M EC H A N I S M S O F D I S E AS E
Mechanisms of Disease
F R A N K L I N H . E P S T E I N , M . D. , Editor
FACTORS THAT INDUCE AND PROMOTE INFLAMMATION OR ATHEROGENESIS
A THEROSCLEROSIS — A N I NFLAMMATORY D ISEASE
RUSSELL ROSS, PH.D.
THEROSCLEROSIS is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent a series of highly specific cellular and molecular responses that can best be described, in aggregate, as an inflammatory disease.6-10 The lesions of atherosclerosis occur principally in large and medium-sized elastic and muscular arteries and can lead to ischemia of the heart, brain, or extremities, resulting in infarction. They may be present throughout a person’s lifetime. In fact, the earliest type of lesion, the so-called fatty streak, which is common in infants and young children,11 is a pure inflammatory lesion, consisting only of monocyte-derived macrophages and T lymphocytes.12 In persons with hypercholesterolemia, the influx of these cells is preceded by the extracellular deposition of amorphous and membranous lipids.11,13 By asking questions about arterial inflammation, we may be able to gain insight into the process of atherogenesis.
From the Department of Pathology, University of Washington School of Medicine, Box 357470, Seattle, WA 98195-7470, where reprint requests should be addressed to Dr. Ross (e-mail: firstname.lastname@example.org). ©1999, Massachusetts Medical Society.
Numerous pathophysiologic observations in humans and animals led to the formulation of the response-to-injury hypothesis of atherosclerosis, which initially proposed that endothelial denudation was the first step in atherosclerosis.6 The most recent version of this hypothesis emphasizes endothelial dysfunction rather than denudation. Whichever process is at work, each characteristic lesion of atherosclerosis represents a different stage in a chronic inflammatory process in the artery; if unabated and excessive, this process will result in an advanced, complicated lesion. Possible causes of endothelial dysfunction leading to atherosclerosis include elevated and modified LDL; free radicals caused by cigarette smoking, hypertension, and diabetes mellitus; genetic alterations; elevated plasma homocysteine concentrations; infectious microorganisms such as herpesviruses or Chlamydia pneumoniae; and combinations of these or other factors. Regardless of the cause of endothelial dysfunction, atherosclerosis is a highly characteristic response of particular arteries.6-9,14 The endothelial dysfunction that results from the injury leads to compensatory responses that alter the normal homeostatic properties of the endothelium. Thus, the different forms of injury increase the adhesiveness of the endothelium with respect to leukocytes or platelets, as well as its permeability. The injury also induces the endothelium to have procoagulant instead of anticoagulant properties and to form vasoactive molecules, cytokines, and growth factors. If the inflammatory response does not effectively neutralize or remove the offending agents, it can continue indefinitely. In doing so, the inflammatory response stimulates migration and proliferation of smooth-muscle cells that become intermixed with the area of inflammation to form an intermediate lesion. If these responses continue unabated, they can thicken the artery wall, which compensates by gradual dilation, so that up to a point, the lumen remains unaltered,15 a phenomenon termed “remodeling.” As for the inflammatory cells, granulocytes are rarely present during any phase of atherogenesis.16 Instead, the response is mediated by monocyte-derived macrophages and specific subtypes of T lymphocytes at every stage of the disease.17,18 Continued inflammation results in increased numbers of macrophages and lymphocytes, which both emigrate from the blood and multiply within the lesion. Activation of these cells leads to the release of hydrolytic enzymes, cytokines, chemokines, and
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modified LDL initiates a series of intracellular events36 that include the induction of urokinase30 and inflammatory cytokines such as interleukin-1.61 These patients have an increased risk of symptomatic atherosclerosis of the coronary. which can lead to increases in intracellular calcium concentrations and in smooth-muscle contraction.25.27 modified LDL is chemotactic for other monocytes and can up-regulate the expression of genes for macrophage colonystimulating factor32.65. glycation (in diabetes).
