Established Atherosclerotic Lesions Research Articles

Trem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis

Atherosclerosis is driven by the expansion of cholesterol-loaded ‘foamy’ macrophages in the arterial intima. Factors regulating foamy macrophage differentiation and survival in plaque remain poorly understood. Here we show, using trajectory analysis of integrated single-cell RNA sequencing data and a genome-wide CRISPR screen, that triggering receptor expressed on myeloid cells 2 (Trem2) is associated with foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up oxidized low-density lipoprotein (oxLDL). Myeloid-specific deletion of Trem2 showed an attenuation of plaque progression, even when targeted in established atherosclerotic lesions, and was independent of changes in circulating cytokines, monocyte recruitment or cholesterol levels. Mechanistically, we link Trem2-deficient macrophages with a failure to upregulate cholesterol efflux molecules, resulting in impaired proliferation and survival. Overall, we identify Trem2 as a regulator of foamy macrophage differentiation and atherosclerotic plaque growth and as a putative therapeutic target for atherosclerosis.

Evaluation on the Effectiveness of High Cholesterol Diet Feeding in Inducing Early and Established Atherosclerotic Lesions in New Zealand White Rabbits.

Various methods were used to induce atherosclerosis in rabbits. One of the most common methods used is high-cholesterol diet (HCD) feeding. However, the exact amount and duration of HCD feeding to induce early and established atherosclerosis in New Zealand white rabbits (NZWR) continue to be debated among researchers. Therefore, this study aims to evaluate the effectiveness of 1% HCD feeding in inducing early and established atherosclerosis lesions in NZWR. A total of 50 g/kg/day of 1% HCD was fed to three to four months old male rabbits weighing 1.8 to 2.0 kg for four and eight weeks to induce early and established atherosclerosis respectively. The body weight and lipid profile were measured at baseline and post-HCD intervention. Following euthanasia, the aorta was excised and prepared for histology and immunohistochemical analysis to confirm the stages of atherosclerosis. The mean body weight of the rabbits in early and established atherosclerosis groups increased significantly up to 17.5% (p = 0.026) and 19.75% (p = 0.019) respectively compared to baseline. The total cholesterol level dramatically elevated up to 13-fold (p = 0.005) and 38-fold (p = 0.013) compared to baseline, after four and eight weeks of 1% HCD feeding respectively. The low-density lipoprotein level significantly increased up to 42-fold (p = 0.006) and 128-fold (p = 0.011) compared to baseline, after four and eight weeks of 1% HCD feeding respectively. Rabbits fed with four and eight weeks 1% HCD significantly developed 5.79% (p = 0.008) and 21.52% (p = 0.008) aortic lesion areas compared to the control group. Histological evaluation in the aorta showed accumulation of foam cells in early atherosclerosis group and formation of fibrous plaque and lipid core in the established atherosclerosis group. Rabbits fed with eight weeks HCD showed higher tissue expressions of ICAM-1, VCAM-1, e-selectin, IL-6, IL-8, NF-κBp65, and MMP-12 compared to four weeks of HCD intervention. A total of 50 g/kg/day of 1% HCD for four and eight weeks is sufficient to induce early and established atherosclerosis in NZWR respectively. The consistent results through this method could facilitate researchers in inducing early and established atherosclerosis in NZWR.

Staphylococcus aureus extracellular adherence protein (Eap) reduces immune cell phenotype in developing but not in established atherosclerotic lesions

