M EC H A NIS MS OF D IS EASE

Review Article

Mechanisms of Disease FACTORS THAT INDUCE AND PROMOTE
INFLAMMATION OR ATHEROGENESIS
Numerous pathophysiologic observations in hu-
F R A N K L I N H . E P S T E I N , M. D. , Editor
mans and animals led to the formulation of the re-
sponse-to-injury hypothesis of atherosclerosis, which
initially proposed that endothelial denudation was
A THEROSCLEROSIS — A N the first step in atherosclerosis.6 The most recent ver-
I NFLAMMATORY D ISEASE sion of this hypothesis emphasizes endothelial dys-
function rather than denudation. Whichever process
is at work, each characteristic lesion of atherosclero-
RUSSELL ROSS, PH.D. sis represents a different stage in a chronic inflamma-
tory process in the artery; if unabated and excessive,
this process will result in an advanced, complicated
lesion. Possible causes of endothelial dysfunction

A
THEROSCLEROSIS is an inflammatory dis- leading to atherosclerosis include elevated and mod-
ease. Because high plasma concentrations of ified LDL; free radicals caused by cigarette smoking,
cholesterol, in particular those of low-density hypertension, and diabetes mellitus; genetic altera-
lipoprotein (LDL) cholesterol, are one of the prin- tions; elevated plasma homocysteine concentrations;
cipal risk factors for atherosclerosis,1 the process of infectious microorganisms such as herpesviruses or
atherogenesis has been considered by many to con- Chlamydia pneumoniae; and combinations of these
sist largely of the accumulation of lipids within the or other factors. Regardless of the cause of endothe-
artery wall; however, it is much more than that. De- lial dysfunction, atherosclerosis is a highly character-
spite changes in lifestyle and the use of new phar- istic response of particular arteries.6-9,14
macologic approaches to lower plasma cholesterol The endothelial dysfunction that results from the
concentrations,2,3 cardiovascular disease continues injury leads to compensatory responses that alter the
to be the principal cause of death in the United normal homeostatic properties of the endothelium.
States, Europe, and much of Asia.4,5 In fact, the le- Thus, the different forms of injury increase the adhe-
sions of atherosclerosis represent a series of highly siveness of the endothelium with respect to leuko-
specific cellular and molecular responses that can cytes or platelets, as well as its permeability. The injury
best be described, in aggregate, as an inflammatory also induces the endothelium to have procoagulant
disease.6-10 instead of anticoagulant properties and to form vaso-
The lesions of atherosclerosis occur principally in active molecules, cytokines, and growth factors. If the
large and medium-sized elastic and muscular arteries inflammatory response does not effectively neutralize
and can lead to ischemia of the heart, brain, or ex- or remove the offending agents, it can continue indef-
tremities, resulting in infarction. They may be present initely. In doing so, the inflammatory response stim-
throughout a person’s lifetime. In fact, the earliest ulates migration and proliferation of smooth-muscle
type of lesion, the so-called fatty streak, which is cells that become intermixed with the area of inflam-
common in infants and young children,11 is a pure in- mation to form an intermediate lesion. If these re-
flammatory lesion, consisting only of monocyte-de- sponses continue unabated, they can thicken the ar-
rived macrophages and T lymphocytes.12 In persons tery wall, which compensates by gradual dilation, so
with hypercholesterolemia, the influx of these cells is that up to a point, the lumen remains unaltered,15 a
preceded by the extracellular deposition of amor- phenomenon termed “remodeling.” As for the in-
phous and membranous lipids.11,13 By asking ques- flammatory cells, granulocytes are rarely present dur-
tions about arterial inflammation, we may be able to ing any phase of atherogenesis.16 Instead, the response
gain insight into the process of atherogenesis. 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 num-
bers of macrophages and lymphocytes, which both
From the Department of Pathology, University of Washington School of emigrate from the blood and multiply within the
Medicine, Box 357470, Seattle, WA 98195-7470, where reprint requests
should be addressed to Dr. Ross (e-mail: rross@u.washington.edu). lesion. Activation of these cells leads to the release
©1999, Massachusetts Medical Society. of hydrolytic enzymes, cytokines, chemokines, and

Vol ume 340 Numb e r 2 · 115

The New England Journal of Medicine
Downloaded from nejm.org on September 2, 2015. For personal use only. No other uses without permission.
Copyright © 1999 Massachusetts Medical Society. All rights reserved.

Thus. anion and hydroxyl radicals in plasma. For personal use only. other antioxidants. perhaps structuring of the lesion.63 ter binding to scavenger receptors in vitro. stances reduce the formation of nitric oxide by the 116 · Janu ar y 14 .25. Specifically. peripheral. The degree to mocysteine is toxic to endothelium57 and is prothrom- which LDL is modified can vary greatly. develops in childhood. LDL acti.40 In animals with hypercholesterole- and eventually lead to focal necrosis.65.org on September 2.22-25 is a major cause of injury to the endothelium initially thought to be associated with advanced ath- and underlying smooth muscle. modification of lipoproteins.61 Antioxidants such as vitamin E can also reduce free. which can increase inflammation and cytokines such as interleukin-1. association with pro. aggregation.55.25-27 When LDL par.56 Ho- ing in the formation of foam cells. flammatory actions. which may be modified by oxidation. they can undergo with homozygous defects in enzymes necessary for progressive oxidation and be internalized by macro. or incorporation into immune complex. erosclerosis on the basis of autopsy findings in patients ticles become trapped in an artery. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne growth factors. Concentrations of angiotensin II. so that it becomes covered by preventing the up-regulation of adhesion mole- by a fibrous cap that overlies a core of lipid and ne. the principal ing the replication of monocyte-derived macrophag.24-28 The internalization In patients with such defects.44 The latter observation suggests that the an- of fibrous tissue lead to further enlargement and re. and macro. No other uses without permission.25. severe atherosclerosis leads to the formation of lipid peroxides and facili. fects in homocysteine metabolism. glyca- tion (in diabetes). modified increased protein synthesis. elevated in many patients who have no enzymatic de- protective role of the macrophage in the inflamma. Hypertension also has proin- circle of inflammation. are often es and the entry of new monocytes into lesions.51 LDL. .60 vates the foam cells. Treatment with folic acid can return their plasma ho- radical formation by modified LDL. antioxidants can reduce the size of lesions. a vicious the oxidation of LDL.58 and it increases collagen production59 and modified and taken up by macrophages. it may Hypertension help expand the inflammatory response by stimulat. mediators of inflammation such as stimulating the growth of smooth muscle.20 which can induce further damage rosis in humans. All rights reserved. At some point. the artery can no longer com. and many have their first my- tates the accumulation of cholesterol esters.63 Angio- tumor necrosis factor a. complicated sistance of human LDL to oxidation ex vivo46 in lesion. product of the renin–angiotensin system. cycles of mia.45 Antioxidants increase the re- crotic tissue — a so-called advanced. II is a potent vasoconstrictor.61 These patients tory response 28-30 and minimize the effects of mod. interleukin-1. elevated in patients with hypertension. 2015. migration and and they reduce fatty streaks in nonhuman pri- proliferation of smooth-muscle cells. of the coronary. cidence of myocardial infarction. proportion to the vitamin E content of the plasma.21 Thus.31 In addition to mocysteine concentrations to normal. Homocysteine teoglycans. progression or possibly even induce the regression of late the expression of genes for macrophage colony. and cerebral arteries. and formation mates. such as cystathionine beta- phages by means of the scavenger receptors on the synthase or methylenetetrahydrofolate reductase. the lesion may then intrude into Vitamin E intake is inversely correlated with the in- the lumen and alter the flow of blood. angiotensin The inflammatory response itself can have a pro.62 stimulating factor32.47-49 In contrast.33 and monocyte chemotactic protein34 derived from endothelial cells.27. High plasma homocysteine concentrations were es. In addition to causing found effect on lipoprotein movement within the ar. decreases the availability of nitric oxide. increasing the formation of hy- and further inflammation can be maintained in the drogen peroxide and free radicals such as superoxide artery by the presence of these lipids.22.50.36 Af. pertrophy. pensate by dilation. and smooth-muscle hy- LDL initiates a series of intracellular events36 that in. have no benefit.27 modified LDL is way to determine whether folic acid will prevent the chemotactic for other monocytes and can up-regu.29 Once botic. concentrations and in smooth-muscle contraction.46. result. atherosclerotic lesions. hypertension. and vitamin E sup- plementation reduced coronary events in a prelimi- Hypercholesterolemia and Modified Lipids nary clinical trial.35.19. Trials are under its ability to injure these cells. homocysteine metabolism.37-39 Thus.66 These sub- Oxidized LDL is present in lesions of atheroscle.25. 19 9 9 The New England Journal of Medicine Downloaded from nejm. resulting in the activation of phospholipase C. ocardial infarction by the age of 20 years. tensin II binds to specific receptors on smooth mus- phage colony-stimulating factor increase binding of cle.27. and Lipoproteins such as beta carotene. cules for monocytes. tioxidants have an antiinflammatory effect. Copyright © 1999 Massachusetts Medical Society.64 It also increases smooth-muscle lipoxy- clude the induction of urokinase30 and inflammatory genase activity. have an increased risk of symptomatic atherosclerosis ified LDL on endothelial and smooth-muscle cells. Removal and sequestration of Plasma homocysteine concentrations are slightly modified LDL are important parts of the initial.52-56 surfaces of these cells.41-44 accumulation of mononuclear cells. LDL to endothelium and smooth muscle and increase which can lead to increases in intracellular calcium the transcription of the LDL-receptor gene. it can contribute to atherogenesis by tery.

