Snake and spider antivenin: risks and benefits of therapy

A case of hepatic mesenchymal hamartoma, found after sudden onset clinical and biological cholestasis, is reported in a 18-year-old man. Abdominal ultrasound examination and computed tomography showed a intrahepatic cystic tumor. The diagnosis of hepatic mesenchymal hamartoma was made by the pathological examination of the resected specimen. This rare tumor is found in most cases in children less than 2 years old. Thirteen cases in adulthood were already reported, five of them in Japanese patients. Our case is peculiar because no hepatic tumor was shown by ultrasound examination, 2 years before, the large size of cysts and presence of smooth muscle fibers in the wall.     

Enhanced expression of angiotensin-converting enzyme is associated with progression of coronary atherosclerosis in humans

BACKGROUND: The clinical usefulness of angiotensin converting enzyme (ACE) inhibitors in preventing the recurrence of myocardial infarction has been investigated in large randomized trials. Results from many studies using animal models have suggested that ACE inhibitors have vasculoprotective effects, which may contribute to the prevention of coronary atherosclerosis. OBJECTIVE: To examine the association between vascular angiotensin generation and the development of coronary atherosclerosis in humans. METHODS: We used immunocytochemical techniques to examine frozen sections from 44 coronary artery segments from 19 corpses. RESULTS: Three segments were sites of plaque rupture in patients who had died from acute myocardial infarction. Other specimens of coronary artery segments were characterized histologically to be normal artery segments with diffuse intimal thickening (n = 6), hypercellular lesions composed of smooth muscle cells with or without infiltration of macrophages (n = 11), atheromatous plaque (n = 12), and fibrosclerotic plaque (n = 12). In normal arteries with diffuse intimal thickening, ACE was expressed in endothelial cells. In those with hypercellular lesions and atheromatous plaques, however, enhanced ACE expression was found in macrophages and smooth muscle cells. In contrast, arteries with fibrosclerotic plaques exhibited little or no ACE expression within the plaque. All three ruptured plaques expressed ACE strongly in macrophages accumulated around the attenuated fibrous cap. CONCLUSION: The strong association of enhanced ACE expression with the histologic characteristics of plaques suggests that ACE in hypercellular lesions, atheromatous plaques, and ruptured plaques contributes greatly to the further progression of atherosclerosis via an increase in vascular angiotensin II formation and inactivation of bradykinin.     

In situ localization of tissue factor in human atherosclerotic plaques by binding of digoxigenin-labeled factors VIIa and X

The mechanism responsible for the thrombotic complications of atherosclerotic plaques is not well understood. Although a role for tissue factor (TF) has been hypothesized, there are scant data on the presence, location, quantity, and activity of TF in atherosclerotic plaques. The purpose of this study was to show the localization of TF in human atherosclerotic plaques. Digoxigenin-labeled factors VIIa and X were used to demonstrate their specific binding sites in formalin-fixed, paraffin-embedded human arteries by incubation of sections with the labeled factor and localization of TF:factor(s) complexes by immunohistochemical staining for digoxigenin. In sections of atherosclerotic plaques, diffuse staining was most intense in the relatively acellular, lipid-rich core but was also present intracellularly in macrophages and smooth muscle cells and, to a lesser extent, in the relatively acellular fibrous tissue of the plaque. Endothelial cells overlying plaques and occasional medial smooth muscle cells stained positively as well. The adventitia routinely stained for TF in both normal and diseased artery segments. Staining for labeled factor VIIa was blocked when sections were preincubated with a 10-fold excess of unlabeled factor VIIa or with a polyclonal antihuman TF antibody. Binding of labeled factors VIIa and X was Ca(2+)-dependent. In conclusion, binding of digoxigenin-labeled factors VIIa and X shows that the lipid rich core of atherosclerotic plaques contains high levels of extracellular TF. This location may be responsible for the rapid initiation of thrombosis when lipid rich atherosclerotic plaques rupture and the core contents are exposed to flowing blood.     