Atherosclerosis is a chronic, inflammatory disease of the vessel wall where triggered immune cells bind to inflamed endothelium, extravasate and sustain local inflammation. Leukocyte adhesion and extravasation are mediated by adhesion molecules expressed by activated endothelial cells, like intercellular adhesion molecule 1 (ICAM-1). Extracellular adherence protein (Eap) from Staphylococcus aureus binds to a plethora of extracellular matrix proteins, including ICAM-1 and its ligands macrophage-1 antigen (Mac-1, αMβ2) and lymphocyte function-associated antigen 1 (LFA-1, αLβ2), thereby disrupting the interaction between leukocytes and endothelial cells. We aimed to use Eap to inhibit the interaction of leukocytes with activated endothelial cells in settings of developing and established atherosclerosis in apolipoprotein E (ApoE) deficient mice on high-fat diet. In developing atherosclerosis, Eap treatment reduced circulating platelet-neutrophil aggregates as well as infiltration of T cells and neutrophils into the growing plaque, accompanied by reduced formation of neutrophil extracellular traps (NETs). However, plaque size did not change. Intervention treatment with Eap of already established plaques did not result in cellular or morphological plaque changes, whereas T cell infiltration was increased and thereby again modulated by Eap. We conclude that although Eap leads to cellular changes in developing plaques, clinical implications might be limited as patients are usually treated at a more advanced stage of disease progression. Hence, usage of Eap might be an interesting mechanistic tool for cellular infiltration during plaque development in basic research but not a clinical target.

2-Hydroxypropyl-beta-cyclodextrin Treatment Does Not Induce Atherosclerotic Lesion Regression in Western-Type Diet-Fed Apolipoprotein E Knockout Mice

2-Hydroxypropyl-beta-cyclodextrin (2HPβCD) is able to bind and solubilize unesterified cholesterol and may therefore be able to reverse the deposition of cholesterol in macrophages within the aortic vessel wall, a hallmark of atherosclerotic cardiovascular disease. However, conflicting results regarding the potential of 2HPβCD to induce regression of established atherosclerotic lesions have been described. In the current study, we therefore also investigated the ability of 2HPβCD to stimulate cholesterol removal from macrophage foam cells in vitro and induce the regression of established atherosclerotic lesions in apolipoprotein E knockout (APOE KO) mice. In vitro studies using murine thioglycollate-elicited peritoneal macrophages verified that 2HPβCD is able to induce cholesterol efflux from macrophages in an ATP-binding cassette transporter-independent manner. Switching Western-type-diet-fed APOE KO mice with established atherosclerotic lesions back to a chow diet was associated with a reduction in the hypercholesterolemia extent and an increase in the absolute lesion size and plaque collagen-to-macrophage ratio. Importantly, parallel subcutaneous administration of 2HPβCD was not able to prevent the diet-switch-associated lesion growth or induce atherosclerosis regression. Although in our hands, 2HPβCD does effectively stimulate cellular cholesterol efflux from macrophages, we do not consider it worthwhile to further pursue 2HPβCD as therapeutic moiety in the atherosclerosis regression context.

Exercise training inhibits atherosclerosis progression and reduces VE-cadherin levels within atherosclerotic plaques in hypercholesterolemic mice

Vascular endothelial-cadherin (VE-cadherin), matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) have emerged as key-factors of atherogenesis. The aim of this study was to evaluate the effects of exercise training (ET) on those key-factors in relation to the progression of atherosclerotic lesions in hypercholesterolemic mice. Thirty male, apoE knockout (apoE−/−) mice were randomly assigned to the following equivalent groups: 1) CO-control: High-fat diet (HFD) administration for 12 weeks. 2) EX-exercise: HFD administration as in CO, and during the last 4 weeks (9th −12th week) ET on treadmill (5sessions/week, 60min/session). At the end of study, blood samples were obtained and all mice were sacrificed. Aortic roots were excised and analysed regarding the percentage of aortic stenosis, and the relative concentrations of collagen, elastin, VE-cadherin, MMP-8,-9 and TIMP-1,-2 within the atherosclerotic lesions. Aortic stenosis was significantly lower in the EX than the CO group (39.63 ± 7.22% vs 62.04 ± 8.55%; p < 0.001), along with considerable increase in fibrous cap thickness and of collagen and elastin contents within plaques (p < 0.05). Compared to controls, exercised-treated mice showed reduced intra-plaque relative concentrations of VE-cadherin (15.09 ± 1.89% vs 23.49 ± 3.01%, p < 0.001), MMP-8 (8.51 ± 2.24% vs 18.51 ± 4.08%, p < 0.001) and MMP-9 (12.1 ± 4.86% vs 18.88 ± 6.23%, p < 0.001). Inversely, the relative concentrations of TIMP-1 and TIMP-2 in the ET group were considerably higher by 62.5% and 31.2% than in the EX group (p < 0.05), respectively. Finally, body weight and lipids concentrations did not differ between groups at the end of the study (p > 0.05). ET treatment induced regression of established atherosclerotic lesions in apoE−/− mice and improved their stability. Those effects seemed to be mediated by favourable modification of VE-cadherin, MMPs and TIMPs.

