Page 2384 - Hematology_ Basic Principles and Practice ( PDFDrive )

2126 Part XII Hemostasis and Thrombosis

trafficking into tissues dramatically protect mice from experimental functions. Unlike the LDL receptor, which is downregulated in the
atherosclerosis. The earliest and most prominent cell types in human setting of excess ligand, SR expression is increased in the presence of
and mouse atherosclerotic lesions are monocytes and macrophages. oxLDL, in part via internalization of oxidized fatty acids that serve
Initial monocyte entry into the arterial intima is in response to poorly as ligands for peroxisome proliferator-activated receptor (PPAR)
understood cues related to endothelial cell dysfunction. Environmen- family transcription factors, particularly PPARγ, which is a major
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tal and genetic influences, such as hypertension, angiotensin II pro- positive regulator of CD36 expression. Thus over many months and
duction, cigarette smoke, diabetes, metabolic syndrome, and chronic years, the continued entry and oxidation of LDL in the intima
periodontal infection may contribute to generalized endothelial coupled with upregulated expression of SRs leads to massive intracel-
dysfunction, but it is likely that the modified lipoproteins, particularly lular accumulation of cholesterol and formation of lipid-laden cells
oxidized LDL (oxLDL), trapped in the vessel wall play a major initiat- known as foam cells.
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ing role. oxLDL activates an endothelial cell receptor known as OxLDL-SR interactions initiate a cascade of events in macro-
LOX1 to induce expression of monocyte adhesion molecules and this phages, including internalization of the bound oxLDL, activation of
response is dramatically amplified in the presence of angiotensin II. proinflammatory pathways, and activation of transcriptional path-
Other components of the “dysfunctional” endothelial cell phenotype ways. The CD36–oxLDL interaction, in addition to promoting ROS
include von Willebrand factor release from Weibel-Palade bodies and formation, also decreases expression of endogenous antioxidant
altered homeostasis of nitric oxide and eicosanoid pathways. pathways and inhibits macrophage migration. These events result in
Monocyte recruitment to the vessel wall (see Fig. 144.4) begins a feed-forward loop that increases leukocyte recruitment into the
with their capture and rolling along the activated endothelium medi- vessel wall, inhibits macrophage migration out of the vessel wall, and
ated by specific interaction of selectin family adhesion molecules increases oxLDL formation. The net effect is formation and accumu-
(L-selectin on circulating monocytes and P-selectin on activated lation of lipid-laden foam cells and proinflammatory immune cells,
endothelial cells) with their counter receptors, including PSGL1. which together form plaque (see Fig. 144.4). In mouse models,
Subsequent signals induced by endothelial-derived chemokines, genetic deletion of SRs, especially CD36, provides substantial protec-
including chemokine (C-C motif) ligand 5 (CCL5)/ regulated upon tion from plaque formation.
activation, normal T-cell expressed, and secreted (RANTES), CCL2/ Although abundant data from animal models and correlative
monocyte chemotactic protein 1 (MCP1), interleukin (IL)-8, and human studies support the oxidative stress hypothesis, considerable
CXC-chemokine ligand 1 (CXCL1), lead to further recruitment of controversy remains because large- and medium-sized interventional
monocytes and facilitate firm adhesion of the rolling monocytes to trials of antioxidant therapy in humans have generally failed to
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the vessel wall. The latter is mediated by interaction of intercellular prevent the complications of atherosclerosis. These trials, however,
adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule are difficult to interpret because of lack of convincing evidence that
(VCAM) on the activated endothelial surface with specific integrin the tested “antioxidant” therapies actually targeted the relevant vas-
family counter receptors on monocytes; β2 integrins for ICAM1 and cular or circulating oxidant pathways. These oxidant systems include
α4β1 for VCAM. By diapedesis, the adherent monocytes then tra- NADPH oxidase, xanthine oxidase, myeloperoxidase (MPO), and
verse the disrupted endothelial junctions and enter the intima. Recent uncoupled nitric oxide synthase. MPO is of particular interest because
studies have suggested that a particular subset of circulating “inflam- it generates a highly specific oxidized phospholipid ligand for CD36
matory” monocytes, defined by high expression of the Ly6C antigen from LDL, and because circulating MPO levels associate with risk
(in mice) or CD14 (in humans), are the predominant source of for atherosclerosis and with risk for acute cardiovascular events.