Primary muscle lymphoma: clinical and imaging findings

PURPOSE: To assess the clinical and imaging findings in primary muscle lymphoma. MATERIALS AND METHODS: Seven patients with biopsy-proved primary muscle lymphoma without evidence of systemic disease underwent imaging with plain radiography or computed tomography (CT) and magnetic resonance (MR) imaging. Four underwent bone scintigraphy, and two underwent gallium scintigraphy and fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) before and after therapy. RESULTS: Plain radiographs at initial examination (n = 5) showed no bone abnormalities. Soft-tissue masses and bone marrow involvement showed isoattenuation at CT (n = 3), but at MR imaging (n = 7), all masses demonstrated increased signal intensity on T2-weighted images that involved multiple muscle compartments and typically spanned a long segment of the extremity. Adjacent bone disease was less extensive than muscle disease, and, in most cases, subcutaneous stranding or extension was observed adjacent to the masses. Good size correlation was observed between findings at MR imaging, gallium scintigraphy, and FDG PET. Two patients developed recurrent multifocal muscle lymphoma several years after initial examination. CONCLUSION: The presence of an extensive soft-tissue mass with infiltration of adjacent subcutaneous fat and minimal or no extension into the bone marrow cavity at MR imaging and normal plain radiographic findings may suggest primary muscle lymphoma.     

Collagen-synthesizing cells in initial and advanced atherosclerotic lesions of human aorta

Accumulation of extracellular matrix, fibrosis, is regarded to be one of the major manifestations of atherosclerosis. Collagen type I is the predominant matrix component in human atherosclerotic plaques. In this work we have demonstrated procollagen type I expressing cells (PCI-cells) and studied their localization in grossly normal human aorta and atherosclerotic lesions: initial lesions, fatty streaks, fibrolipid lesions (fibrolipid plaque, fibroatheroma), fibrotic lesions (fibrous plaque). PCI-cells were revealed immunocytochemically using SPI.D8 monoclonal antibody against human procollagen type I. We failed to detect PCI-cells in the areas of grossly normal aorta and media underlying atherosclerotic lesions. Positively stained cells were shown in the areas of initial lesions, fatty streaks, fibrolipid and fibrous plaques. The largest amount of PCI-cells was revealed in fatty streaks. These cells were predominantly localized in the preluminal proteoglycan-rich intimal sublayer. Intimal cells in grossly normal regions formed a common cellular network contacting each other with their processes. The cellular network is found to be partly disintegrated in atherosclerotic lesions, which leads to the appearance of isolated cells. The share of isolated PCI-cells localized outside the intimal cellular network was higher in advanced lesions than in the areas of early atherosclerotic lesions. In initial lesions most of PCI-cells were identified as smooth muscle cells using antibodies to smooth muscle alpha-actin. In fatty streaks PCI-expressing smooth muscle cells were fewer in number. Much fewer cells double-stained with anti-alpha-actin and anti-PCI antibodies were found in fibrolipid and fibrous plaques. The proportion of these double stained cells was higher among total number of PCI-cells involved in the cellular network versus PCI-cells outside the network. The results of the study demonstrated that the most active de novo synthesis of interstitial collagen takes place in the regions of atherosclerotic lesions characterized by lipid deposition, which may lead to the further progression of atherosclerotic lesions.     

The carcinoid endocardial plaque; an ultrastructural study

Ultrastructural studies disclosed that the plaque-like endocardial thickenings in three patients with the carcinoid syndrome were composed of smooth muscle cells embedded in a stroma that was rich in acid mucopolysaccharides, collagen, and microfibrils, but devoid of elastic fibers. The smooth muscle cells contained variable numbers of myofilaments and cisterns of rough surfaced endoplasmic reticulum, and their basement membranes were greatly thickened, reduplicated, and arranged in layers. The endocardial plaques appeared histologically and ultrastructurally similar regardless of their location in the heart. The smooth muscle cells in these plaques appear to have been derived from primitive mesenchymal cells, which normally are present in the subendocardial endothelial space. These observations are interpreted as indicating that the plaques develop as a result of healing of a superficial endocardial injury, which may be initiated by release of bradykinin from hepatic metastases of a carcinoid tumor.     