Effects of Nicorandil on Inflammation, Apoptosis and Atherosclerotic Plaque Progression.

Nicorandil, a balanced vasodilator, is used in the second-line therapy of angina pectoris. In this study, we aimed to illuminate the effects of nicorandil on inflammation, apoptosis, and atherosclerotic plaque progression. Twenty-five LDL-R -/- mice were fed a high-fat diet for 14 weeks. After 6 weeks mice were randomly allocated to treatment with nicorandil (10 mg/kg/day) or tap water. Nicorandil treatment led to a more stable plaque phenotype, displaying an increased thickness of the fibrous cap (p = 0.014), a significant reduction in cholesterol clefts (p = 0.045), and enhanced smooth muscle cell content (p = 0.009). In endothelial cells nicorandil did not reduce the induction of adhesion molecules or proinflammatory cytokines. In H2O2 challenged endothelial cells, pretreatment with nicorandil significantly reduced the percentage of late apoptotic/necrotic cells (p = 0.016) and the ratio of apoptotic to living cells (p = 0.036). Atherosclerotic lesions of animals treated with nicorandil exhibited a significantly decreased content of cleaved caspase-3 (p = 0.034), lower numbers of apoptotic nuclei (p = 0.040), and reduced 8-oxogunanine staining (p = 0.039), demonstrating a stabilizing effect of nicorandil in established atherosclerotic lesions. We suggest that nicorandil has a positive effect on atherosclerotic plaque stabilization by reducing apoptosis.

LongShengZhi Capsule Reduces Established Atherosclerotic Lesions in apoE-Deficient Mice by Ameliorating Hepatic Lipid Metabolism and Inhibiting Inflammation.

Disorders of lipid metabolism and inflammation play an important role in atherosclerosis. LongShengZhi (LSZ) capsule, a Chinese herbal medicine, has been used for treatment of patients with vascular diseases for many years. In this article, we determined the effect of LSZ on the progression of established atherosclerotic lesions in apoE-deficient (apoE) mice. ApoE mice were prefed high-fat diet (HFD) for 8 weeks to induce atherosclerosis, then started with LSZ treatment contained in HFD for 10 weeks. Although LSZ had little effect on HFD-induced hypercholesterolemia, it substantially reduced en face and sinus aortic lesions. The reduction of lesions was associated with reduced macrophage/foam cell accumulation by activating ABCA1/ABCG1 expression. LSZ maintained the integrity of arterial wall by increasing collagen or smooth muscle cell content and inhibiting cell apoptosis. LSZ also attenuated HFD-induced fatty liver by down-regulating expression of lipogenic and cholesterol synthetic genes while activating expression of triglyceride catabolism genes. Moreover, LSZ demonstrated potent anti-inflammatory effects. In vivo, LSZ reduced serum TNF-α levels, infiltration of neutrophils, Kupffer cells, and expression of inflammatory cytokines in the liver. In vitro, it inhibited lipopolysaccharide or palmitate-induced expression of inflammatory cytokines in macrophages. Therefore, LSZ reduces atherosclerosis by ameliorating hepatic lipid metabolism and inhibiting inflammation.

Follicular regulatory T cell in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease involving the infiltration of immune cells, such as monocytes/macrophages, neutrophils, T cells, and B cells, into the inner layer of vessel walls. T and B cell functions in the process of atherogenesis, as well as their mutual regulation, have been investigated but several aspects remain to be clarified. In the present review, we give a brief overview of the functions of follicular regulatory T cell (Tfr) on follicular T (Tfh) and B cell regulation related to atherosclerosis pathogenesis, including their influence on lymphangiogenesis and lipoprotein metabolism. We will also discuss their potential therapeutics properties in the resolution of established atherosclerotic lesions.