74. platelet-derived growth factor. of monocytes and T cells. No other uses without permission. whether shear sclerosis in some patients. including L-selectin.80 and modified LDL — to at- that infection. prostacyclin. intercellular adhesion molecule 1.70 Increased titers of antibodies71 to these which act as receptors for glycoconjugates and inte- organisms have been used as a predictor of further grins present on monocytes and T cells. which include E-selectin. platelet-derived growth factor.68. and T Cells Infection Specific arterial sites. including decreased shear stress at least two types of infectious microorganisms.33 responsible for the genesis of the lesions of athero.77 At these sites.68. there is no direct evi. The nature of the flow — that is. P-selectin.67 increase leukocyte adhesion. smooth muscle.68-70 Both organisms molecules form on the endothelium that are respon- have been identified in atheromatous lesions in cor.75 Although these organisms are lium.72. All rights reserved. and the up-regulation of endothelial adhesion molecules. Monocytes. endothelium. THE NATURE OF THE INFLAMMATORY crease peripheral resistance. and platelet–endothelial-cell adhesion molecule 1.66 and in. pneumoniae.org on September 2. interleukin-8. These changes include increased endothelial permeability to lipoproteins and other plasma constituents. combined with other factors. Interactions among Endothelial Cells. and vascular-cell adhesion mol- ecule 1. such as platelet–endothelial-cell adhesion mol- ubiquitous in many tissues and organs. and increased turbulence.78 Molecules associated dence that these organisms can cause the lesions of with the migration of leukocytes across the endothe- atherosclerosis.79 act in conjunction with chemoattractant mol- lesions cannot be induced experimentally in animals ecules generated by the endothelium. 1). cular-cell adhesion molecules. such as branches. Such adhesion molecules. up-regulation of leukocyte adhesion molecules. It is nevertheless possible protein 1. by injection of the organisms leaves their role as eti. and accumulation onary arteries and in other organs obtained at au. Copyright © 1999 Massachusetts Medical Society. . macrophage colony-stimulating factor. the fact that ecules. specific pesviruses and C. For personal use only. sible for the adherence. osteopontin. include sever- adverse events in patients who have had a myocardial al selectins. integrins.69. which is mediated by nitric oxide. Endothelial Dysfunction in Atherosclerosis. 2015.73 Nonetheless. angioten- sin II. her. migration. and curvatures. and osteopontin. and vas- infarction. cause characteristic alterations the incidence of atherosclerosis and the presence of in the flow of blood. which is mediated by oxidized low-density lipoprotein. bifurca- Several reports have shown a correlation between tions.76 stress or turbulence is high or low — appears to be Vol ume 340 Numb e r 2 · 117 The New England Journal of Medicine Downloaded from nejm. M EC H A NIS MS OF D IS EASE 3 3 Endothelial3 Leukocyte3 Endothelial3 Leukocyte3 permeability3 migration3 adhesion3 adhesion3 3 3 3 3 Figure 1. The earliest changes that precede the formation of lesions of atherosclerosis take place in the endo- thelium. topsy. and monocytes — such as monocyte chemotactic ologic agents in question. RESPONSE tion mediates some of the effects of both hyperten- sion and hypercholesterolemia. intercellular adhesion molecules. monocyte chemotactic protein 1. and migration of leukocytes into the artery wall. free-radical forma. may be tract monocytes and T cells into the artery (Fig. Thus. and endothelin.

All rights reserved. Copyright © 1999 Massachusetts Medical Society. modified LDL. tissue factor. tin. P-selec- tor interactions further activate mononuclear cells. which taxis and accumulation of macrophages in fatty streaks may act in concert with chemotactic molecules such (Fig. it is present on pression is increased by reduced shear stress. or combinations of these molecules. same sites as intercellular adhesion molecule 1 in mice ulation of adhesion molecules on both the endothe. the several adhesion molecules be sufficient to de- integrins that bind adhesion molecules of the im. fibrin. and receptors that bind process of atherogenesis? In mice that are completely chemoattractant molecules. adherence lium and the leukocytes. 2). No other uses without permission. interleukin-2.87. in one or more of the adhesion molecules. lipid 3 3 3 3 3 Adherence and3 Adherence3 Smooth-muscle3 Foam-cell3 T-cell3 aggregation of3 and entry3 migration3 formation3 activation platelets of leukocytes Figure 2.88 Activation of monocytes and T cells as monocyte chemotactic protein 1. P-selectin. 19 9 9 The New England Journal of Medicine Downloaded from nejm. macrophage colony-stimulating factor. mice and is increased in mice with apolipoprotein E termining which arterial sites are prone to have le. 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 induce cell proliferation. and transforming growth factor b. creased at lesion-prone sites. or leads to up-regulation of receptors on their surfaces. In contrast. fibroblast growth factor 2. calize the inflammatory response at the sites of le- sion of genes that have elements in their promoter sions (Fig. which is stimulated by platelet-derived growth factor. Fatty streaks initially consist of lipid-laden monocytes and macrophages (foam cells) together with T lymphocytes. .81 platelet. Changes in flow alter the expres. of monocytes and T cells may occur after an increase Chemokines may be responsible for the chemo. the In genetically modified mice that are deficient in genes for intercellular adhesion molecule 1. For example. T-cell activation.86 In fact. with apolipoprotein E deficiency. 1). The steps involved in this process include smooth-muscle migration.78 These ligand–recep.org on September 2. 118 · Ja nu ar y 14 . vascular-cell adhesion mole- sions. deficiency. crease inflammation and thus slow or counteract the munoglobulin superfamily. which is mediated by tumor necrosis factor a. which are stimulated by integrins. and their ex. and platelet adherence and aggregation.85. Fatty-Streak Formation in Atherosclerosis. For personal use only. interleukin-8. and granulocyte–macrophage colony-stimulating factor.84 Thus. foam- cell formation. and the factors described in Figure 1 as responsible for the adherence and migration of leukocytes. which is mediated by oxidized low-density lipoprotein. the surface of the endothelium at these sites in normal alterations in blood flow appear to be critical in de. and help define and lo- these vascular sites.82 and tissue factor 83 intercellular adhesion molecule 1 is constitutively in- in endothelial cells have these elements. Would interference with only one of such as the mucin-like molecules that bind selectins. apolipoprotein E (and have hypercholesterolemia). regions that respond to shear stress. 2015. tumor necrosis factor a.86 Rolling and adherence of monocytes and cule 1 is absent in normal mice but is present at the T cells occur at these sites as a result of the up-reg. Later they are joined by various numbers of smooth-muscle cells. CD18.86 Thus. derived growth factor B chain. and interleukin-1.77. thromboxane A2. deficient in intercellular adhesion molecule 1.