Clear-cell smooth muscle tumor of the skin

We report a case of a previously undescribed benign neoplasm characterized by a poorly circumscribed proliferation of clear cells, arranged both singly and in elongated fascicles oriented in haphazard fashion within the middle and lower reticular dermis. The fascicles consisted of spindle-shaped cells that were periodic acid-Schiff positive and diastase labile. These cells were characterized by oval, hyperchromatic, cigar-shaped nuclei and clear cytoplasm. Immunohistochemically, neoplastic cells were diffusely positive for smooth muscle actin (1A4), common muscle actin (HHF-35), and vimentin. Immunoreactivity for fibronectin was also focally noted. The neoplasm, which we designated clear-cell smooth muscle tumor of the skin, should be distinguished from smooth muscle hamartoma and other smooth muscle proliferations at cutaneous level. We highlight in this case report the histopathologic differential diagnosis among other tumors with myofibroblastic, melanocytic, and neural differentiation.     

Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues

Advanced glycation end products (AGEs), the final products of nonenzymatic glycation and oxidation of proteins, are found in the plasma and accumulate in the tissues during aging and at an accelerated rate in diabetes. A novel integral membrane protein, termed receptor for AGE (RAGE), forms a central part of the cell surface binding site for AGEs. Using monospecific, polyclonal antibody raised to human recombinant and bovine RAGE, immunostaining of bovine tissues showed RAGE in the vasculature, endothelium, and smooth muscle cells and in mononuclear cells in the tissues. Consistent with these data, RAGE antigen and mRNA were identified in cultured bovine endothelium, vascular smooth muscle, and monocyte-derived macrophages. RAGE antigen was also visualized in bovine cardiac myocytes as well as in cultures of neonatal rat cardiac myocytes and in neural tissue where motor neurons, peripheral nerves, and a population of cortical neurons were positive. In situ hybridization confirmed the presence of RAGE mRNA in the tissues, and studies with rat PC12 pheochromocytes indicated that they provide a neuronal-related cell culture model for examining RAGE expression. Pathological studies of human atherosclerotic plaques showed infiltration of RAGE-expressing cells in the expanded intima. These results indicate that RAGE is present in multiple tissues and suggest the potential relevance of AGE-RAGE interactions for modulating properties of the vasculature as well as neural and cardiac function, prominent areas of involvement in diabetes and in the normal aging process.     

Metabolism of native and naturally occurring multiple modified low density lipoprotein in smooth muscle cells of human aortic intima

The subfraction of low density lipoprotein (LDL) with low sialic acid content that caused accumulation of cholesterol esters in human aortic smooth muscle cells has been found in the blood of coronary atherosclerosis patients. It was demonstrated that this subfraction consists of LDL with small size, high electronegative charge, reduced lipid content, altered tertiary structure of apolipoprotein B, etc. LDL of this subfraction is naturally occurring multiple-modified LDL (nomLDL). In this study we compared the binding, uptake and proteolytic degradation of native LDL and nomLDL by smooth muscle cells cultured from human grossly normal intima, fatty streaks, and atherosclerotic plaques. Uptake of nomLDL by normal and atherosclerotic cells was 3.5- and 6-fold, respectively, higher than uptake of native LDL. Increased uptake of nomLDL was due to increased binding of this LDL by intimal smooth muscle cells. The enhanced binding is explained by the interaction of nomLDL with cellular receptors other than LDL-receptor. Modified LDL interacted with the scavenger receptor, asialoglycoprotein receptor, and also with cell surface proteoglycans. Rates of degradation of nomLDL were 1.5- and 5-fold lower than degradation of native LDL by normal and atherosclerotic cells, respectively. A low rate of nomLDL degradation was also demonstrated in homogenates of intimal cells. Activities of lysosomal proteinases of atherosclerotic cells were decreased compared with normal cells. Pepstatin A, a cathepsin D inhibitor, completely inhibited lipoprotein degradation, while serine, thiol, or metallo-proteinase inhibitors had partial effect. This fact reveals that cathepsin D is involved in initial stages of apoB degradation by intimal smooth muscle cells. Obtained data show that increased uptake and decreased lysosomal degradation of nomLDL may be the main cause of LDL accumulation in human aortic smooth muscle cells, leading to foam cell formation.     