. migration and proliferation of smooth-muscle cells. The degree to which LDL is modified can vary greatly. The inflammatory response itself can have a profound effect on lipoprotein movement within the artery. angiotensin II is a potent vasoconstrictor. LDL activates the foam cells. and smooth-muscle hypertrophy. At some point. 2005 .36 After binding to scavenger receptors in vitro. Copyright © 1999 Massachusetts Medical Society.60 Plasma homocysteine concentrations are slightly elevated in many patients who have no enzymatic defects in homocysteine metabolism. such as cystathionine betasynthase or methylenetetrahydrofolate reductase.63 Angiotensin II binds to specific receptors on smooth muscle.62
Concentrations of angiotensin II.27. association with proteoglycans. and many have their first myocardial infarction by the age of 20 years. perhaps by preventing the up-regulation of adhesion molecules for monocytes. modification of lipoproteins.41-44 and they reduce fatty streaks in nonhuman primates.25. severe atherosclerosis develops in childhood.58 and it increases collagen production59 and decreases the availability of nitric oxide. Vitamin E intake is inversely correlated with the incidence of myocardial infarction.31 In addition to its ability to injure these cells. antioxidants can reduce the size of lesions.66 These substances reduce the formation of nitric oxide by the
Downloaded from www. and formation of fibrous tissue lead to further enlargement and restructuring of the lesion. and cerebral arteries. increasing the formation of hydrogen peroxide and free radicals such as superoxide anion and hydroxyl radicals in plasma.22. Removal and sequestration of modified LDL are important parts of the initial.20 which can induce further damage and eventually lead to focal necrosis. are often elevated in patients with hypertension.27.51
LDL. they can undergo progressive oxidation and be internalized by macrophages by means of the scavenger receptors on the surfaces of these cells.45 Antioxidants increase the resistance of human LDL to oxidation ex vivo46 in proportion to the vitamin E content of the plasma.25-27 When LDL particles become trapped in an artery.50. Oxidized LDL is present in lesions of atheroscle116 ·
Ja n u a r y 14 .40 In animals with hypercholesterolemia. aggregation. peripheral. Thus.35. a vicious circle of inflammation. have no benefit.33 and monocyte chemotactic protein34 derived from endothelial cells.64 It also increases smooth-muscle lipoxygenase activity. mediators of inflammation such as tumor necrosis factor a. Antioxidants such as vitamin E can also reduce freeradical formation by modified LDL. which can increase inflammation and the oxidation of LDL. such as beta carotene. Specifically. and vitamin E supplementation reduced coronary events in a preliminary clinical trial.21 Thus.37-39 Thus. resulting in the formation of foam cells.55. Trials are under way to determine whether folic acid will prevent the progression or possibly even induce the regression of atherosclerotic lesions. the principal product of the renin–angiotensin system.25.61 Treatment with folic acid can return their plasma homocysteine concentrations to normal. or incorporation into immune complexes.24-28 The internalization leads to the formation of lipid peroxides and facilitates the accumulation of cholesterol esters. 19 9 9
High plasma homocysteine concentrations were initially thought to be associated with advanced atherosclerosis on the basis of autopsy findings in patients with homozygous defects in enzymes necessary for homocysteine metabolism.46.56 Homocysteine is toxic to endothelium57 and is prothrombotic.
Hypercholesterolemia and Modified Lipids and Lipoproteins
rosis in humans.44 The latter observation suggests that the antioxidants have an antiinflammatory effect. the artery can no longer compensate by dilation. interleukin-1.52-56 In patients with such defects. and further inflammation can be maintained in the artery by the presence of these lipids. All rights reserved. resulting in the activation of phospholipase C. it may help expand the inflammatory response by stimulating the replication of monocyte-derived macrophages and the entry of new monocytes into lesions. complicated lesion. which may be modified by oxidation.19. cycles of accumulation of mononuclear cells. it can contribute to atherogenesis by stimulating the growth of smooth muscle. Hypertension also has proinflammatory actions. so that it becomes covered by a fibrous cap that overlies a core of lipid and necrotic tissue — a so-called advanced.63 increased protein synthesis.22-25 is a major cause of injury to the endothelium and underlying smooth muscle. the lesion may then intrude into the lumen and alter the flow of blood.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
growth factors.nejm.29 Once modified and taken up by macrophages. protective role of the macrophage in the inflammatory response 28-30 and minimize the effects of modified LDL on endothelial and smooth-muscle cells. In addition to causing hypertension.47-49 In contrast.org at RUTH LILLY MED LIBRARY on June 14. other antioxidants. and macrophage colony-stimulating factor increase binding of LDL to endothelium and smooth muscle and increase the transcription of the LDL-receptor gene.
which include E-selectin. macrophage colony-stimulating factor. up-regulation of leukocyte adhesion molecules.68.M EC H A N I S M S O F D I S E AS E
Figure 1.74. pneumoniae.