they tend to form a fibrous cap that walls off the lesion from the lumen.org on September 2. tory diseases. the precursor of macro- rophages. The necrotic core represents the results of apoptosis and necrosis. tients at risk for atherosclerosis or other inflamma- A recently discovered class of molecules. found in normal arteries. granulocyte–macrophage colony-stimulating factor tin sheddase). Monocyte-derived macrophages are scav- tain a metalloproteinase sequence in their extracellu. which suggests that in situations of for monocytes and interleukin-2 for lymphocytes. As fatty streaks progress to intermediate and advanced lesions. such as tumor necrosis factor a. smooth muscle. which may form a necrotic core. No other uses without permission.93. and possibly to multiply within the lesions. The fibrous cap forms as a result of increased activity of platelet-derived growth factor. and they secrete lar segment that permits them to activate molecules cytokines. The continuing entry. in inflammation in the arteries and the microvascu. and osteopontin and of decreased connective-tissue degradation. Complicated Lesion of Atherosclerosis. such as the different adhesion ing factor permits macrophages to survive in vitro molecules. In con- 3 3 3 3 3 Macrophage accumulation Formation of3 Fibrous-cap formation necrotic core Figure 3.90 con. growth-regulating molecules. dis- integrin-like. survival. and lipid accumulation. interleukin-1. .89 flammatory response. 2015. chemokines. but one of them. monocyte chemotactic protein 1. For personal use only. The principal factors associated with macro- phage accumulation include macrophage colony-stimulating factor. and mac. This represents a type of healing or fibrous response to the injury. The fibrous cap covers a mixture of leukocytes. and debris. chronic inflammation it may be possible to measure Continued exposure to macrophage colony-stimulat- the “shed” molecules. ogenesis. has been Monocytes and Immunity identified in endothelium. it may be detectable in different types of inflamma- lature may provide clues to the relative feasibility of tory responses. transforming growth factor b.90 These transmembrane proteins. 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. is present in every phase of ather- appear to be involved in cell–cell interactions. Increased plasma concentrations of modifying the inflammatory process at these sites. All rights reserved. Vol ume 340 Numb e r 2 · 119 The New England Journal of Medicine Downloaded from nejm.91. MDC15. MECH A NIS MS OF D IS EASE feeding leads to smaller lesions of atherosclerosis. The ubiquitous monocyte. Copyright © 1999 Massachusetts Medical Society.94 Disintegrins may partici- Comparison of the relative roles of these molecules pate in these shedding processes. in plasma. the disin. If shedding occurs. Formation of an Advanced. cysteine-rich proteins (MDCs). and replication of is present in lesions of atherosclerosis. lipid. tegrins. sometimes called metalloproteinase-like.92 They are not and metalloproteinases and other hydrolytic enzymes. and oxidized low-density lipoprotein. enging and antigen-presenting cells. which phages in all tissues. increased proteolytic activity. as markers of a sustained in. tumor necrosis factor a. shed molecules might then be used to identify pa- and thus of modifying atherosclerosis.90 Adhesion mononuclear cells in lesions depend in part on factors molecules such as L-selectin can be cleaved from the such as macrophage colony-stimulating factor and surface of leukocytes by a metalloproteinase (L-selec.

In the ex- bly. it is important component of the platelets is the glyco- not surprising that cell-mediated immune responses protein IIb/IIIa receptor. pulmonary teins perform several functions.20 Thus. although the early response begins with granulocytes. and breakdown of pro. 19 9 9 The New England Journal of Medicine Downloaded from nejm. 2015.21. which belongs to the in- may be involved in atherogenesis. may contribute to the migration and proliferation advanced. lets can accumulate on the walls of arteries and recruit patibility antigens such as HLA-DR that allow them additional platelets into an expanding thrombus. T-cell activation results in the secretion of tagonists to them prevent thrombus formation in cytokines. and pancreas in vivo. fibrosis.96. or into leukotrienes.108 factor a and b. This and other heat-shock pro. insulin-like growth factor I) may be critical in the 4). macrophages may be. 2). the response of each particular tis- teins and the prevention of protein denaturation. intracellular transport.104 Inhibition of CD40 with blocking anti. and its receptor. .99 Heat-shock protein 60 may also contribute matory–fibroproliferative diseases such as cirrhosis.95 The ability of macrophages to produce cyto. one of the most potent macrophages and T cells is probably of equal impor.98 which can be produced by macro. CD40 Inflammatory Response ligand induces the release of interleukin-1b by vas. When activated. tissue or organ.9 placed by fibrous tissue (pannus). However. joints (rheumatoid arthritis). they are Platelets found primarily within the joint cavity. In pulmonary fi- 120 · Ja nu ar y 14 . and appears on the surface of platelets during plate- es of the process. If this occurs in vivo. Macrophages Platelet adhesion and mural thrombosis are ubiq. which contain cyto- optosis). including interferon-g and tumor necrosis patients who have had a myocardial infarction. and transforming growth factor b). OTHER CHRONIC INFLAMMATORY sumably induced by interferon-g. its blood and lymph supply. Both are up-regulated in lesions of ath. complicated lesions (Fig. proteolytic en. potentially enhancing the inflammatory from that in other tissues? Granulocytes are rare in response. No other uses without permission. and among the other disorders in Ta- bodies reduces lesion formation in apolipoprotein ble 1. liver (cirrho- can be expressed by macrophages. of smooth-muscle cells and monocytes.103 Furthermore. glomerulosclerosis. lead- uitous in the initiation and generation of the lesions ing to erosion of cartilage and bone. 3).org on September 2. since both CD4 tegrin superfamily of adhesion-molecule receptors and CD8 T cells are present in the lesions at all stag.9. Thus. and lymphocytes predominate in the synovium. and growth plications of advanced lesions that lead to unstable factors (such as platelet-derived growth factor and coronary syndromes or myocardial infarction (Fig. including the assem. rheumatoid arthritis. Plaque rupture and thrombosis are notable com- zymes (particularly metalloproteinases). and an- phages. Copyright © 1999 Massachusetts Medical Society. 2). interleukin-1. providing further evidence of immune activation in the lesions. damentally no different from those in chronic inflam- phages.107 Platelets are important in maintaining vas- role of these cells in the damage and repair that en. All rights reserved. and can also present DISEASES antigens to T cells. replication of monocyte-derived such as thromboxane A2. ing against spontaneous hemorrhage. endothe. vasoconstricting and platelet-aggregating substances tance. they are present only in rheumatoid arthritis and E–deficient mice. tors serve an important hemostatic function.97 One possible antigen may be The cellular interactions in atherogenesis are fun- oxidized LDL.105 pulmonary fibrosis. tivate macrophages and under certain circumstances exposed collagen. inflammatory response. is expressed on the (pancreatitis) are similar yet are characteristic of each same cells. the only cells thought to proliferate during of platelets leads to the formation of free arachidonic expansion of atherosclerotic lesions were smooth-mus. acid. cular integrity in the absence of injury and protect- sue as the lesions progress (Fig. kidneys (glomeru- lium. These recep- bind antigen processed and presented by macro. the cellular re- An immunoregulatory molecule. known. erosclerosis. sis). together with throm- come involved in the necrotic cores characteristic of bin. In the case of arthritis.106 Activation Initially. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne trast. inflammatory cytokines such as interferon-g ac. to autoimmunity. CD40 ligand. which can amplify the kines (such as tumor necrosis factor a. and the and participate in immune responses. sue or organ depends on its characteristic cells and These proteins may be elevated on endothelial cells architecture. which can be transformed into prostaglandins cle cells. and smooth muscle in atherosclerotic lesions losclerosis). and macrophages. An to present antigens to T lymphocytes. amples in Table 1.97 Smooth-muscle cells from the lesions also ATHEROSCLEROSIS IN RELATION TO have class II HLA molecules on their surfaces. platelets release their granules. which is re- of atherosclerosis in animals and humans (Fig. Does the inflammatory response in arteries differ cular cells. Platelets can adhere to dysfunctional endothelium. atherosclerosis.100 nature of the offending agents. Activated plate- Activated macrophages express class II histocom. CD40. For personal use only. that amplify the inflammatory re- sponse. T cells. and chronic pancreatitis (Table 1). induce them to undergo programmed cell death (ap.102.101 sponses in the arteries (atherosclerosis). kines and growth factors that. pre.97 T cells are activated when they let activation and thrombus formation. lungs (pulmonary fibrosis).