Anti-inflammatory effect of low molecular weight fucoidan from Saccharina japonica on atherosclerosis in apoE-knockout mice

Atherosclerosis (AS) is the key cause of many cardiovascular and cerebrovascular diseases. The inflammatory response and lipid metabolism disorders contribute to the development and progression of AS. This work aims to study the anti-inflammatory effect and mechanism of low molecular weight fucoidan (LMWF) obtained from Saccharina japonica on atherosclerosis in apoE-knockout mice. The experimental results showed that LMWF statistically decreased the levels of triglyceride (TRIG) and oxidative low-density lipoproteins (ox-LDL) and stabilized established atherosclerotic lesions. LMWF ameliorated the inflammatory response by down regulating IL-6 and by up regulating IL-10 transcriptional levels, and LMWF returned p-JNK and cyclin D1 to normal levels. Moreover, LMWF increased the mRNA level of CD11b in the aorta and suppressed the expression of CD11b in the intimal layer of the aorta. Therefore, LMWF prevented macrophages from developing into foam cells and prevented SMCs from migrating into the intimal layer of the aorta, which inhibited the formation of atherosclerotic plaques; and ameliorated the occurrence and development of AS.

Leukocyte ABCA1 impedes progression of established atherosclerotic lesions after dietary cholesterol lowering in LDLr-/- mice

The ATP-binding cassette transporter A1 (ABCA1) facilitates the efflux of cholesterol and phospholipids to lipid-free apolipoprotein A1 and small dense high-density lipoproteins. Various studies have shown that leukocyte ABCA1 is an anti-atherogenic factor. Dietary cholesterol lowering stabilizes atherosclerotic lesions, however the role of ABCA1 in this process is unknown. Therefore, this study aims to investigate the effect of leukocyte ABCA1 on diet-induced atherosclerotic lesions after withdrawal of the atherogenic diet . Leukocyte ABCA1 was studied by transplanting bone marrow cells from donor mice that were either knock-out (ABCA1-/-) or wild-type for ABCA1 or that overexpressed ABCA1 (ABCA1Tg) into low-density lipoprotein receptor knock-out (LDLr-/-) mice. All three groups of chimeric mice were fed a Western-type diet (WTD: 0.25%cholesterol, 15Ecao butter) for 6 weeks to induce atherosclerotic lesion development. After this period, a baseline group was sacrificed (ABCA1-/- >LDLr-/- n=12; wild-type >LDLr-/- n=14; ABCA1Tg >LDLr-/- n=9) for lesion assessment. The remainder of chimeric mice was switched to a chow diet (low fat, no added cholesterol) for 3 weeks to lower plasma cholesterol levels (ABCA1-/- >LDLr-/- n=14; wild-type >LDLr-/- n=14; ABCA1Tg >LDLr-/- n=12).Withdrawal of the atherogenic diet normalized plasma cholesterol levels in all three groups. As a result, lesion development was stabilized in both the wild-type >LDLr-/- and ABCA1Tg >LDLr-/- mice, however not in the ABCA1-/- >LDLr-/- mice, which displayed a 1.5-fold increase (p Leukocyte ABCA1 is required to halt atherosclerotic lesion progression after dietary cholesterol lowering. Overexpression of ABCA1 did not result in any additional beneficial effects.

Inactivation of Semicarbazide-Sensitive Amine Oxidase Stabilizes the Established Atherosclerotic Lesions via Inducing the Phenotypic Switch of Smooth Muscle Cells.