THE NATURE OF THE INFLAMMATORY RESPONSE
Interactions among Endothelial Cells. It is nevertheless possible that infection. 2005 . and migration of leukocytes into the artery wall. All rights reserved. P-selectin.66 and increase peripheral resistance. such as branches. Such adhesion molecules.70 Increased titers of antibodies71 to these organisms have been used as a predictor of further adverse events in patients who have had a myocardial infarction. monocyte chemotactic protein 1. intercellular adhesion molecules. and osteopontin.79 act in conjunction with chemoattractant molecules generated by the endothelium. platelet-derived growth factor.76
Specific arterial sites. prostacyclin. and platelet–endothelial-cell adhesion molecule 1. and endothelin. angiotensin II. including L-selectin.73 Nonetheless. and the up-regulation of endothelial adhesion molecules. Endothelial Dysfunction in Atherosclerosis. there is no direct evidence that these organisms can cause the lesions of atherosclerosis.77 At these sites. platelet-derived growth factor. and vascular-cell adhesion molecules.nejm. herpesviruses and C.68. and vascular-cell adhesion molecule 1. bifurcations. and curvatures.67 increase leukocyte adhesion. which is mediated by nitric oxide. and T Cells
Several reports have shown a correlation between the incidence of atherosclerosis and the presence of at least two types of infectious microorganisms. and accumulation of monocytes and T cells. including decreased shear stress and increased turbulence.75 Although these organisms are ubiquitous in many tissues and organs. whether shear stress or turbulence is high or low — appears to be
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Downloaded from www. smooth muscle.68-70 Both organisms have been identified in atheromatous lesions in coronary arteries and in other organs obtained at autopsy.
. specific molecules form on the endothelium that are responsible for the adherence.78 Molecules associated with the migration of leukocytes across the endothelium. 1). free-radical formation mediates some of the effects of both hypertension and hypercholesterolemia. cause characteristic alterations in the flow of blood.72. which is mediated by oxidized low-density lipoprotein. and monocytes — such as monocyte chemotactic protein 1. combined with other factors. interleukin-8. Thus. These changes include increased endothelial permeability to lipoproteins and other plasma constituents.33 The nature of the flow — that is. migration. Copyright © 1999 Massachusetts Medical Society. such as platelet–endothelial-cell adhesion molecules.80 and modified LDL — to attract monocytes and T cells into the artery (Fig. which act as receptors for glycoconjugates and integrins present on monocytes and T cells.org at RUTH LILLY MED LIBRARY on June 14. integrins. may be responsible for the genesis of the lesions of atherosclerosis in some patients. include several selectins. The earliest changes that precede the formation of lesions of atherosclerosis take place in the endothelium. osteopontin.69.
endothelium. intercellular adhesion molecule 1. Monocytes. the fact that lesions cannot be induced experimentally in animals by injection of the organisms leaves their role as etiologic agents in question.
induce cell proliferation.85.nejm. the genes for intercellular adhesion molecule 1.
. thromboxane A2. and granulocyte–macrophage colony-stimulating factor.86 Thus. or combinations of these molecules. and their expression is increased by reduced shear stress.87. Chemokines may be responsible for the chemotaxis and accumulation of macrophages in fatty streaks (Fig.81 plateletderived growth factor B chain. or modified LDL. intercellular adhesion molecule 1 is constitutively increased at lesion-prone sites. adherence of monocytes and T cells may occur after an increase in one or more of the adhesion molecules. Changes in flow alter the expression of genes that have elements in their promoter regions that respond to shear stress. tumor necrosis factor a. fibrin. P-selectin.org at RUTH LILLY MED LIBRARY on June 14. which is mediated by tumor necrosis factor a.86 Rolling and adherence of monocytes and T cells occur at these sites as a result of the up-regulation of adhesion molecules on both the endothelium and the leukocytes. 19 9 9 Downloaded from www. 2005 .