is infiltrated by macrophages and lymphocytes. or nullified by the inflammatory response and the Stable advanced lesions usually have uniformly inflammation progresses. 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. Such constant are often nonocclusive and thus difficult to diagnose or repetitive injury can stimulate each tissue to re. and rupture of the fibrous cap. brosis. which. where fibrosis becomes part of the disease process (Table 1). there are parallels between ath. Unstable Fibrous Plaques in Atherosclerosis. by angiography.126 Activated T cells and microvascular endothelium such that different may stimulate metalloproteinase production by mac- types of monocytes are attracted to each. These enzymes cause degradation of the ma- trix. however. 4). No other uses without permission. tions occur as a result of erosion or uneven thinning rophages. gan. interleukin-4. In most patients myocardial infarc- to advantage? At least three different types of mac. Thus. mostatic factors. Thinning of the fibrous cap is apparently due to the continuing influx and activation of macrophages. yet at autopsy active inflammation is pair or wall off the damage by means of a fibropro.125 ences raise the question whether there are subgroups Degradation of the fibrous cap may result from elab- of monocytes that “home” to a specific tissue or or. interleukin-10) have been identified. evident in the accumulation of macrophages at sites liferative response.103 try to use such differences to modify the inflamma. interleukin-2. accumulate. the lung parenchyma. and could rophages in the lesions. of plaque rupture. MEC H A NIS MS OF D IS EASE Plaque rupture Thinning of fibrous cap Hemorrhage from plaque3 microvessels Figure 4. These changes may also be accompanied by the pro- tory response so as to emphasize its protective rather duction of tissue-factor procoagulant and other he- than its destructive characteristics.102. each regulated by different T-cell cyto. which release metallo- proteinases and other proteolytic enzymes at these sites. and of the lesion where macrophages enter. Copyright © 1999 Massachusetts Medical Society. diminish. and stromelysins (Fig. All rights reserved. when excessive. For personal use only.107 Macrophage accumulation may Vol ume 340 Numb e r 2 · 121 The New England Journal of Medicine Downloaded from nejm. The potentially dangerous lesions a protective to an injurious response. which promotes plaque insta- one take advantage of such differences?123 One might bility and further implicates an immune response. often at the shoulders kines (interferon-g. granulocytes initially appear in the alveolar es the functional capacity of the tissue or organ and spaces. 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.122 These differ. ultimately occurs. oration of metalloproteinases such as collagenases. Are there differences in arterial endothelium elastases. .org on September 2. 2015. Chronic inflammatory responses are often associ- Are there particular aspects of the chronic inflam.124. ated with specific types of injurious or granuloma- matory response in atherosclerosis that can be used inducing agents. Instability and Rupture of Plaque erosclerosis and these other inflammatory diseases. and are activated and where apoptosis may occur. the response changes from dense fibrous caps.127 further increasing the possibil- If the injurious agent or agents are not removed ity of thrombosis.

it The Role of the Matrix may be helpful to understand the embryonic deriva- tion of the smooth-muscle cells that make up the ar. are surrounded by different types different embryonic origins. proteoglycan matrix formation and degra. 19 9 9 The New England Journal of Medicine Downloaded from nejm. new matrix formation Pulmonary fibrosis + + +/¡ Smooth-muscle cells.131. smooth-muscle cells in the upper portion of lagen. No other uses without permission.2 DiMagno tial fat necrosis.1Sarles et al. with different bosis may be responsible for as many as 50 percent proliferative and matrix-producing capabilities. intermixed with loosely mal source.org on September 2.Lukacs and tensive matrix deposition and Ward. be associated with increased plasma concentrations ently to the stimuli that generate atherosclerotic of both fibrinogen and C-reactive protein. fibrous cap. . necrotic core Fuster110 Cirrhosis + + ¡ Fibroblasts.and endothelial-cell Johnson. fibronectin. or AND PROGRESSION OF LESIONS extracellular matrixes. CHARACTERISTICS OF ATHEROSCLEROSIS AND OTHER CHRONIC INFLAMMATORY DISEASES. this inhibitory environment. All rights reserved.21 cells raise questions about whether these cells. Copyright © 1999 Massachusetts Medical Society.132 Plaque rupture and throm. These differences in the origin of smooth-muscle dial infarction. elastin.Ross.128. may allow the smooth- ferent parts of the arterial tree may respond differ.112 necrotic parenchyma Rheumatoid + + +/¡ Synovial fibroblasts Collagen types I and Synovial-cell injury.113 teoglycan (pannus) Harris 114 Glomerulosclerosis + + ¡ Mesangial cells Collagen types I and Epithelial..121 formation *Plus signs denote the presence of a cell type. matrix consists largely of type I and III fibrillar col- brates. III. the collagen by collagenase. In some verte. Ross and dation. Endothelial-cell injury and dys. Epithelial (ductal) injury. the ment of the arterial system involved. as teries in different regions.109 nectin. mitogens. fibro.111 Antho- III matrix and scarring replacing ny et al. organized by ex.137 In vivo degradation of intracardiac mesenchyme.118 Brody scarring et al. depending on the seg. chemotactic factors. Ito cells Collagen types I and Parenchymal-cell injury.135-137 Is there selection of a Smooth Muscle particular lineage based on the cells’ responses to To understand the factors that are important in these different substances? Does cell lineage help to the proliferative and migratory responses that lead to explain why lesions in peripheral arteries differ from differences in the organization and enlargement of those in the carotid and coronary arteries? the lesions in different parts of the arterial tree. The are plated on collagen in fibrillar form. cartilage. de. In the media of arteries.117 fibroblasts IV. sists largely of proteoglycan. fibronectin and bronchi. pro.120 proteoglycan ductal inflammation. smooth-muscle cells within the media of atherosclerosis.9 Libby and and IV.119 Chronic pancreatitis + + ¡ Fibroblasts Collagen. LYMPHO. fibronectin. The existence of these dif. new Hansson. whereas those in the abdominal aorta scattered collagen fibrils. peri. fibronectin injury and dysfunction. erosion of Sewell and arthritis III. are derived from a mesenchymal source.133 Although When cultured human arterial smooth-muscle cells likely. and minus signs its absence. the collagen smooth-muscle cells of coronary arteries appear to inhibits cell proliferation by up-regulating specific originate from a third precursor population in the inhibitors of the cell cycle. For personal use only. 2015. Smooth-muscle cells in the media of arteries.115 Magil IV. To complicate matters markers of inflammation thought to be early signs of further. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 1. whereas in the lesions of atherosclerosis it con- the thoracic aorta are derived from a neuroectoder. new matrix et al.* MONOCYTES ANDMACRO. new matrix scarring Trentham.128-130 two lesions at each of these sites. of connective tissue. Smooth-muscle cells have well as in lesions. muscle cells to respond to mitogenic stimuli and rep- 122 · Ja nu ar y 14 . function. intersti. Collagen types III and Inflammatory exudate in alveoli Kuhn et al. new Maher. this has not been confirmed in humans. on the basis of their lineage.134 of cases of acute coronary syndromes and myocar. respond differently to dif- NEW PERSPECTIVES ON THE FORMATION ferent cytokines. and Cohen116 crease in glomerular filtra- tion. large arteries may be heterogeneous. or migration away from ferent lineages suggests that smooth muscle in dif. CONNECTIVE-TISSUE EXTRACELLULAR DISEASE PHAGES CYTES LOCYTES CELLS MATRIX PATHOGENETIC MECHANISMS STUDIES Atherosclerosis + + ¡ Smooth-muscle cells Collagen types I. GRANU..