Aortic intimal changes in aging swine

Aortic intimal lesions in aging swine contained smooth muscle, monocyte-like and unclassifiable cells. The most frequent cellular constituent was the smooth muscle cell that had slightly different features than those in the media. Monocyte-like and unclassified cells appeared largely in the innermost layer of the intima; both types of cells were ultrastructurally similar in appearance except the former had heterophagic vacuoles and overall resemblance to circulating monocytes in shape and size. These cells seemed to preexist in aortic lesions of untreated, aging swine. The intima-media strips of the grossly normal thoracic aortas in 3 1/2 year old swine showed significantly higher contents of cholesterol, triglycerides, phospholipids and total lipids than those of a 6 month old swine. Three to four month old cultured aortic cells accumulated extracellular components, such as fibriles, electron dense substances and cellular debris, which appeared similar to the extracellular matrix of aortic plaques in aged swine.     

Tufted folliculitis of the scalp: a distinctive clinicohistological variant of folliculitis decalvans

Tufted folliculitis is an uncommon folliculitis of the scalp that resolves with patches of scarring alopecia within which multiple hair tufts emerge from dilated follicular orifices. The clinicohistological data from a group of 15 patients with tufted folliculitis were reviewed and compared with those of seven patients with folliculitis decalvans, five with acne keloidalis nuchae, four with dissecting cellulitis of the scalp, three with kerion celsi and 20 with follicular lichen planus. It was found that tufted folliculitis could be differentiated from folliculitis decalvans only by finding several hair tufts scattered within patches of scarring alopecia. Histologically, a single tuft consisted of peculiar clustering of adjacent follicular units opening at the bottom of an epidermal depression. Conversely, the presence of keloidal plaques in acne keloidalis nuchae, coalescing nodules discharging purulent material in dissecting cellulitis of the scalp, erythematous plaques covered by pustules replete with fungal elements in kerion celsi, and the absence of follicular pustules in follicular lichen planus distinguished these diseases from tufted folliculitis. On the basis of these findings, it is suggested that tufted folliculitis should be considered as a distinctive clinicohistological variant of folliculitis decalvans. Tufting of hair is caused by clustering of adjacent follicular units due to a fibrosing process and to retention of telogen hairs within the involved follicular units.     

Lambl's excrescence as tumorous heart valve mass

HISTORY AND CLINICAL FINDINGS: A 44 year old woman consulted a general physician because of weakness and fatigue. 5 months ago otitis media and a urinary tract infection had been treated successfully with antibiotics. The physical examination was unremarkable except for healed scars after an orthopedic operation about 35 years ago and a resection of a benign tumor of the left breast about 14 years ago. INVESTIGATIONS: Except for a slightly elevated antistreptolysin titer the laboratory tests were normal. The ECG showed sinus rhythm, left axis deviation and normal ST-segments. In the transthoracic echocardiogram an echogenic mass adherent on the ventricular side of the noncoronary cusp of the aortic valve in size of 2 x 1.5 cm could be demonstrated. The mass moved with the normally functioning valve and prolapsed into the aorta ascendens. The Doppler-echocardiogram was normal. TREATMENT AND COURSE: Because of the size of this echogenic mass with unknown origin and the risk of an embolic event its removal was indicated. This was done without destroying the aortic valve. Postoperative echocardiography demonstrated normal valve function. The histologic examination showed an endothelialized mass, rich in fibers and with only a few fibroblasts and histiocytes, without smooth muscle cells, according to a Lambl's excrescence. CONCLUSION: Cardiac valve tumors are rare. The differentiation between surface excrescences on the cardiac valve and neoplasia is only possible by histologic examination. Because of its possible malignancy and the potential risk of emboli surgical treatment is indicated.     