Given that the elevated serum semicarbazide-sensitive amine oxidase (SSAO) activity is associated with the severity of carotid atherosclerosis in clinic, the current study aims to investigate whether SSAO inactivation by semicarbazide is beneficial for established atherosclerotic lesions in LDLr knockout mice on a high-fat/high- cholesterol Western-type diet or after dietary lipid lowering. Despite no impact on plasma total cholesterol levels, the infiltration of circulating monocytes into peripheral tissues, and the size of atherosclerotic lesions, abrogation of SSAO activity resulted in the stabilization of established lesions as evidenced by the increased collagen contents under both conditions. Moreover, SSAO inactivation decreased Ly6Chigh monocytosis and lesion macrophage contents in hypercholesterolemic mice, while no effect was observed in mice after normalization of hypercholesterolemia by dietary lipid lowering. Strikingly, abrogation of SSAO activity significantly increased not only the absolute numbers of smooth muscle cells (SMCs), but also the percent of SMCs with a synthetic phenotype in established lesions of mice regardless of plasma cholesterol levels. Overall, our data indicate that SSAO inactivation in vivo stabilizes the established plaques mainly via inducing the switch of SMCs from a contractile to a synthetic phenotype. Targeting SSAO activity thus may represent a potential treatment for patients with atherosclerosis.

Imaging of Intracellular and Extracellular ROS Levels in Atherosclerotic Mouse Aortas Ex Vivo: Effects of Lipid Lowering by Diet or Atorvastatin

ObjectiveThe first objective was to investigate if intracellular and extracellular levels of reactive oxygen species (ROS) within the mouse aorta increase before or after diet-induced lesion formation. The second objective was to investigate if intracellular and extracellular ROS correlates to cell composition in atherosclerotic lesions. The third objective was to investigate if intracellular and extracellular ROS levels within established atherosclerotic lesions can be reduced by lipid lowering by diet or atorvastatin.Approach and ResultsTo address our objectives, we established a new imaging technique to visualize and quantify intracellular and extracellular ROS levels within intact mouse aortas ex vivo. Using this technique, we found that intracellular, but not extracellular, ROS levels increased prior to lesion formation in mouse aortas. Both intracellular and extracellular ROS levels were increased in advanced lesions. Intracellular ROS correlated with lesion content of macrophages. Extracellular ROS correlated with lesion content of smooth muscle cells. The high levels of ROS in advanced lesions were reduced by 5 days high dose atorvastatin treatment but not by lipid lowering by diet. Atorvastatin treatment did not affect lesion inflammation (aortic arch mRNA levels of CXCL 1, ICAM-1, MCP-1, TNF-α, VCAM, IL-6, and IL-1β) or cellular composition (smooth muscle cell, macrophage, and T-cell content).ConclusionsAortic levels of intracellular ROS increase prior to lesion formation and may be important in initiation of atherosclerosis. Our results suggest that within lesions, macrophages produce mainly intracellular ROS whereas smooth muscle cells produce extracellular ROS. Short term atorvastatin treatment, but not lipid lowering by diet, decreases ROS levels within established advanced lesions; this may help explain the lesion stabilizing and anti-inflammatory effects of long term statin treatment.

Promoting macrophage survival delays progression of pre-existing atherosclerotic lesions through macrophage-derived apoE.

Macrophage apoptosis is a prominent feature of atherosclerosis, yet whether cell death-protected macrophages would favour the resolution of already established atherosclerotic lesions, and thus hold therapeutic potential, remains unknown. We irradiated then transplanted into Apoe(-/-) or LDLr(-/-) recipient mice harbouring established atherosclerotic lesions, bone marrow cells from mice displaying enhanced macrophage survival through overexpression of the antiapoptotic gene hBcl-2 (Mø-hBcl2 Apoe(-/-) or Mø-hBcl2 Apoe(+/+) LDLr(-/-)). Both recipient mice exhibited decreased lesional apoptotic cell content and reduced necrotic areas when repopulated with Mø-hBcl2 mouse-derived bone marrow cells. In contrast, only LDLr(-/-) recipients showed a reduction in plasma cholesterol levels and in atherosclerotic lesions. The absence of significant reduction of plasma cholesterol levels in the context of apoE deficiency highlighted macrophage-derived apoE as key in both the regulation of plasma and tissue cholesterol levels and the progression of pre-existing lesion. Accordingly, hBcl2 expression in macrophages was associated with larger pools of Kupffer cells and Ly-6C(low) monocytes, both high producers of apoE. Additionally, increased Kupffer cells population was associated with improved clearance of apoptotic cells and modified lipoproteins. Collectively, these data show that promoting macrophage survival provides a supplemental source of apoE, which hinders pre-existing plaque progression.