Prevention of coronary heart dis- atherosclerosis is a multigenic disease. Other matrix molecules. in particular to Elaine Raines for her main quiescent or multiply in response to growth support and scientific endeavors and for her critical reading of the factors. 9. To explore the role of monocytes 12. monomeric collagen. Mancini FP. studies are under way in which apo. Breslow JL. The pathogenesis of atherosclerosis. Am J Pathol 1986. Ross R. al events in atherogenesis: accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperlipidemic tor in circulating monocytes and platelets. Dr. Beck- vascular disease. Arteriosclerosis 1986. N Engl J Med 1976. van der Loos CM. Ross R.362:801-9. Evaluation. cholesterol ester transfer protein. 1. Ross R. Atherosclerotic lesions in humans: in situ immunophenotypic analysis consideration. may be in. Philadelphia: Lippincott-Raven. lesions of atherosclerosis.org on September 2.3:600-1. Studies in transgenic mice have revealed that 14. and smooth muscle cells in the hu- man atherosclerotic plaque. Vol ume 340 Numb e r 2 · 123 The New England Journal of Medicine Downloaded from nejm. Napoli C. the patterns of gene expression may 5.149 17. lipoprotein E–deficient mice. Simionescu N. response. Momtaz Wassef for their review and suggestions. concerns. 8. Second report of the Expert environment. Weisenberg E. Md.146. Cells may express different constellations of genes REFERENCES and therefore vary phenotypically. 2015. American atherogenesis. Simionescu M. effect on atherogenesis. David Hajjar.89:2462-78. and other molecules have little Compensatory enlargement of human atherosclerotic coronary arteries. et al. N Engl J Med 1987. 3. worked with me over the years. 420-5.5 other factors need to be taken into er AE.314:488-500. density lipoprotein). Skalli O. N Engl mal models that are useful in studying the genetics J Med 1986. Supported in part by a grant (HL18645) from the National Institutes of ly influence the inflammatory and fibroproliferative Health. to Dr. Vol. the matrix that surrounds the cells I am indebted to all the fellows. Kolettis GJ. 4. et al. Atherosclerosis and coronary artery disease. understanding ease with pravastatin in men with hypercholesterolemia.138-140 If these interac- tions were to occur in arteries. No other uses without permission. N Engl J Med patterns of gene expression may help to explain dif. 16. Idem. as they do when they are cultured on non.147 In the absence of 10. Shepherd J. Atheroscle- regulation of the numbers of monocytes and macro. roles of their products in disease. 1996:463-74.: National Heart.337:1360-9. Nature 1993. lipoprotein remnants are not car. Fatty streak formation ried to the liver. occurs in human fetal aortas and is greatly enhanced by maternal hyper- lized. Regional ac- Thus. 18. N Engl J Med sites and may provide clues regarding genetic differ.180:1332-9.143:987-1002. Chandler AB. Randomised trial of what patterns. . Jonasson L. although hypercholesterolemia is important cumulations of T cells. 1993. Glagov S.145 Numerous ani. and assistants who have is not neutral and may determine whether they re. Bethesda.344:1383-9. A definition of initial. new avenues for the diagnosis and management of volved. Libby P. and Blood Institute. et al. apolipoprotein A (the principal apoprotein of high. The histological classification of atherosclerotic lesions in ny-stimulating factor appears to be important in the human coronary arteries. Vasile E. Lancet 1994. Atherosclerosis is clearly an inflamma. Goran Hansson. we may create such as fibronectin and heparan sulfate. Ross R. phages and in lesion formation. 15. 93-3095. Stary HC. Das PK. 6. Glomset JA. information about which genes are expressed and in Lung. rabbit. Idem. Samuel Wright. 293-311. depending on their 1. NIH funding decreases. Arteriosclerosis 1981. Scandinavian Simvastatin Survival Study Group. Am J Pathol apolipoprotein E.6:131-8. Topol EJ. Cytokines and growth regulatory molecules. Heart Association. Topol EJ. such as apo.295: sible to remove or insert genes and to determine the 369-77. 1996:585-94. National Cholesterol Education Program. The pathogenesis of atherosclerosis: a perspective for the 1990s. 11. Lupu F. Atherosclerosis — a problem of the biology of arterial wall cells and their interactions with blood components. Lab Invest 1989. Copyright © 1999 Massachusetts Medical Society. Idem. and the mice become hypercholesterolemic and cholesterolemia: intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. fatty and platelets and of platelet-derived growth factor in streak. van der Wal AC. Holm J. CONCLUSIONS and to Barbara Droker for assistance in preparing the manuscript. Philadelphia: Lippincott-Raven. (NIH publication no.1: Lp(a) lipoprotein. they could profound. and Treatment of High Blood Cholesterol to identify DNA that should yield a vast amount of in Adults (Adult Treatment Panel II). harmful components of inflammation in the arteries fibrillar. chemokines by macrophages. The pathogenesis of atherosclerosis — an update. For personal use only. Zarins CK. Cardiovascular disease burden increases. Bondjers G. Stankunavicius R. information that should help decipher cholesterol lowering in 4 444 patients with coronary heart disease: the the complex nature of atherogenesis. suggesting an immune mediated response. macrophages.333:1301-7.123:109-25. Furthermore. Hansson GK. those in humans. All rights reserved. New techniques have been developed Panel on Detection. and disease in the 50 percent of patients with cardiovas- cell–matrix interactions can lead to the expression of cular disease who do not have hypercholesterolemia. lipoprotein E–deficient mice have been made chi. 1997.100:2680-90. rosis and coronary artery disease. Stary HC.316:1371-5.141 Thus. If we can selectively modify the Vol. and intermediate lesions of atherosclerosis: a report from the Com- mittee on Vascular Lesions of the Council on Arteriosclerosis. Ford I. MEC H A NIS MS OF D IS EASE licate.148. 1995. Bentz van de Berg D. because they can also inhibit the cell cycle. Science 1973. eds. 19. manuscript. 1993. Circulation 1994. D’Armiento FP. 13. Cobbe SM.61:166-70. in approximately 50 percent of patients with cardio. Fuster V. 1. Dr. and Dr. of atherogenesis have been produced. and leave the protective aspects intact. ferences in susceptibility to agents that cause disease. Atherosclerosis and the arterial smooth muscle ences in susceptibility as well as response to therapy. Atherosclerosis: a defense mechanism gone awry. eds. whereas macrophage colo. 7. students. Ross R. cell: proliferation of smooth muscle is a key event in the genesis of the Advances in molecular genetics have made it pos.142-144 Because Scandinavian Simvastatin Survival Study (4S). Popescu G.) 2. and opportunities. In: Fuster V. Glagov S. Nat Med 1997. lesions of atherosclerosis develop that are similar to J Clin Invest 1997. Prelesion- meric for a deficiency of platelet-derived growth fac. In: tory disease and does not result simply from the ac. where they are normally metabo. Braunwald E. Ross R. Shattuck Lecture — cardiovascular medicine at the turn vary in lesions from different persons and at different of the millennium: triumphs. cumulation of lipids.

