage. RESULTS: In both experimental groups, tissue damage was apparent. In the investigations carried out under light microscopy, it was observed that the damage caused by balloon occlusion was remarkably less than the damage caused by the cross-clamp technique. In the balloon group, eight tissue samples (66.7%) had grade 1 damage. On the other hand, five tissue samples had grade 3 damage, all of which were in the clamp group. Investigation by electron microscopy revealed that greater intimal, medial, and adventitial damage occurred in the vascular walls of the clamp group samples, and this also corresponded with an increase in immune response and intraluminal thrombosis. CONCLUSION: External clamp and internal balloon occlusion techniques applied to the aorta were compared, and widespread intimal and medial damage were observed in both techniques. However, endoluminal occlusion of the aorta should be the technique of choice in properly selected cases, since it results in lower damage grades, and it should also be used if application of an external clamp is technically difficult.

Increased CD74 expression in human atherosclerotic plaques: contribution to inflammatory responses in vascular cells.

AIMS: The purpose of this study was to analyse the expression of CD74 in human atherosclerotic plaques and peripheral blood mononuclear cells (PBMC) as well as its potential participation in proinflammatory responses in cultured human vascular smooth muscle cells (VSMC). METHODS AND RESULTS: CD74 expression was analysed in human atherosclerotic plaques (immunohistochemistry), PBMC (real-time PCR), and human aortic VSMC (real-time PCR and western blotting). Nuclear factor-kappaB (NF-kappaB) activation was assessed by southwestern histochemistry and electrophoretic mobility shift assay. Monocyte chemoattractant protein-1 (MCP-1) levels were studied by both real-time PCR and enzyme-linked immunosorbent assay. CD74 immunostaining was increased in the inflammatory vs. the fibrous region of atherosclerotic plaques (n = 70, 18.2 +/- 1.3 vs. 7.8 +/- 0.6% positive staining/mm2, P < 0.001). CD74 colocalized with the transcription factor NF-kappaB in both VSMC and macrophages. In cultured VSMC, CD74 expression was induced by interferon gamma (IFNgamma). Incubation with an agonistic anti-CD74 antibody or with IFNgamma elicited MCP-1 expression, which was prevented by AKT and gamma-secretase inhibitors. Moreover, CD74 small-interfering RNA decreased NF-kappaB activation and MCP-1 production induced by IFNgamma in VSMC. Finally, CD74 mRNA levels in PBMC from patients with carotid stenosis were higher than in healthy subjects (n = 20, 3 +/- 0.5 vs. 2 +/- 0.5 AU, P < 0.001). Additionally, a linear trend between CD74 mRNA expression tertiles and intima-media thickness (IMT) was observed in PBMC from asymptomatic subjects (n = 185, P < 0.001). CONCLUSION: CD74 levels are increased in plaques and PBMC from patients with carotid stenosis and are associated with IMT in subjects free from clinical cardiovascular diseases. CD74 could be a novel therapeutic target to decrease the inflammatory response in atherosclerosis.

Plasma interleukin-5 levels are related to antibodies binding to oxidized low-density lipoprotein and to decreased subclinical atherosclerosis.

OBJECTIVES: This study's aim was to assess the role of interleukin (IL)-5 in modulating the levels of antibodies binding to oxidized low-density lipoprotein (OxLDL) in human atherosclerosis. BACKGROUND: Various pro- and anti-inflammatory cytokines have been implicated in atherogenesis, and recent findings in mice indicate that the cytokine IL-5 plays a protective role in atherosclerosis in part via the induction of antibodies binding to OxLDL. METHODS: Plasma IL-5 levels and antibody titers to 2 most commonly used models of OxLDL (copper OxLDL and malondialdehyde-modified LDL) were measured in 1,011 Finnish middle-aged subjects with chemiluminescent enzyme-linked immunosorbent assay. Intima-media thickness (IMT) was assessed ultrasonographically from the internal carotid artery, the bifurcation, and the common carotid artery. RESULTS: There was a significant positive association between plasma IL-5 levels and antibody titers to copper OxLDL (p = 0.010 and p = 0.044, immunoglobin [Ig] M and G, respectively) and IgM to malondialdehyde-modified LDL (p < 0.001) in the association analysis performed between different IL-5 quartiles. Furthermore, plasma IL-5 levels were found to be inversely associated with bifurcational IMT, and even after adjustments for traditional risk factors of atherosclerosis (age, gender, smoking, systolic blood pressure, LDL, and body mass index), IL-5 remained an independent determinant of the mean bifurcational IMT (p = 0.010). CONCLUSIONS: Our data demonstrate that plasma IL-5 levels are related to the plasma levels of antibodies binding to OxLDL and to decreased subclinical atherosclerosis in humans. These results are in line with earlier findings in murine atherosclerosis and indicate for the first time that IL-5 may play a role in human atherosclerosis.

Arterial stiffness after successful renal transplantation.