Voluntary exercise slows the progression of established angiotensin II-dependent advanced atherosclerotic lesions

Objectives: We have previously demonstrated that exercise training prevents the development of Angiotensin (Ang) II-induced atherosclerosis and vulnerable plaques in ApoE-/- mice. In the present study, we investigated whether exercise attenuates the progression of established Ang II-dependent atherosclerosis.

Heat shock protein 27 is a novel athero-biomarker that halts atherosclerotic lesion progression and enhances lesion remodeling

Objectives: Previously we showed the following about Heat Shock Protein 27 (HSP27): i) Increasing serum levels either via over-expression (HSP27o/e mice), bone marrow transplantation or recombinant HSP27 (rHSP27) injection attenuate de novo atherogenesis, and ii) low serum levels represent a novel biomarker for human atherosclerotic events (MI, CVA, Death). We now test the ability of rHSP27 to modulate the progression of established atherosclerotic lesions.

Proliferating Macrophages Populate Established Atherosclerotic Lesions

A new study reveals that the majority of macrophages in established atherosclerotic lesions are derived from local proliferation, rather than from the influx of blood-borne monocytes. While the factors driving proliferation remain to be understood, the findings suggest that targeting macrophage proliferation could represent a new therapeutic opportunity in established atherosclerosis.

Delayed Blood Pressure Recovery Ratio and Its Relation to Endothelial Function and Left Ventricular Diastolic Function in Prediabetics

Endothelial function plays a key role in determining the clinical manifestations of established atherosclerotic lesions and has shown to be associated with suppressed sympathetic tone. Abnormal heart rate recovery (HRR) and systolic blood pressure (SBP) response during recovery has been found to have diagnostic role for detecting cardiovascular risk. To investigate whether with abnormal HRR and delayed SBP recovery ratio after exercise could predict endothelial dysfunction in prediabetic subjects. Ninety-two prediabetic patients underwent brachial artery flow-mediated dilatation (FMD) test and a maximal exercise stress test. Seventy-eight healthy subjects served as a control group. HRR at 1 minute (HRR1 ) and SBP recovery ratio (SBPRR3 ) was defined as the SBP at minute 3 of recovery divided by SBP at peak exercise. Left ventricular diastolic function was assessed utilizing both conventional and tissue Doppler echocardiography. Flow-mediated dilatation was significantly decreased in prediabetics versus controls (P < 0.0001). Isovolumetric relaxation time and E/E' were significantly increased in prediabetics (P < 0.01 and <0.001). Delayed SBPRR3 was significantly correlated with impaired endothelial function and (E/E') in prediabetics (r = 0.62, P < 0.001 and r = 0.56, P < 0.001, respectively). Stepwise linear regression analysis revealed that HRR1 and SBPRR3 were significant predictors of endothelial dysfunction (r = 0.61, r(2) = 0.37, P < 0.01 and r = 0.51; r(2) = 27; P < 0.0001). Abnormal HRR1 and delayed SBP response detected during recovery imply a significant correlation with impaired endothelial function and diastolic dysfunction in prediabetics.

Toll-like receptor 7 stimulation by imiquimod induces macrophage autophagy and inflammation in atherosclerotic plaques