Copyright © 1999 Massachusetts Medical Society. I. Rosner B. Ascherio A. the pathogenesis of arteriosclerosis.344:254-7. 37:1-31. Oxidative stress and cardiovascular dis. low density lipoproteins increase the functional expression of the macro. scler Thromb Vasc Biol 1997. disease: Cambridge Heart Antioxidant Study. Arterioscle. 1996:492-510. Rosenfeld ME. Steinberg D. J Biol Chem 1997. in the Dahl hypertensive rat. 2. Gibbons GH. and M-CSF in the aortic 96:404-7. Adam E. Hennekens CH. Atherosclerosis and coronary artery disease. 1987. Arterioscler Thromb Vasc Biol 1997. Fruebis J. Motulsky AG. King SB III. Schofield PM. women. 25. 69. J Biol Chem 1997.16:831-42. Renin angiotensin system and atherosclerotic ma: colocalization with interleukin-1 beta-converting enzyme. tion of low density lipoprotein receptor gene transcription in HepG2 cells.91:2873-9. 54. Randomised controlled trial of vitamin E in patients with coronary aggregates. Low density lipoprotein oxidation and its pathobiological Willett WC. Shah PK. Cheeseman K. Vitamin E consumption and the risk of coronary heart disease significance. Raines EW. Vergilio JA. Nicholson AC. 62. Beltz WF. Leonard EJ. Inhibition of 72. Skovby F.41:173-6.94:155-64. Chang MY. Cytomegalovirus and atheroscle- hypercholesterolemia-induced atherosclerosis in the nonhuman primate by rosis.136:23-8. Ross R. Sasahara M. Nygård O. Swei A.347:781-6. Lacy F. Andalibi A.268:17489-94.84:1086-95. Vascular smooth muscle cell hyper- to the scavenger receptor in human monocytes and the THP-1 cell line. Griendling KK. Palkama T. Beresford SAA. Ueland PM. 71. Oxidative stress lesions of rabbit and man. J Clin Invest 1989. ified low density lipoproteins: a potential role in recruitment and retention 58. Topol EJ. bination of beta carotene and vitamin A on lung cancer and cardiovascular toxicity induced by free radical peroxidation of lipid. Libby P. CD36. sion determines growth response to angiotensin II. Raines EW. Carew TE. Effects of a com- 26. Specificity of detection 84:5928-31. Goodman GE. Lacy F. MCP-1. Thornquist MD. The Yin and Yang of oxida. Pathogenesis of plaque disruption. Mendall MA. innocent bystander hypothesis. Pezacka EH. McCully KS. Vitamin E consumption and the risk of coronary disease in rosis 1988. 52. smooth muscle cells. Reaven PD. Matikainen S. Majors A.15:1631-40. 33. Berliner JA. BC. van Boven CP. Manson JE. idants in vivo can selectively inhibit low density lipoprotein degradation in 68. Frei B.11:97-101. et al. 23. Watson AD. For personal use only. J Biol Chem 1991. Enhanced macro. Plasma homocysteine levels and mortality in patients with coronary urokinase expression by polyanions is protein kinase C-dependent and artery disease. O’Connor DT. 1070-6. Pio F.90: 39.53:283-8. Scott CR. Philadelphia: Lippincott-Raven.150:1785-90. 53. Low density lipoprotein cyto. Lack of effect of long- tion in the development of the fatty streak: a review based on the 1994 term supplementation with beta carotene on the incidence of malignant George Lyman Duff Memorial Lecture. 47. Stampfer MJ. Antioxidants and atheroscle.337:408-16. Rimm EB. Yoshimura T. Native and modified tinuria due to cystathionine b-synthase deficiency.96:4095-103.11:547-51. Mudd SH. oxide production in hypertensives and normotensive subjects at genetic risk 40.org on September 2. Oxidatively mod. Yokode M. Keaney JF Jr. Endothelium-dependent responses in probucol unrelated to its hypocholesterolemic effect: evidence that antiox. J Hypertens 1998. Schmidt RA.17:1289-302. The natural history of homocys- 28. Evidence for apoptosis in advanced human athero. N Engl J Med 1993. Jackson LA. Tyrosine kinase activity is involved 456-61. Willett WC. 41.6:559-67. Hajjar DP. Schmid-Schönbein GW. Ross R. Malinow MR. et al. 1. Morel DW. Territo MC.8:348-58. Homocysteine-induced modulation of tissue plasminogen of monocyte/macrophages during atherogenesis.328:1444-9. Vollset 30. Witztum JL. Levy HL. 37. Silvestre M. Vitamins C and E inhibit O2¡ production in the pig coronary artery. min E but not by beta-carotene.16:291-303. et al.14:Suppl K:30-8.12:1258-66. diovascular disease.56:111-28.272:22975-8. Bruggeman CA. Induction of interleukin-1 production by ligands binding 64. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne 20. et al. Nunes GL. J Clin Invest U S A 1987.272:21654-9. Navab M. Schmid-Schönbein GW. Stampfer MJ. Parthasarathy S. et al. Homocystine-induced Circulation 1997. 50. requires protein and RNA synthesis. Circulation 1997.319:100-4. Clin Chem 1995. Homocysteine as a risk factor for lial cell expression of granulocyte and macrophage colony-stimulating fac. cardiovascular events. Homocysteinemia as a risk fac- 29. 124 · Ja nu ar y 14 . Steinberg D. Ross R. 59. Circulation 1997. Diaz MN. ease. ease. Proc Natl Acad Sci U S A research. Kaski JC. Salimans MM.96:3593-601. arteriosclerosis: the role of endothelial cell injury and platelet response in 32.58:731-41. eds. Circulation 1998. Khoo JC. 2015. Nutr Rev 1995. Am J Pathol vascular disease. N Engl J Med 1996. Hypertension 1997. Cardiovasc Surg 1997. Steinberg D. 24.30:1628-33. Porter JM. Harker LA. Circulation 1997. J Biol Chem 1997. Nordrehaug JE. 1996:237-42. 55. 1996. 48. Carrington D. Leatham EW. Rosenfeld ME.13:590-600. Mitch- antibodies against LDL further enhance macrophage uptake of LDL inson MJ. Stopeck AT. Arterioscler Thromb 1993. 46.266:22726-32. Effect of probucol azithromycin in male survivors of myocardial infarction. Falcone DJ. Topol EJ. Omenn GS. Chait A. Mancini FP. and 45. onary artery disease. All rights reserved. Monoclonal 49.97:421-4. . Plasma homocyst(e)ine and arterial occlusive diseases: 31. probucol.84:2995-8. Khouw A. Palinski W. Topol EJ. et al. Stimulation of macrophage SE. 1993. N Engl J Med 1997. Preventing coronary heart lecular Trojan horses and cellular saboteurs. Hajjar DP. Fabian AJ. an animal suffering from grade III atherosclerosis. 35. Haberland ME. Robinson K. in the protein kinase C induced expression of interleukin-1 beta gene in 65. 57. McLoughlin P. Hypertens Res 1995. Manson JE. hypertension. Am J Pathol 1990. Lipoprotein trafficking in vascular cells: mo. olemia-induced atherosclerosis in the nonhuman primate by probucol. Schwenke DC. Homocyst(e)ine decreases (MCP-1). Kalynych A. 19 9 9 The New England Journal of Medicine Downloaded from nejm. Prospective studies of homocysteine and car- J Biol Chem 1993. tor for atherosclerosis: a review. In: Fuster of dietary antioxidant combinations in humans: protection of LDL by vita- V. Farstad M. Hennekens CH.18:87-98. Effect 21. rotic heart disease. Miller E. Induction of endothe. et al. Cellular composition and proliferation. McCaffrey TA. J Clin Invest 1992. Skarlatos S. Falk E. Palkama T. Taylor LM Jr. Buring JE. Human monocyte chemoattractant protein-1 60. Vol. Nature 1990. 34. Slichter SJ. Debakey ME. Chait A. 1996:539-55. Geng Y-J. model for familial hypercholesterolemia. Nehler MR. bioavailable nitric oxide by a mechanism involving glutathione peroxidase. Arterioscler Thromb Vasc Biol neoplasms and cardiovascular disease. Raines EW. Febbraio M. Eur Heart J 1993. Grayston JT. 61. J Clin Invest 1976.328:1450-6. Giovannucci E. Kita T. Roles of infectious agents in atheroscle- macrophage-rich fatty streaks and slow the progression of atherosclerosis rosis and restenosis: an assessment of the evidence and need for future in the Watanabe heritable hyperlipidemic rabbit. Chobanian AV. 56. phage class B scavenger receptor. Elevated Chlamydia pneumoniae antibodies. Palinski W.272:17012-7. 1. 63. Gonzalez V. Alexander RW. its genesis. Steinberg D. Vol. Pratt RE. 51.334:1150-5.96:3264-5.74:432-8. Inhibition of hypercholester. Hajjar DP. Thom DH. Han J. Berk a mini-review. Proc Natl Acad Sci U S A 1987. et al. Chlamydia pneumoniae strain Is the extent of atherosclerosis related to resistance of LDL to oxidation? TWAR antibody and angiographically demonstrated coronary artery dis- J Clin Invest 1994. Nagano Y. Vanhoutte PM. Fong LG.17:2074-81. Am J Pathol 1969. in men. Philadelphia: Lippincott-Raven. trophy vs. of Chlamydia pneumoniae in cardiovascular atheroma: evaluation of the 43.337:230-6. Stampfer MJ. Arterioscler Thromb 73. Ross R. Welch GN. Am J Hum Genet 1985. Hajjar KA. N Engl J Med 1997. Steinberg D. Lancet 1996. No other uses without permission. Upchurch GR Jr. Ross R. N Engl J Med 1993. Hessler JR. et al. Fuster V. J Biol Chem 1997. Rajavashisth TB. eds. DeLano FA. In: Fuster V. Quinn MT. Antiatherogenic effect of 67. Dzau VJ. 70. hyperplasia: autocrine transforming growth factor-beta 1 expres- Immunology 1991. Ylä-Herttuala S. Probucol prevents the progression prevalence of latently present cytomegalovirus in arterial walls of patients of atherosclerosis in Watanabe heritable hyperlipidemic rabbit. vascular disease: enhanced collagen production and accumulation by tors by modified low-density lipoproteins. Dzau VJ. Cytokine regula. Atherosclerosis and coronary artery dis.24: disease. High 42. Sasahara M. Vita JA. Witztum JL. et al. Atherosclerosis and cor- 1995. FEBS Lett 1993. Immunol Today 1990. Camm Vasc Biol 1995. presence of oxidatively modified low density lipoprotein in atherosclerotic 66. Vascular pathology of homocysteinemia: implications for 27. Khoo JC. Nicholson AC. Parthasarathy S. Kelly F. Sgoutas DS. Plasma hydrogen per- monocytic cells. Omenn GS. Arterioscler Thromb 1992. Vol. Arterioscler Thromb 1991.272:20963-6. In: wall of LDL receptor-deficient rabbits during early atherogenesis. Chisholm GM. Melnick JL.147:251-66.334:1145-9. II. 22. Am J Pathol 1997. ease. treatment on gene expression of VCAM-1. N Engl J Med 1996. Campbell LA. Hurme M. disease: B vitamins and homocysteine. Ehrhart LA. Colditz GA. Boulanger CM. phage uptake of low density lipoprotein after self-aggregation. Gupta S. Egan D. The role of macrophages. 44. Evidence for the of hypertension. 36. Hendrix MG. 38. J Lipid Res 1983. et al. Refsum H. Colditz GA. AJ. Arterio- Fuster V. Libby P. Wang SP. Proc Natl Acad Sci activator binding to its endothelial cell membrane receptor. eds. Parsons A. Verhoef P. Miller E. Ross R. Philadelphia: Lippincott-Raven.84:7725-9. Stephens NG.