Ja n u a r y 14 . and help define and localize the inflammatory response at the sites of lesions (Fig.84 Thus. and receptors that bind chemoattractant molecules. foamcell formation. The steps involved in this process include smooth-muscle migration. and platelet adherence and aggregation. All rights reserved. vascular-cell adhesion molecule 1 is absent in normal mice but is present at the same sites as intercellular adhesion molecule 1 in mice with apolipoprotein E deficiency. which may act in concert with chemotactic molecules such as monocyte chemotactic protein 1.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
important in determining whether lesions occur at these vascular sites. macrophage colony-stimulating factor. T-cell activation. and transforming growth factor b. which is mediated by oxidized low-density lipoprotein. Later they are joined by various numbers of smooth-muscle cells. alterations in blood flow appear to be critical in determining which arterial sites are prone to have lesions. 1). CD18. 2). and interleukin-1. interleukin-8. integrins that bind adhesion molecules of the immunoglobulin superfamily.88 Activation of monocytes and T cells leads to up-regulation of receptors on their surfaces. which are stimulated by integrins. For example. fibroblast growth factor 2. lipid
Adherence and aggregation of platelets
Adherence and entry of leukocytes
Figure 2. Copyright © 1999 Massachusetts Medical Society. In contrast. interleukin-2. which is stimulated by platelet-derived growth factor. Fatty-Streak Formation in Atherosclerosis. P-selectin. In genetically modified mice that are deficient in apolipoprotein E (and have hypercholesterolemia).78 These ligand–receptor interactions further activate mononuclear cells. Fatty streaks initially consist of lipid-laden monocytes and macrophages (foam cells) together with T lymphocytes. and the factors described in Figure 1 as responsible for the adherence and migration of leukocytes. such as the mucin-like molecules that bind selectins.82 and tissue factor 83 in endothelial cells have these elements.77. tissue factor. it is present on the surface of the endothelium at these sites in normal mice and is increased in mice with apolipoprotein E deficiency. Would interference with only one of the several adhesion molecules be sufficient to decrease inflammation and thus slow or counteract the process of atherogenesis? In mice that are completely deficient in intercellular adhesion molecule 1.86 In fact.
Monocyte-derived macrophages are scavenging and antigen-presenting cells. growth-regulating molecules. and replication of mononuclear cells in lesions depend in part on factors such as macrophage colony-stimulating factor and granulocyte–macrophage colony-stimulating factor for monocytes and interleukin-2 for lymphocytes. they tend to form a fibrous cap that walls off the lesion from the lumen.
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. 2005 .89 Comparison of the relative roles of these molecules in inflammation in the arteries and the microvasculature may provide clues to the relative feasibility of modifying the inflammatory process at these sites. the precursor of macrophages in all tissues. is present in lesions of atherosclerosis. which appear to be involved in cell–cell interactions. which suggests that in situations of chronic inflammation it may be possible to measure the “shed” molecules. it may be detectable in different types of inflammatory responses. The principal factors associated with macrophage accumulation include macrophage colony-stimulating factor.org at RUTH LILLY MED LIBRARY on June 14. The fibrous cap covers a mixture of leukocytes. The fibrous cap forms as a result of increased activity of platelet-derived growth factor.94 Disintegrins may participate in these shedding processes. and osteopontin and of decreased connective-tissue degradation.90 These transmembrane proteins. As fatty streaks progress to intermediate and advanced lesions. increased proteolytic activity. Increased plasma concentrations of shed molecules might then be used to identify patients at risk for atherosclerosis or other inflammatory diseases. All rights reserved. These lesions expand at their shoulders by means of continued leukocyte adhesion and entry caused by the same factors as those listed in Figures 1 and 2. Formation of an Advanced. cysteine-rich proteins (MDCs). A recently discovered class of molecules.