Prevalence of Helicobacter pylori infection in children from urban and rural West Virginia

BACKGROUND AND PURPOSE: Chlamydia pneumoniae infection has recently become noteworthy in relation to atherosclerosis. We investigated by immunohistochemistry the distribution of C pneumoniae infection in the atherosclerotic carotid artery. METHODS: Twenty carotid atherosclerotic lesions that were resected during carotid endarterectomy were investigated. Parallel sections were stained immunohistochemically with monoclonal antibodies for a C pneumoniae-specific antigen, macrophages, and smooth muscle cells. RESULTS: Immunoreactivity for the C pneumoniae-specific antigen was observed in 11 of 20 specimens (55%), and intense immunoreactivity was observed in 7 of 20 (35%). C pneumoniae infection was observed in endothelial cells, macrophages and in smooth muscle cells that had migrated into the atheromatous plaque, as well as in smooth muscle cells and small arteries in the media underlying the atheromatous plaques. C pneumoniae infection was most prominently observed in smooth muscle cells. The severity of the infection as demonstrated by immunohistochemistry was not significantly related to general risk factors for atherosclerosis. CONCLUSIONS: C pneumoniae widely infects endothelial cells, macrophages, and smooth muscle cells in the atherosclerotic carotid artery. The results of the present study can help us to understand how C pneumoniae infection contributes to the progression of carotid atherosclerosis.     

Upregulation of IGF-I and collagen I mRNA in human atherosclerotic tissue is not accompanied by changes in type 1 IGF receptor or collagen III mRNA: an in situ hybridization study

BACKGROUND: Immunoreactive insulin-like growth factor-I (IGF-I) has recently been localized to vascular smooth muscle cells in coronary atherectomy plaques, but it remains unclear whether these cells are the source of this growth factor. We therefore investigated the gene expression of this factor, and the expression of the genes for its receptor and two types of collagen known to be regulated by IGF-I, in vascular tissue samples from patients with atherosclerosis or restenosis. METHODS: Gene expression and localization were investigated by in situ hybridization, using 35S-labelled complementary RNA probes specific for IGF-I, its type a receptor, collagen I, and collagen III. The cellular composition of the tissue samples was determined by immunohistochemistry using antibodies specific for smooth muscle cells and macrophages. RESULTS: IGF-I and collagen I messenger RNAs were found in areas containing smooth muscle cells and macrophages, but collagen III and type 1 IGF receptor gene expression could not be detected in any tissue samples. CONCLUSION: IGF-I appears to be involved in the progression of the atherosclerotic plaque, even at an advanced stage, but preliminary data from two restenotic plaques indicate that it may not be involved in the later stages of restenosis.     

The virus causing encephalomyelitis in sheep in Spain: a new member of the tick-borne encephalitis group

An analysis of endothelin in atherosclerotic plaques using immunohistochemical methods showed that endothelin not only existed in endothelial cells, large amounts were also found in the proliferating intimal vascular smooth muscle cells (VSMC). In the de-endothelized thoracic aorta of rats, significant amounts of endothelin could be produced by proliferating intimal VSMC. Radio-immunological studies demonstrated that the extent of VSMC proliferation was in direct ratio to endothelin content, which suggests that production of endothelin is related to proliferation of VSMC in atherosclerotic plaques.     

Dopamine D1/D2 antagonist combinations as antagonists of the discriminative stimulus effects of cocaine