Cardiovascular disease is a major barrier to the long-term survival of transplant recipients. The aim of this study was to determine whether successful renal transplantation improves the arterial stiffness resulting from chronic renal failure. This study involved a group of 9 recipients (23-56 years) who underwent successful renal transplantation at our clinic. The brachial-ankle pulse wave velocity and--intima-media thickness of the bilateral common carotid arteries were measured in each patient before and 1 year after successful renal transplantation. One year after renal transplantation, the 9 patients showed a mean serum creatinine level of 1.41 mg/dL. Assessment of arterial stiffness in this group revealed that the mean brachial-ankle pulse wave velocity was reduced after renal transplantation, but there was no reduction in the mean intima-media thickness of the bilateral common carotid arteries. There was a significant correlation between the variance ratios of pulse wave velocity and median blood pressure. The more effective blood pressure control provided by renal transplantation may functionally improve arterial stiffness. However, organic arterial stiffness remained unchanged 1 year after transplantation.

Immunologic targets in the etiology of allograft vasculopathy: endothelium versus media.

The respective roles of the endothelium and the media as allo-immune targets in the generation of allograft vasculopathy (AV) have yet to be clearly defined. Although endothelial damage has been implicated in the progression of AV, evidence from mechanical vascular injury models suggests that medial injury may play a more dominant role. The overall objective of this research was to determine the relative importance of the endothelium versus the media as a target for immune injury and induction of AV. To investigate this we developed a novel model which involved the creation of chimeric aortic segments. To accomplish this we removed aortic segments from C3H/HeJ (C3H) mice and stripped them of endothelium by a short pulse with EDTA. The stripped C3H grafts were implanted into immunodeficient C57BL/6 (B6) RAG1(-/-) mice for a period of 21 days. As the immunodeficient mice did not mount an allo-immune response to the grafts, the endothelium was renewed by normal repair mechanisms. The new endothelium was recipient in origin, resulting in a chimeric graft with C3H media and B6 endothelium. We confirmed complete denudement by immunocytochemistry for endothelial specific markers, as well as by transmission and scanning electron microscopy. Replacement of endothelium with recipient endothelial cells was confirmed by immunocytochemistry, electron microscopy and by using a green fluorescent protein mouse transplant combination. Subsequent re-transplantation of the chimeric grafts into either B6 or C3H recipients demonstrated that an allogeneic media is more important than an allogeneic endothelium in inducing robust AV.

Induction of indoleamine 2,3-dioxygenase in vascular smooth muscle cells by interferon-gamma contributes to medial immunoprivilege.

Atherosclerosis and graft arteriosclerosis are characterized by leukocytic infiltration of the vessel wall that spares the media. The mechanism(s) for medial immunoprivilege is unknown. In a chimeric humanized mouse model of allograft rejection, medial immunoprivilege was associated with expression of IDO by vascular smooth muscle cells (VSMCs) of rejecting human coronary artery grafts. Inhibition of IDO by 1-methyl-tryptophan (1-MT) increased medial infiltration by allogeneic T cells and increased VSMC loss. IFN-gamma-induced IDO expression and activity in cultured human VSMCs was considerably greater than in endothelial cells (ECs) or T cells. IFN-gamma-treated VSMCs, but not untreated VSMCs nor ECs with or without IFN-gamma pretreatment, inhibited memory Th cell alloresponses across a semipermeable membrane in vitro. This effect was reversed by 1-MT treatment or tryptophan supplementation and replicated by the absence of tryptophan, but not by addition of tryptophan metabolites. However, IFN-gamma-treated VSMCs did not activate allogeneic memory Th cells, even after addition of 1-MT or tryptophan. Our work extends the concept of medial immunoprivilege to include immune regulation, establishes the compartmentalization of immune responses within the vessel wall due to distinct microenvironments, and demonstrates a duality of stimulatory EC signals versus inhibitory VSMC signals to artery-infiltrating T cells that may contribute to the chronicity of arteriosclerotic diseases.

Calcification of coronary intima and media: immunohistochemistry, backscatter imaging, and x-ray analysis in renal and nonrenal patients.

Coronary calcification is a potent predictor of cardiac events. In patients with chronic renal disease, both prevalence and intensity of coronary calcification are increased. It has remained uncertain whether it is the intima of the coronaries or the media that is calcified and whether the morphologic details of calcified plaques differ between renal and nonrenal patients. Autopsy samples of coronaries were obtained from standard sites in 23 renal and 23 age- and gender-matched nonuremic patients. Specimens were examined using light and electron microscopy, immunohistochemistry, backscatter imaging, and x-ray analysis. In coronaries, calcified plaques occupied a similar proportion of the intima area in renal versus nonrenal patients (17.3 +/- 11.9 versus 18.1 +/- 11.9%) but occupied a significantly higher proportion of the media (16.6 +/- 10.6 versus 3.8 +/- 2.31%). Expression of the proteins osteocalcin, C-reactive protein, TGF-beta, and collagen IV was significantly more intensive around coronary plaques of renal compared with nonrenal patients. The non-plaque-bearing intima of renal patients showed minimal staining for fetuin, but fetuin staining was seen surrounding calcified plaques. In addition, more pronounced deposition of C5b-9 was found around coronary plaques of renal patients, and glycophorin deposition pointed to more past intraplaque hemorrhage in renal patients. Calcification by electron backscatter analysis is more intense in the coronary media, but not if the intima is more intense in renal compared with nonrenal patients. A more marked inflammatory response in renal patients is suggested by more frequent presence and greater intensity of markers of inflammation.