Vo l u m e 3 4 0 Downloaded from www.90 Adhesion molecules such as L-selectin can be cleaved from the surface of leukocytes by a metalloproteinase (L-selectin sheddase). disintegrin-like.93. smooth muscle. such as the different adhesion molecules. but one of them.92 They are not found in normal arteries. Copyright © 1999 Massachusetts Medical Society. and debris. chemokines. Complicated Lesion of Atherosclerosis. and they secrete cytokines.91. tumor necrosis factor a. lipid. interleukin-1. as markers of a sustained in-
flammatory response. is present in every phase of atherogenesis. in plasma. The necrotic core represents the results of apoptosis and necrosis. The continuing entry. monocyte chemotactic protein 1. If shedding occurs. the disintegrins. which may form a necrotic core. and metalloproteinases and other hydrolytic enzymes. and oxidized low-density lipoprotein. survival. has been identified in endothelium.M EC H A N I S M S O F D I S E AS E
feeding leads to smaller lesions of atherosclerosis. transforming growth factor b. Continued exposure to macrophage colony-stimulating factor permits macrophages to survive in vitro and possibly to multiply within the lesions.
Monocytes and Immunity
The ubiquitous monocyte. and lipid accumulation.90 contain a metalloproteinase sequence in their extracellular segment that permits them to activate molecules such as tumor necrosis factor a. and thus of modifying atherosclerosis. In con-
Formation of necrotic core
Figure 3. sometimes called metalloproteinase-like. This represents a type of healing or fibrous response to the injury. and macrophages.nejm. MDC15.
rheumatoid arthritis. CD40. its blood and lymph supply. endothelium. complicated lesions (Fig. proteolytic enzymes (particularly metalloproteinases). replication of monocyte-derived macrophages and T cells is probably of equal importance. which can amplify the inflammatory response. An important component of the platelets is the glycoprotein IIb/IIIa receptor. and antagonists to them prevent thrombus formation in patients who have had a myocardial infarction. which is replaced by fibrous tissue (pannus). Initially. Activated platelets can accumulate on the walls of arteries and recruit additional platelets into an expanding thrombus. CD40 ligand induces the release of interleukin-1b by vascular cells. macrophages may become involved in the necrotic cores characteristic of advanced.97 One possible antigen may be oxidized LDL. and breakdown of proteins and the prevention of protein denaturation. and transforming growth factor b). and pancreas (pancreatitis) are similar yet are characteristic of each tissue or organ. CD40 ligand. and smooth muscle in atherosclerotic lesions in vivo. and among the other disorders in Table 1. 4). and growth factors (such as platelet-derived growth factor and insulin-like growth factor I) may be critical in the role of these cells in the damage and repair that ensue as the lesions progress (Fig. In the examples in Table 1.108
ATHEROSCLEROSIS IN RELATION TO OTHER CHRONIC INFLAMMATORY DISEASES
The cellular interactions in atherogenesis are fundamentally no different from those in chronic inflammatory–fibroproliferative diseases such as cirrhosis.20 Thus.nejm.98 which can be produced by macrophages. although the early response begins with granulocytes. Plaque rupture and thrombosis are notable complications of advanced lesions that lead to unstable coronary syndromes or myocardial infarction (Fig. kidneys (glomerulosclerosis). Macrophages and lymphocytes predominate in the synovium. In pulmonary fi-
Downloaded from www. including the assembly. pulmonary fibrosis. the cellular responses in the arteries (atherosclerosis).106 Activation of platelets leads to the formation of free arachidonic acid. presumably induced by interferon-g.org at RUTH LILLY MED LIBRARY on June 14. All rights reserved. joints (rheumatoid arthritis). However.103 Furthermore. 2005 . they are found primarily within the joint cavity. providing further evidence of immune activation in the lesions. one of the most potent vasoconstricting and platelet-aggregating substances known. and can also present antigens to T cells.107 Platelets are important in maintaining vascular integrity in the absence of injury and protecting against spontaneous hemorrhage. that amplify the inflammatory response. which belongs to the integrin superfamily of adhesion-molecule receptors and appears on the surface of platelets during platelet activation and thrombus formation. T-cell activation results in the secretion of cytokines. inflammatory cytokines such as interferon-g activate macrophages and under certain circumstances induce them to undergo programmed cell death (apoptosis). 19 9 9
Does the inflammatory response in arteries differ from that in other tissues? Granulocytes are rare in atherosclerosis.105
Platelets can adhere to dysfunctional endothelium. lungs (pulmonary fibrosis). is expressed on the same cells.99 Heat-shock protein 60 may also contribute to autoimmunity. exposed collagen. Copyright © 1999 Massachusetts Medical Society. T cells. since both CD4 and CD8 T cells are present in the lesions at all stages of the process. When activated. or into leukotrienes.101 can be expressed by macrophages.96. liver (cirrhosis).97 Smooth-muscle cells from the lesions also have class II HLA molecules on their surfaces. interleukin-1. 3). potentially enhancing the inflammatory response. If this occurs in vivo. the only cells thought to proliferate during expansion of atherosclerotic lesions were smooth-muscle cells.