Nature 1997.152:353-8. Crouch E. Milla ME. Sewell KL. Sukhova GK. Regulation of matrix metal- Biol 1998. Johnson RJ. Philadelphia: Lippincott-Raven. Libby 77. Amberger A. Immune mechanisms matrix metalloproteinases and matrix degrading activity in vulnerable re- in atherosclerosis. McMillan DE. Jin S-LC. Kuhn C III. Ev. Adhesion of activated platelets phia: Lippincott-Raven. Arterioscler Thromb Vasc Biol 1998.385:729-33. bosis: etiologic agents or ubiquitous bystanders? Arterioscler Thromb Vasc 103. Vol. 1. Terkeltaub RA. Pyke SDM. disease: is there a link? Lancet 1997. Murry CE. cytokines. Circulation 1997. Seifert PS. Romen M. Vol. An immunohistochemical study of architectural remodeling and connective rophages in atherosclerotic lesions of LDL receptor-deficient mice. Aamir R. 1996:441-60. Meyer B. Chen HH. Soler P. Lukacs NW.96:396-9. In: Fuster V. J Clin Invest 1997. van de Loo JCW. and E-selectin in carotid atherosclerosis and T-cell cytokines may control the balance of functionally distinct macro- incident coronary heart disease cases: the Atherosclerosis Risk in Commu. Burke CM. Herpesviruses in atherosclerosis and throm.17:1193-202. Chronic pancreatitis. Ward PA. Cushman M. Mach F. Harris ED Jr. Am Rev Respir Dis 1989. Gimbrone MA Jr. Moss ML. Mach F. Feigen LP. Mondy JS. Brody AR. 96. 1993. J Biol Chem 1997. et al. Witztum JL. Hajjar DP. healthy men. Lebenthal E. Dewey CF Jr. loproteinase expression in human vascular smooth muscle cells by T lympho- 76. Nayak NC.272:19569-74. Peto R. Scheele GA. 115. Lab 2 knockout mice. Lancet 1997. Harlan JM. Resnick N. 84. Arteriosclerosis 1990. 1996:557-68. Basta G. plaques. sion molecules in pulmonary inflammation and injury. Pathogenesis and epidemiology of loproteinase that processes precursor tumour necrosis factor-a. et al.2:207-20. Leonard C. Hennekens CH. Heterogeneity of endothelial cells: specific 95.336:973-9. Black RA. 1. Poulter LW. 114. Cathcart MK. Eur J Clin Invest 1997. and adhe- molecules in mice. Am J Pathol 1997. What mediates progressive glomerulosclerosis? The glo- 87. Danesh J. PECAM-1 is required nism and novel roles for endothelial intercellular adhesion molecule 1 for transendothelial migration of leukocytes. Arterioscler Thromb Vasc Biol 1997. 1997. In: Go VLW. Arteriosclerosis 1989.17:2646-54. Libby P. eds. The role of rheology in atherosclerotic coronary P. 106. pathological stimuli in vivo. Pathogenesis of rheumatoid arthritis.187:329-39. 703. et al. Garlanda C. Boisvert WA. Pro- nity. Libby P. Lee RT.90:463-9. Circulation 1997. 394:200-3. Santiago R.101:353-63. Fabricant J.98:2193-5.81:320-7. J Clin tissue synthesis in pulmonary fibrosis. J Exp Med 1998. 111. Macrophage and smooth muscle cell prolifer. 119. Poulsen HE. the tissue factor gene. Deng X. Cloning of a disintegrin metal. 2015. Reber HA. 123. markers. Fabricant CG. factor. Langille BL.16:582-7. Immunology 1997. N Engl J Med 1990. in cultured human vascular cells and in vivo. Faber B.92:3893-7. 18:842-51. tion of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endo. Almus-Jacobs F. Virus-induced ath. Hynes RO. King TE Jr. Giachelli CM. and GPIba. Topol EJ. et al. 126. Rheumatoid arthritis: pathophysiology and implica- thelium in the ApoE-deficient mouse. 129. Genetic manipulation of vascular adhesion 118. and disease. Curtiss LK. Schönbeck U. Ishak KG. Topol EJ. ation in atherosclerotic lesions of WHHL and comparably hypercholester. Ross R. to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mecha- 79. duction of C-reactive protein and risk of coronary events in stable and un- 101. J Clin Invest 1994. Atherosclerosis and cor. Boldt J. Faul J. Vartio T. A macro and micro view of coronary vascular insult in idence for a role of osteopontin in macrophage infiltration in response to ischemic heart disease. Cybulsky MI. Berk BC. BHT-oxygen-induced fibrosis in mice.11:1199-207. et al. Arterioscler Thromb Vasc Biol Inflammation.385:733-6. et al. avb3 integrin. 104. LH. Breslow JL.81:448-54. Wagner DD. Haverkate F. cultured human vascular endothelial cells. autoimmu. . studies of vascular biology. Jonasson L. Sukhova GK. A metalloproteinase disintegrin mesenchymal associations of cells in human pulmonary fibrosis and in that releases tumor-necrosis factor-a from cells. In: Fuster V. Cohen AH. et al. Springer TA. Sobin to altered blood flow in vivo. Increased expression of 97. eds. Almeida M. Sarles H.27:568-74. 1996:511-38. Circulating adhesion 122. Proc Natl Acad Sci U S A 110. tions for therapy. Scheuer PJ. Circ Res 1997. pathobiology. Gim. 117. Biol 1997. Am J Pathol 1998. The pathogenesis of atherosclerosis. 108. Wick G. A leukocyte ho. eds. nities (ARIC) study. Haverkate F. Tormey VJ. Clain JE. Hajjar DP. Annu Rev Med 1989. oxidation by activated human monocytes. 93. Stroke 1985. 80. McDonald JA. 99. Bombeli T. gions of human atherosclerotic plaques.90:4591-5. Fuster V. Atherosclerosis. Mach F. 100. Lan- 86. Rosenfeld ME. Soluble vascular cell ad.99:737-44. FASEB J 1997. 107. Raines EW. Adv Immunol 1996. Libby P. Atkinson E.94:2493-503. Sharrett AR. Nakashima Y. Hepatic fibrosis caused by alcohol. Hollenbaugh D. Hansson GK. N Engl J Med 1995. Ross R. 94. Kozlosky CJ. J Clin Invest 1994.17:1954-61. Bernard JP. Magil AB. Dewey CF Jr. Circulation 1990. Bonnefoy J-Y.122:62-70. Schönbeck U. Platelet-derived growth factor B chain promoter contains a 1991. Gosling J. Folcik VA. eds. 1996:595. Raines EW. The hesion molecule-1 as a biohumoral correlate of atherosclerosis. mologue of the IL-8 receptor CXCR-2 mediates the accumulation of mac. Edwards CP. Pober JS. 92. No other uses without permission. oration of active interleukin 1b. tion by ligation of CD40: induction of collagenase.61:404-9 88. Shear stress induction of Philadelphia: Lippincott-Raven.322:1277-89. and vascular-associated lymphoid tissue. In: Fuster V. Minick CR. Tracy RP. Gallimore JR. Atherosclerosis and coronary artery disease. Vol.90:2126-46. and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 116. Schwartz BR.64:5-15. Nicholson AC. 1. Mach F. De Caterina R. Semin Liver Dis 1990. atherogenesis: current knowledge and unanswered questions. Bull World Health Organization 1977. cytes in health. Circulation 1994. Trentham DE. Mechanisms leading to myocardial infarction: insights from olemic fat-fed rabbits. Topol EJ. inflammation. of atherosclerosis in mice by inhibition of CD40 signalling. Holm J. Copyright © 1999 Massachusetts Medical Society.11:173-80.96:4219-25. Expression of stable angina: European Concerted Action on Thrombosis and Disabilities functional CD40 by vascular endothelial cells. J Clin Invest 1996. FASEB J 1997. 98. Miyashiro JK. ICAM-1. Weigl SA. molecules VCAM-1. Inflammatory mediators. Layer P. Exp Lung Res 1981. Ross R. 606. Libby P. 120.349:462-6. 10:66-74. Nature chronic pancreatitis. Lark MW. Atkinson W. Platelet-derived growth factor ligand and receptor expression in response 112. Collins R. Johnson C. Hansson GK. 90. and the risk of cardiovascular disease in apparently 1997. eds. Lin MC. Fuster V. 89. Reduction 78. Proc Natl Acad Sci U S A 1995. J Exp Med 1995. Atherosclerosis and coronary artery disease.94:885-91. activity in vascular smooth muscle and endothelial cells and promotes elab- onary artery disease. Invest 1989.140:1693- Invest 1998. in patients with angina pectoris. 109. For personal use only. Lab Invest brone MA Jr. J Clin Invest 1997. Herren B. Ross 125.55:521-40. Ballantyne CM. et al.40:453-68. Phillips DM. Pyke SD. and atherosclerosis. Dean RH.350:430-6. Witschi H. Philadel. Ross R.17:1859-67. Kienast J. Galis ZS. Upregula. Loppnow H. Rauch CT. Thompson SG. Libby P. Am J Pathol 1986. Atherosclerosis and coronary artery disease. Shear severe arterial lesions is inhibited by oral administration of a glycoprotein stress selectively upregulates intercellular adhesion molecule-1 expression in IIb/IIIa antagonist.18:339-48. T lymphocytes from human atherosclerotic plaques recognize oxidized low Hemostatic factors and the risk of myocardial infarction or sudden death density lipoprotein. Stemme S. Stemme S. N Engl J Med 1997. Ross R. 83. Bonthron DT. Thompson SG. nomenclature. Schönbeck U. Lombardi D. Chensue SW. Atkinson WJ. The unstable atheroma. Collins T. and classifica- 85. and tissue 75. Impaired monocyte migration merular endothelium comes of age. Expression of a disintegrin-like protein 62:257-304. Hansson GK. Dilmec A. Schönbeck U. stromelysin. DiMagno EP. 121. Mischel-Petty N.182:33-40.10:680-7. Hwang S-J. Vol. 102. The role of the lymphocyte. 127. Epithelial- 91. Hansson GK. Johnson RJ. 105. Ridker PM. Badimon JJ. Activation erosclerosis: herpesvirus infection alters aortic cholesterol metabolism and of monocyte/macrophage functions related to acute atheroma complica- accumulation. Boring L. et al. Sukhova GK. Dejana E. Flad H-D. et al. 2nd ed. Geary RL. Arterioscler Thromb Vasc R. The morphology of cirrhosis: definition. Davies MJ. Bonnefoy J-Y. In: Fuster V.82:Suppl II:II-38–II-46. 113.341:283-6. Libby P. Lazzerini G.9:567-78. DiMagno EP.332:635-41. cis-acting fluid shear-stress-responsive element. (ICAM-1). Topol EJ. Muller WA. Lindner V. Angina Pectoris Study Group. cet 1993. Monocytes and focal glomerulosclerosis. phage populations. Ligation of CD40 activates interleukin 1b-converting enzyme (caspase-1) artery disease. adelphia: Lippincott-Raven. Gardner JD. Ross R. Traffic signals on endothelium for leuko. Anthony PP. Press.151:1179-81.org on September 2. Resnick N. Plump AS. Nagel T. J Exp Med 1993. Thrombosis triggered by 81.178:449-60. Maher JJ. All rights reserved. aspirin. Stampfer MJ. Pepys MB. Vol ume 340 Numb e r 2 · 125 The New England Journal of Medicine Downloaded from nejm.100:2552-61. MEC H A NIS MS OF D IS EASE 74. Phil. Chronic infections and coronary heart cytes: a role for CD40 signaling in plaque rupture? Circ Res 1997. Gotlieb AI. Involvement of the immune system in human 82. Haschek WM. Blood flow and the localization of atherosclerotic tion. Nature 1998. Ross R. Arterioscler pancreas: biology. 1993:665-706. Cytokine modulation of LDL 128. Wiklund O. 124. 1. New York: Raven Thromb Vasc Biol 1997. Basset F.