Atherosclerotic plaques tend to rupture as a consequence of a weakened fibrous cap, particularly in the shoulder regions where most macrophages reside. Macrophages express Toll-like receptors to recognize pathogens and eliminate intracellular pathogens by inducing autophagy. Because Toll-like receptor 7 (TLR7) is thought to be expressed in macrophages but not in smooth muscle cells (SMCs), we investigated whether induction of macrophage autophagic death by TLR7 ligand imiquimod can affect the composition of atherosclerotic plaques in favor of their stability. Immunohistochemical staining of human carotid plaques as well as Western blotting of cultured macrophages and SMCs confirmed that TLR7 was expressed in macrophages, but not in SMCs. In vitro experiments showed that only TLR7 expressing cells underwent imiquimod-induced cell death, which was characterized by autophagosome formation. Imiquimod-treated macrophages activated nuclear factor-κB (NF-κB) and released pro-inflammatory cytokines and chemokines. This effect was inhibited by the glucocorticoid dexamethasone. Imiquimod-induced cytokine release was significantly decreased in autophagy-deficient macrophages because these cells died by necrosis at an accelerated pace. Local in vivo administration of imiquimod to established atherosclerotic lesions in rabbit carotid arteries induced macrophage autophagy without induction of cell death, and triggered cytokine production, upregulation of vascular adhesion molecule-1, infiltration of T-lymphocytes, accumulation of macrophages and enlargement of plaque area. Treatment with dexamethasone suppressed these pro-inflammatory effects in vivo. SMCs and endothelial cells in imiquimod-treated plaques were not affected. In conclusion, imiquimod induces macrophage autophagy in atherosclerotic plaques, but stimulates plaque progression through cytokine release and enhanced infiltration of inflammatory cells.

Dominance of macrophage derived IFN-γ in atheromatous lesions (35.3)

Abstract IFN-γ activates macrophages that are abundant in atheromas, periodontal lesions, and other sites of chronic inflammation. It is thought that the IFN-γ present in athromas is derived from Th-1 cells. However, macrophages dominate the inflammatory infiltrate in atheromas and macrophages can produce IFN-γ prompting the hypothesis that macrophages are the source of a significant proportion of IFN-γ in established atherosclerotic lesions. To test this, CD14+, CD3+, and CD14- &amp; 3- cells were isolated from endarterectomy tissue and examined for spontaneous production of IFN-γ, IL-1β, IL-6, and TNF-α in supernatant fluids from 48 hr cell cultures. The CD14+ macrophages, including foam cells, were responsible not only for the TNF-α, IL-1β &amp; IL-6 but also for the vast majority of the IFN-γ produced in culture. Moreover, this spontaneous macrophage IFN-γ response was maintained in culture for over two weeks. IL-12 induced IFN-γ responses in macrophages and IL-12 was induced by incubating DCs with A. actinomycetemcomitans and far more dramatically by opsonized A. actinomycetemcomitans. In short, engagement of DCs in the intima of the arterial wall with opsonized microorganisms from the blood could trigger IL-12 production, and the released IL-12 could induce a sustained IFN-γ response by macrophages. This macrophage INF-γ response induced by DC-IL-12 bypasses a need for T cells to produce IFN-γ in established atheromas.

Bronchial Arteries: An Arteriosclerosis-Resistant Circulation

Background: Until now, it is unknown whether and to what extent arteriosclerotic disease affects the bronchial arteries. Objectives: We conducted this pilot study to estimate the prevalence of arteriosclerosis of the bronchial arteries, to correlate it with certain clinicolaboratory arteriosclerotic parameters or any coexistent coronary artery disease (CAD) and to validate the clinical significance. Methods: Bronchial arteries 10–15 mm long were obtained from 40 patients with a mean age of 62.3 years who underwent major thoracic procedures. Their medical history and detailed clinical and laboratory arteriosclerotic risk factors were documented. Results: The mean diameter of bronchial artery specimens was 0.97 mm. Histology revealed medial calcific sclerosis only in 1 patient (2.5%) without simultaneous, established atherosclerotic lesions or narrowing of the lumen. Furthermore, the vessel diameter was significantly correlated not only with the advanced stage of the disease (p = 0.031), but also with the proximal occlusion of the bronchial tree (p = 0.042). We noted a marginally not significant correlation between arteriosclerosis and metabolic syndrome (p = 0.075), independent from a history of CAD (p = 0.84). Conclusions: Bronchial arteries exhibit only medial calcific sclerosis. CAD and chronic obstructive pulmonary disease do not seem to affect them in terms of atherosclerotic alteration findings or vessel diameter changes. The bronchial resistance to arteriosclerosis might support the mediastinal status quo through their anastomoses, contributing to all its structures, and might be indirect evidence of a different physiological function of the bronchial endothelium, which needs to be further investigated.