. including interferon-g and tumor necrosis factor a and b. leading to erosion of cartilage and bone. These proteins may be elevated on endothelial cells and participate in immune responses. it is not surprising that cell-mediated immune responses may be involved in atherogenesis.21. and the nature of the offending agents.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
trast. and its receptor. and macrophages. and chronic pancreatitis (Table 1). 2).97 T cells are activated when they bind antigen processed and presented by macrophages. These receptors serve an important hemostatic function. 2).95 The ability of macrophages to produce cytokines (such as tumor necrosis factor a. may contribute to the migration and proliferation of smooth-muscle cells and monocytes. they are present only in rheumatoid arthritis and pulmonary fibrosis.102. intracellular transport. Thus. Activated macrophages express class II histocompatibility antigens such as HLA-DR that allow them to present antigens to T lymphocytes.100 An immunoregulatory molecule. platelets release their granules. Both are up-regulated in lesions of atherosclerosis.9
Ja n u a r y 14 .104 Inhibition of CD40 with blocking antibodies reduces lesion formation in apolipoprotein E–deficient mice. which contain cytokines and growth factors that. In the case of arthritis. the response of each particular tissue or organ depends on its characteristic cells and architecture. glomerulosclerosis. together with thrombin.
Platelet adhesion and mural thrombosis are ubiquitous in the initiation and generation of the lesions of atherosclerosis in animals and humans (Fig. This and other heat-shock proteins perform several functions.9. which can be transformed into prostaglandins such as thromboxane A2.
however. when excessive. Are there differences in arterial endothelium and microvascular endothelium such that different types of monocytes are attracted to each. yet at autopsy active inflammation is evident in the accumulation of macrophages at sites of plaque rupture.102. which can lead to hemorrhage from the vasa vasorum or from the lumen of the artery and can result in thrombus formation and occlusion of the artery. Are there particular aspects of the chronic inflammatory response in atherosclerosis that can be used to advantage? At least three different types of macrophages. In most patients myocardial infarctions occur as a result of erosion or uneven thinning and rupture of the fibrous cap.M EC H A N I S M S O F D I S E AS E
Thinning of fibrous cap
Hemorrhage from plaque microvessels
Figure 4.122 These differences raise the question whether there are subgroups of monocytes that “home” to a specific tissue or organ. granulocytes initially appear in the alveolar spaces. elastases. interleukin-4. All rights reserved.124. Stable advanced lesions usually have uniformly dense fibrous caps. and could one take advantage of such differences?123 One might try to use such differences to modify the inflammatory response so as to emphasize its protective rather than its destructive characteristics. If the injurious agent or agents are not removed or nullified by the inflammatory response and the inflammation progresses. Unstable Fibrous Plaques in Atherosclerosis. These enzymes cause degradation of the matrix. there are parallels between atherosclerosis and these other inflammatory diseases.107 Macrophage accumulation may
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brosis. which promotes plaque instability and further implicates an immune response. interleukin-2. and interleukin-10) have been identified. each regulated by different T-cell cytokines (interferon-g. diminish-
es the functional capacity of the tissue or organ and becomes part of the disease process (Table 1). The potentially dangerous lesions are often nonocclusive and thus difficult to diagnose by angiography. is infiltrated by macrophages and lymphocytes. which release metalloproteinases and other proteolytic enzymes at these sites. Rupture of the fibrous cap or ulceration of the fibrous plaque can rapidly lead to thrombosis and usually occurs at sites of thinning of the fibrous cap that covers the advanced lesion.org at RUTH LILLY MED LIBRARY on June 14. accumulate. the lung parenchyma.nejm. often at the shoulders of the lesion where macrophages enter. 2005 . Copyright © 1999 Massachusetts Medical Society.103 These changes may also be accompanied by the production of tissue-factor procoagulant and other hemostatic factors. Thinning of the fibrous cap is apparently due to the continuing influx and activation of macrophages.127 further increasing the possibility of thrombosis. and stromelysins (Fig.