Platelet-derived growth factor (PDGF) exists as a dimer composed of two homologous but distinct peptides termed PDGF-A and -B chains, and may exist as AA, AB, and BB isoforms. The PDGF-B chain has been implicated as a mediator of renal vascular rejection by virtue of up-regulated expression of its receptor, PDGF beta-receptor, in affected arteries. A role for PDGF-A chain in mediating intimal proliferation has been suggested in human atherosclerosis (Rekhter MD, Gordon D: Does platelet-derived growth factor-A chain stimulate proliferation of arterial mesenchymal cells in human atherosclerotic plaques? Circ Res 1994, 75:410), but no studies of this molecule in human renal allograft injury have been reported to date. We used two polyclonal antisera to detect expression of PDGF-A chain and one monoclonal antibody to detect PDGF-B chain by immunohistochemistry in fixed, paraffin-embedded tissue from 1) normal adult kidneys, 2) a series of renal transplant biopsies chosen to emphasize features of vascular rejection, and 3) allograft nephrectomies. Immunohistochemistry was correlated with in situ hybridization on adjacent, formalin fixed tissue sections from nephrectomies utilizing riboprobes made from PDGF-A and -B chain cDNA. PDGF-A chain is widely expressed by medial smooth muscle cells of normal and rejecting renal arterial vessels of all sizes by immunohistochemistry and in situ hybridization. PDGF-A chain is also expressed by a population of smooth muscle cells (shown by double immunolabeling with an antibody to alpha-smooth muscle actin) comprising the intima in chronic vascular rejection. In arteries demonstrating acute rejection, up-regulated expression of PDGF-A chain by endothelial cells was detected by both immunohistochemistry and in situ hybridization. In contrast, PDGF-B chain was identified principally in infiltrating monocytes within the rejecting arteries, similar to its localization in infiltrating monocytes in human atherosclerosis. Although less prominent than the case for PDGF-A chain, PDGF-B chain also was present in medial and intimal smooth muscle cells in both rejecting and nonrejecting renal arteries. PDGF-A and -B chains have now been localized at both the mRNA and protein levels to the intimal proliferative lesions of vascular rejection. These peptides, which are known stimuli for smooth muscle cell migration and proliferation in experimental vascular injury, may have similar stimulatory effects on smooth muscle cells in an autocrine and/or paracrine manner to promote further intimal expansion and lesion progression in this form of human vasculopathy.     

Fibrinogen and atherosclerosis

Fibrin appears to be a multi-potential component of atherogenesis, intervening at virtually all stages of lesion development. Fibrin and microthrombus deposition on normal intima is associated with endothelial disruption and intimal oedema, and oedema is a primary characteristic of early proliferative lesions. Fibrin strands on or in the intima encourage smooth muscle cell (SMC) migration and proliferation, and contribute to the growth of plaques. Fibrin also provides a continuing source of fibrin degradation products (FDP), and these have mitogenic activity which will sustain SMC proliferation in growing plaques, and act as chemoattractants for blood leucocytes. Accumulation of the lipid core in fibrous plaques may also be influenced by fibrin which appears to bind the lipoprotein Lp(a) with high affinity, thereby immobilizing its lipid moiety within the lesion.     

Ascorbate affects proliferation of guinea-pig vascular smooth muscle cells by direct and extracellular matrix-mediated effects

Proliferation of smooth muscle cells and deposition of extracellular matrix proteins are important events in the formation of atherosclerotic plaques. We have investigated the direct and matrix-mediated effects of ascorbate on the proliferation rate of vascular smooth muscle cells (VSMC) isolated from the guinea-pig aorta. In the presence of ascorbate, cells showed a bi-phasic growth pattern. At 125 microM ascorbate, -3H--thymidine incorporation was stimulated 25%. However, higher concentrations of ascorbate gradually decreased cell-incorporated radioactivity up to 50% at 2 mM ascorbate. These effects of ascorbate on DNA synthesis in VSMC were paralleled by the changes in cell number and were not due to ascorbate cytotoxicity. Alpha-tocopherol (0.1 mM), individually and in combinations with 1 mm ascorbate, also inhibited DNA synthesis in VSMC. Ascorbate also influenced proliferation of smooth muscle cells through matrix-mediated effect. New VSMC culture plated on extracellular matrices deposited by smooth muscle cells in the presence of 0.1-1 mM ascorbate had up to 50% lower proliferation rate than on matrices from ascorbate-deficient cells, as assessed by [3H]-thymidine incorporation. This effect was independent from alpha-tocopherol and specific inhibitors of collagen synthesis: L-azetidine-2-carboxylic acid and pyridine-2,4-dicarboxylic acid. An ascorbate-dependent matrix effect was specific for smooth muscle cells grown on VSMC and human skin fibroblast-originated matrices, but not for human vascular endothelial cells. The possible involvement of ascorbate in the regulation of smooth muscle cells proliferation by its antioxidant/pro-oxidant effects and regulation of extracellular matrix composition are discussed.     