18:432- protein in ‘active’ coronary artery disease. et al. Elevation of C-reactive blood monocytes in vitro.nejm. No other uses without permission. Stenmark KR. Tararak EM.14:133-40. Smooth muscle lineage diversity in the 612-9. Frid MG. Genes and physiology: molecular physiology in genetical- ent response of cultured aortic smooth muscle to serum mitogens. subscribers can use their passwords to log on for electronic access to the entire Journal from any computer that is connected to the Internet. a full-text search capacity. Alexander RW. analyse gene expression patterns in human cancer. 149.89:379-83. Cdk2 inhibitors. subscribers should go to the Journal’s home page (www. Dempsey EC.96:4204-10.6:639-45. Wallentin L. J Clin Invest 1996. zation.18:631-40. Cell 1992. Levenson J. Darley E. Simon A. After this one-time registration. 135. Chien KR. 2015. 40. Cell- and silent atherosclerosis in subjects with cardiovascular risk factors. Shalon D. Nakashima Y.15:1263-8. Plump AS.14:457- hibit unique phenotypes and distinct growth capabilities. Dansky HM. DeRisi J. Ross R. Brown PO. Bobryshev YV. Lukacs NW. Babaev VR. Miyata M. Dev Biol 1996. 134. 146. Kunkel SL. 60. Gariepy J. Raines EW.71:343-53. Tripathi J.150:1687-99. Majesky MW. Severe hypercholesterolemia 136. de Villiers WJS. Genome Res 1996. and free software for downloading articles so they can be printed in a format that is virtually identical to that of the typeset pages. Breslow JL. Plump AS. Qiao J-H. chick embryo: two types of aortic smooth muscle cell differ in growth and 142. 2436-9. 144. Gordon 139. Smith SJ. Fibrinogen 141. Ross R. Copyright © 1999 Massachusetts Medical Society. Fibrillar deficient mice develop lesions of all phases of atherosclerosis throughout collagen inhibits arterial smooth muscle proliferation through regulation of the arterial tree. Stenina OV. The extracellular matrix as a cell cycle stimulating factor in atherosclerosis: studies of osteopetrotic mice. Arterioscler Thromb Vasc Biol 1998. Penland L. Ross R. Features include a library of all issues since January 1993. Cell 1996.98: J Pathol 1997. Strieter RM. 132. Nat Genet 1996. Circ Res 1998. Use of a cDNA microarray to cells isolated from discrete compartments of the mature vascular media ex. important component of the inflammatory lesion. To use this Web site.16:40-4. 81:940-52. Roberts JM. J Cell ly engineered animals. Arterioscler Thromb Vasc 548-56.178:430-45. Extracellular matrix increased fibrinogen and C-reactive protein levels in unstable coronary modulates macrophage functions characteristic to atheroma: collagen type artery disease. Biol 1998. . ApoE- 137. Koyama H. 147. I enhances acquisition of resident macrophage traits by human peripheral 131. Giral P. Bornfeldt KE. Nat Biotechnol 1998. and atherosclerosis in apolipoprotein E-deficient mice created by homolo- Heterogeneity of smooth muscle cells in atheromatous plaque of human gous recombination in ES cells. Wesley RB II. Topouzis S. Raines EW.97:901-9. Marcantonio EE. Mishra NK. A DNA microarray system for ana- receptor-mediated transcriptional responses to transforming growth factor. 145. a personal archive for saving articles and search results of interest. Role of macrophage colony- 138. Lindahl B. Meng X. Circulation 1997. Ramsay G. 19 9 9 The New England Journal of Medicine Downloaded from nejm. Am J Pathol 1990. Mercurius KO. Chamley-Campbell JH. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne 130.org) and register by entering their names and subscriber numbers as they appear on their mailing labels. J Leukoc Biol 1997.82: stimulating factor (op) and apolipoprotein E. et al. Godin D. Macrophage phenotype in mice deficient in both macrophage-colony- growth by inhibition of fibronectin matrix assembly. Biol 1981. Circ Res 1997. Phenotype-depend. J Clin Invest 1996. Smooth muscle 143. Assoian RK. Morla AO. lyzing complex DNA samples using two-color fluorescent probe hybridi- b. Galis ZS. Smith JD.65:168-72. Prognostic influence of 140. FULL TEXT OF ALL JOURNAL ARTICLES ON THE WORLD WIDE WEB Access to the complete text of the Journal on the Internet is free to all subscribers. Hogaboam CM. Inhibition of vascular smooth muscle cell S. Berk BC. 126 · Ja nu ar y 14 . All rights reserved.136:1031-42. et al.62: 133. Razavian M. Campbell GR. aorta. 148. Arterioscler Thromb 1994. Gabbiani G. Smith RE. Aldashev AA. to-cell and cell-to-matrix interactions mediate chemokine expression: an Arterioscler Thromb Vasc Biol 1995. Smith JD.org on September 2. For personal use only. Am control element in atherosclerosis and restenosis. Weintraub WS. Toss H.87:1069-78. DNA chips: state-of-the-art. Hayek T. Brown PO. Siegbahn A. Am J Cardiol 1990.