Page 968 - Clinical Immunology_ Principles and Practice ( PDFDrive )

69

Inflammation and Atherothrombosis

Giovanna Liuzzo, Daniela Pedicino, Davide Flego, Filippo Crea

2
The spectrum of the clinical syndromes caused by coronary (Table 69.1). The atherogenic process develops over the course
atherosclerosis ranges from asymptomatic disease and stable of decades, beginning in the early teenage years. It is the same
angina (SA) to acute coronary syndromes (ACSs). The latter worldwide, regardless of gender and race, and proceeds at a
include unstable angina (UA) and acute myocardial infarction faster speed in patients with risk factors such as hypertension,
(MI), which is further classified according to electrocardiographic tobacco smoking, diabetes mellitus, obesity, and genetic predis-
changes as non-ST elevation myocardial infarction (NSTEMI) position. In the early phase, this process is triggered by suben-
and ST elevation myocardial infarction (STEMI), and sudden dothelial retention of cholesterol-containing plasma lipoproteins
cardiac death. and by flow-mediated inflammatory changes in endothelial cells
Although the early outcome of ACS has considerably improved (Table 69.2). At this stage of the disease, endothelial cells show
in the past decade, cardiovascular diseases still represent the an altered response to vasodilator and vasoconstrictor stimuli,
main cause of morbidity and mortality worldwide, mainly because due in part to nitric oxide reduction as well as to increased
chronic-smoldering ACS eventually leads to heart failure and expression of endothelin. Moreover, the cells express increased
sudden cardiac death. The gravity of the syndrome calls for a levels of adhesion molecules such as intercellular adhesion
reappraisal of the mechanisms responsible for coronary instability molecule (ICAM) and vascular cell adhesion molecule (VCAM)
and for innovative preventive and therapeutic strategies. and produce higher levels of chemotactic molecules such as
The life-threatening complications of coronary artery disease interleukin (IL)-8 and monocyte chemotactic protein (MCP),
arise as nonlinear events in an otherwise slowly progressive with the consequent increase in leukocytes’ recruitment. These
process. This nonlinearity has been attributed to a combination mechanisms act together to induce endothelial dysfunction
of factors, of which plaque rupture or erosion and superimposed and a chronic self-maintaining inflammatory state. Plaque forma-
thrombosis are considered to be the most important. Although tion is preceded by a fatty streak, an accumulation of lipid,
the pathways leading to plaque rupture or erosion are incompletely macrophages/foam cells, and T cells beneath the endothelium.
understood, our understanding of the importance of inflammation Fatty streaks may disappear or progress to atherosclerotic plaques,
in the process has considerably increased. Atherosclerosis is a asymmetrical focal thickenings of the intima with a core region
chronic inflammatory disease by itself, but an outburst of the of foam cells and extracellular lipids surrounded by a cap of
inflammatory process within the atherosclerotic plaque of coro- smooth-muscle cells and collagen. Atherosclerotic lesions contain
nary arteries can lead to plaque rupture with thrombosis, resulting monocyte-derived macrophages and T cells interspersed with
in myocardial ischemia and necrosis. The latter is an additional lipids and debris from dead cells; the lesions are embedded in
source for local and systemic inflammation. Furthermore, patients an extracellular matrix composed of collagen fibers and other
with ACS frequently undergo percutaneous coronary intervention constituents produced primarily by vascular smooth muscle cells.
(PCI), which may cause iatrogenic myocardial injury, a further T cells, macrophages, and mast cells infiltrate the lesion; they
source of inflammation. Moreover, plaque instability promotes are particularly abundant in the shoulder region of the atheroma,
hyperreactivity to the inflammatory stimulus of myocardial producing proinflammatory cytokines, costimulatory factors for
necrosis, which in turn accelerates plaque instability: Inflammation immune activation, eicosanoids, and reactive oxygen and nitrogen
begets inflammation (Fig. 69.1). Thus it is not surprising that a species. On the other hand, many immune cells beneath the
plethora of previous studies have consistently shown a marked plaque show antiinflammatory features: Macrophages internalize
elevation of circulating levels of high-sensitivity C-reactive protein cholesterol through their scavenger receptors and produce
(hs-CRP) or of other soluble markers of inflammation at the antiinflammatory cytokines, and T cells of the regulatory phe-
time of hospital admission. Interestingly, the intensity of this notype produce antiinflammatory and immunosuppressive
inflammatory surge predicts short- and long-term outcome. cytokines. The perturbation of this delicate balance between
Overall, these observations suggest that specific antiinflammatory pro- and antiinflammatory signals is involved both in the
treatment might improve the outcome of ACS. 1 nonresolving, chronic inflammation linked to disease progression
and in the eventual breakdown of endothelial continuity, with
ATHEROSCLEROSIS: A CHRONIC thrombus formation and plaque instability (Fig. 69.1). Fibrous
INFLAMMATORY DISEASE plaques appear in a later stage of the disease, with the chronic
accumulation of collagen and calcification. Erosion of the surfaces
Atherosclerosis is a chronic nonresolving inflammatory of some plaques and rupture of a plaque’s calcific nodule into
3
process that typically occurs at sites of blood flow disturbance the artery lumen may trigger thrombosis. Overall, mechanisms
935