Early morning dystonia in Parkinson''s disease

Proliferation of arterial smooth muscle cells has held center stage as the culprit in restenosis for almost two decades. Many strategies for combating restenosis target smooth muscle replication. However, none have proven beneficial in clinical trials. Indeed, inhibition of smooth muscle proliferation in human patients might produce the undesired effect of destabilizing vulnerable atherosclerotic plaques because these cells furnish the collagen responsible for the biomechanical strength of the plaque. Actually, in some cases the benefit of angioplasty may depend on stimulating smooth muscle replication and collagen elaboration, converting an "unstable" to a more stable plaque. Moreover, recent clinical and experimental evidence suggests that restenosis depends less on neointimal hyperplasia than on constrictive remodeling (i.e., advential scarring, producing a smaller lumen), a process independent of smooth muscle replication. The recognition that plaques vulnerable to disruption often do not produce flow-limiting stenoses highlights a need for reassessment of the strategies to treat or prevent the acute coronary syndromes. We should strive to treat aggressively risk factors such as hyperlipidemia whose control appears to stabilize plaques. Trials are even underway comparing such risk factor management with coronary artery intervention. If we could identify potentially unstable atheroma before they are evident, clinically, we might even contemplate angioplasty of nonsignificant stenoses to induce smooth muscle cell proliferation and reinforce the plaque's fibrous cap. This proposal may seem preposterous, yet we perform "primary" angioplasty every day in patients with an acute myocardial infarction whose "culprit" lesions underlying the thrombus are often not critical. Our knowledge of the biology of restenosis has lagged behind our practice of coronary intervention. Advances in understanding the biology of the complications of interventional therapy, hand in hand with technical advances, should help us to devise more rational and enduring approaches to benefiting our patients.     

Atheromatous plaque macrophages produce plasminogen activator inhibitor type-1 and stimulate its production by endothelial cells and vascular smooth muscle cells

The capacity of macrophages to influence directly and indirectly fibrinolytic processes in atherosclerosis was studied using macrophages isolated from atherosclerotic plaques of patients undergoing surgical repair of distal aortic and femoral arteries. These cells were characterized by their morphology, adherence, esterase positivity, and expression of CD14 antigen. Production of plasminogen activator inhibitor type-1 (PAI-1) by plaque macrophages (6.7 +/- 2.7 ng/10(5) cells/24 hours [mean +/- SEM]) was significantly greater than PAI-1 production by blood monocytes isolated simultaneously from the same patients (1.8 +/- 1.5 ng/10(5) cells/24 hours). Production of tissue type plasminogen activator and urokinase type was not augmented compared to blood monocytes. Conditioned medium from cultured plaque macrophages significantly increased production of PAI-1 by endothelial cells (85 +/- 11% above basal) and vascular smooth muscle cells (25 +/- 10%) in vitro. This response was significantly greater than the response to monocyte-conditioned medium (endothelial cells 38 +/- 11%, vascular smooth muscle cells 2.5 +/- 2.0%). Stimulation of endothelial cell PAI-1 production by macrophage-conditioned medium was partially inhibitable by a monoclonal antibody to transforming growth factor-beta. Tissue type plasminogen activator production by endothelial cells and vascular smooth muscle cells was not affected by plaque macrophage- or monocyte-conditioned medium. Urokinase type plasminogen activator production by endothelial cells and vascular smooth muscle cells was undetectable in control medium and was augmented to similar levels in response to plaque macrophage- and monocyte-conditioned media. These results demonstrate upregulation of PAI-1 production by macrophages in atheromatous plaques and the capacity of soluble products from plaque macrophages to upregulate PAI-1 production by endothelial cells and vascular smooth muscle cells in vitro. These data suggest that macrophages in atherosclerotic plaques may inhibit thrombolysis both directly and indirectly by effects of their soluble products on endothelial cells and vascular smooth muscle cells.