Instability and Rupture of Plaque
Chronic inflammatory responses are often associated with specific types of injurious or granulomainducing agents. the response changes from a protective to an injurious response.
.125 Degradation of the fibrous cap may result from elaboration of metalloproteinases such as collagenases. Such constant or repetitive injury can stimulate each tissue to repair or wall off the damage by means of a fibroproliferative response. and are activated and where apoptosis may occur. which. where fibrosis ultimately occurs.126 Activated T cells may stimulate metalloproteinase production by macrophages in the lesions. 4). Thus.
118 Brody scarring et al. new matrix formation Collagen types III and Inflammatory exudate in alveoli Kuhn et al. The existence of these different lineages suggests that smooth muscle in different parts of the arterial tree may respond differ122 ·
Ja n u a r y 14 .109 function. All rights reserved. proteoglycan matrix formation and degraFuster110 dation.117 IV. whereas in the lesions of atherosclerosis it consists largely of proteoglycan. it may be helpful to understand the embryonic derivation of the smooth-muscle cells that make up the arteries in different regions. smooth-muscle cells within the media of large arteries may be heterogeneous. fibroblasts Fibroblasts
Collagen types I.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
TABLE 1. The smooth-muscle cells of coronary arteries appear to originate from a third precursor population in the intracardiac mesenchyme.134 These differences in the origin of smooth-muscle cells raise questions about whether these cells.112 necrotic parenchyma Collagen types I and Synovial-cell injury. CHARACTERISTICS
OTHER CHRONIC INFLAMMATORY DISEASES. new Maher. the matrix consists largely of type I and III fibrillar collagen. mitogens. When cultured human arterial smooth-muscle cells are plated on collagen in fibrillar form.1Sarles et al.
be associated with increased plasma concentrations of both fibrinogen and C-reactive protein.115 Magil IV.128. are surrounded by different types of connective tissue. fibronectin injury and dysfunction. as well as in lesions. peri. Smooth-muscle cells have different embryonic origins.org at RUTH LILLY MED LIBRARY on June 14. III. or migration away from this inhibitory environment..135-137 Is there selection of a particular lineage based on the cells’ responses to these different substances? Does cell lineage help to explain why lesions in peripheral arteries differ from those in the carotid and coronary arteries?