entering cells. The normal vasculature also contains a small number Another potential problem with the antioxidant clinical trials is
of resident macrophages, as well as “patrolling” monocytes. The latter that the choice of antioxidants may have been flawed. The most used
+
hi
are distinct from the Ly6C /CD14 cells and exhibit a less inflam- vitamin E formulations contain mainly α-tocopherol. Recent studies
matory phenotype. showed that tocopherols, in addition to having activity as antioxi-
The ultimate fate of monocytes within the intima is probably dants, have important cell-signaling functions mediated by specific
determined in part by lineage-commitment programs carried by the cellular receptors. Therapy with formulations containing primarily
entering monocytes and in part by local environmental cues. Most, α-tocopherol may downregulate endogenous γ-tocopherol levels,
however, seem to polarize toward the so-called M1 inflammatory leading to imbalance in natural tocopherol signaling pathways. Fur-
macrophage phenotype. Investigators have, however, detected dendritic thermore, tocopherols are lipid-based structures that are themselves
cell-like phenotypes (expressing CD11c), M2-like cells that express subject to oxidation, producing lipid peroxides that can actually
arginase and endothelial nitric oxide synthase (eNOS) and are highly promote further oxidative stress. Nevertheless, it is possible that
phagocytic and antiinflammatory, and proangiogenic VEGF- pathways of cholesterol uptake unrelated to LDL oxidation and SR
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expressing macrophage phenotypes within plaque. In addition to expression, such as by micro- and macro-pinocytosis of “native” LDL
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monocytes, lymphocytes, particularly T cells, also enter the intima, or aggregated LDL, may play a significant role in foam cell
where they contribute to plaque formation by secreting cytokines and formation.
other mediators. Of these infiltrating lymphocytes, interferon-γ–pro- Important unresolved issues in the pathogenesis of early athero-
ducing T-helper (Th)1 cells and IL-17–producing Th17 cells have sclerotic lesions include understanding why macrophages do not exit
been shown to promote atherosclerosis, whereas the regulatory T cell the vessel wall and travel to regional nodes after ingesting modified
subset is protective. LDL, as they would after ingesting exogenous pathogens, and why
Reactive oxygen species (ROS) are generated by the inflammatory cholesterol efflux cannot keep up with LDL uptake to maintain a
milieu within the atherogenic vessel wall and modify the trapped homeostatic state. oxLDL inhibition of macrophage migration (see
LDL by oxidizing both protein and lipid moieties (see Fig. 144.4), Fig. 144.4) may explain the former, suggesting that blocking oxLDL-
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creating what are called collectively oxLDL. Modified LDL lose mediated signaling pathways might have therapeutic potential by
their affinity for the LDL receptor but gain affinity for a genetically facilitating macrophage exit from developing plaque. Indeed, in
unrelated family of receptors known as scavenger receptors (SRs), experimental animals, transplantation of atherosclerotic aortae from
including SRA1 and CD36, which are present at high levels on the hypercholesterolemic animals into normal recipients induces migra-
macrophage surface. These receptors are part of the innate immune tion of lipid-laden macrophages out of the vessel wall and plaque
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system, and their recognition of specific structures within oxLDL regression. The second issue might relate to differential gene regula-
presumably relates to their mimicry of similar structures found on tion of SRs compared with cholesterol efflux transporters, and/or to
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pathogenic organisms. CD36, for example, also recognizes myco- intracellular cholesterol trafficking that might make it inaccessible to
bacterial and Staphylococcus cell wall components, certain fungal efflux transporters. In addition, as noted previously, HDL particles,
structures, and falciparum malaria-infected erythrocytes. Toll-like similar to LDL, are sensitive to oxidative modification and such
receptor (TLR) family members, including TLR2, TLR4, and TLR6, oxidation may produce dysfunctional HDL that does not function
can also recognize modified LDL and can partner with CD36 in these optimally in RCT and thus loses its atheroprotective activity. 6