The Role of the Matrix
Smooth-muscle cells in the media of arteries.111 AnthoIII matrix and scarring replacing ny et al.*
Cirrhosis Rheumatoid arthritis Glomerulosclerosis
+ + +
+ + +
¡ +/¡ ¡
Fibroblasts.131. intermixed with loosely scattered collagen fibrils.119 Collagen. or extracellular matrixes.nejm. whereas those in the abdominal aorta are derived from a mesenchymal source. necrotic core Collagen types I and Parenchymal-cell injury. fibronectin and bronchi. erosion of Sewell and III. Copyright © 1999 Massachusetts Medical Society. chemotactic factors. 19 9 9
ently to the stimuli that generate atherosclerotic lesions at each of these sites. Ito cells Synovial fibroblasts Mesangial cells
NEW PERSPECTIVES ON THE FORMATION AND PROGRESSION OF LESIONS
To understand the factors that are important in the proliferative and migratory responses that lead to differences in the organization and enlargement of the lesions in different parts of the arterial tree. Endothelial-cell injury and dys.128-130 two markers of inflammation thought to be early signs of atherosclerosis. fibronectin. fibronectin. respond differently to different cytokines. with different proliferative and matrix-producing capabilities.137 In vivo degradation of the collagen by collagenase. intersti. the collagen inhibits cell proliferation by up-regulating specific inhibitors of the cell cycle.2 DiMagno tial fat necrosis.132 Plaque rupture and thrombosis may be responsible for as many as 50 percent of cases of acute coronary syndromes and myocardial infarction. To complicate matters further.121 formation
*Plus signs denote the presence of a cell type. may allow the smoothmuscle cells to respond to mitogenic stimuli and rep-
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.113 Harris 114 teoglycan (pannus) Collagen types I and Epithelial.133 Although likely. 2005 . and minus signs its absence. new matrix et al. Epithelial (ductal) injury. depending on the segment of the arterial system involved. fibrous cap. new matrix scarring Trentham.and endothelial-cell Johnson.Lukacs and tensive matrix deposition and Ward. In the media of arteries. on the basis of their lineage. In some vertebrates.. this has not been confirmed in humans.9 Libby and and IV. organized by ex. smooth-muscle cells in the upper portion of the thoracic aorta are derived from a neuroectodermal source.Ross.120 proteoglycan ductal inflammation. fibroHansson. new Ross and nectin. procartilage. deand Cohen116 crease in glomerular filtration. elastin.
and Dr. the matrix that surrounds the cells is not neutral and may determine whether they remain quiescent or multiply in response to growth factors. Ross R . Atherosclerotic lesions in humans: in situ immunophenotypic analysis suggesting an immune mediated response.6:131-8.
Vo l u m e 3 4 0 Downloaded from www. et al.295: 369-77. Goran Hansson. we may create new avenues for the diagnosis and management of disease in the 50 percent of patients with cardiovascular disease who do not have hypercholesterolemia. students. Breslow JL.180:1332-9. Atherosclerosis is clearly an inflammatory disease and does not result simply from the accumulation of lipids. cholesterol ester transfer protein. Atherosclerosis and coronary artery disease. If we can selectively modify the
1.138-140 If these interactions were to occur in arteries. Bentz van de Berg D. and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis. 93-3095. 2005 . fatty streak. Ford I. Circulation 1994. and other molecules have little effect on atherogenesis. to Dr.147 In the absence of apolipoprotein E.146. Simionescu M. Kolettis GJ. Am J Pathol 1986.M EC H A N I S M S O F D I S E AS E
licate.142-144 Because atherosclerosis is a multigenic disease.344:1383-9. New techniques have been developed to identify DNA that should yield a vast amount of information about which genes are expressed and in what patterns.
harmful components of inflammation in the arteries and leave the protective aspects intact. Simionescu N. The pathogenesis of atherosclerosis. et al. monomeric collagen. Shepherd J. Topol EJ.3:600-1. 6. eds. 17. Libby P. Jonasson L. Scandinavian Simvastatin Survival Study Group. Copyright © 1999 Massachusetts Medical Society. Science 1973. and the mice become hypercholesterolemic and lesions of atherosclerosis develop that are similar to those in humans. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia: intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. Bondjers G. such as apolipoprotein E–deficient mice.: National Heart. Weisenberg E. Lab Invest 1989. Atherosclerosis: a defense mechanism gone awry.
I am indebted to all the fellows. Samuel Wright.143:987-1002. 18. Ross R . Dr. Shattuck Lecture — cardiovascular medicine at the turn of the millennium: triumphs. Cytokines and growth regulatory molecules.89:2462-78. D’Armiento FP. 4. The pathogenesis of atherosclerosis — an update. and cell–matrix interactions can lead to the expression of chemokines by macrophages. The pathogenesis of atherosclerosis: a perspective for the 1990s. Second report of the Expert Panel on Detection. Stary HC. concerns. Nat Med 1997. Hansson GK. 7. Popescu G. as they do when they are cultured on nonfibrillar. Advances in molecular genetics have made it possible to remove or insert genes and to determine the roles of their products in disease. Idem. Nature 1993. (NIH publication no.145 Numerous animal models that are useful in studying the genetics of atherogenesis have been produced.148. and opportunities. Ross R.
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