Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_35_библиотеки_им_акад_М_И_Перельмана
.pdf
Vascular Endothelial Dysfunction
https://t.me/medicina_free
andInflammatory States
SamuelChijiokeOnyewu, AliceTolbertCoombs,
andFatoumataKromah
22
Overview ofEndothelial Cell andFunction
Embryologically, EC arises from the mesoderm which is
located on the ventral oor of the dorsal aorta within the
aorto-gonado-mesonephros region [1, 2]. Mesenchymal
cells, which arise from the mesoderm, differentiate into
hemangioblasts and angioblasts. Hemangioblasts further differentiate into EC and other hematopoietic cell lines [1, 2]
(Fig.22.1).
Endothelial cells (ECs) form the endothelium as a single
layer of cells lining blood vessels and lymphatics (Fig.22.2).
The endothelium forms a semi-permeable membrane barrier
that limits uid, solute, and large molecule access to the
interstitium of various organs [3].
Description ofEndothelial Cell andFunction
Morphologically, the EC surface in an adult is composed of
approximately 20–60 trillion cells and covers 3–7m2 surface
area. EC are generally at; however, the thickness of ECs
is determined by the dynamic structure lying on its luminal surface [4]. The thickness of EC varies from less than
0.1 to 1 micrometer in capillaries, veins, and aorta, respectively [5, 6]. Depending on which organ it is located, ECs
can be fenestrated or un-fenestrated [5]. ECs are covered by
a “thick” endothelial glycocalyx layer which prevents capillary leakage and activation by the coagulation system. The
glycocalyx covering is vital as it also acts as a barrier to regulate uid and molecule movement and balance [3]. When
ECs are fenestrated, they have pores and openings between
cells that promote increased permeability and allow large
molecules to pass through capillaries. Fenestrated ECs are
present in the capillaries of small intestine, endocrine glands,
S. C. Onyewu · A. T. Coombs · F. Kromah (*)
Virginia Commonwealth University Health System,
Department of Anesthesiology, Richmond, VA, USA
e-mail: Alice.coomb@vcuhealth.org;
Fatoumata.kromah@vcuhealth.org
kidney (glomeruli and renal tubules), and the choroid plexus.
In contrast, ECs that are un-fenestrated are found in arteries,
veins, and capillaries of the brain, skin, heart, and lung. The
EC surface is cohesive, adhesive, and luminal thus allowing
EC to play an integral role in the binding of transport and
regulatory proteins circulating with blood cells [7]. ECs are
involved in the expression of inammatory and growth factors such as endothelial cell selectin (E-selectin) and vascular endothelial growth factor (VEGF). E-Selectin plays a key
role in leukocytes adhesion. VEGF is important for the generation of ECs and maintenance of endothelial fenestrae [7].
ECs synthesize other metabolically active substances which
are summarized in Table22.1 [8–10].
ECs perform other metabolic functions and possess contractile proteins – actin, myosin, and tropomyosin. These
contractile proteins generate the shape and elasticity of ECs
and are integral in the vasoactive function of blood vessels
[7]. One of the most important functions in the vasomotor
balance is that ECs produce nitric oxide (NO) [4, 11]. NO is
a principal substrate required for the maintenance of vascular
tone and reactivity of blood vessels. NO inhibits the action
of angiotensin II (AG II) and endothelin 1 (ET 1). ET 1 is a
cellular substance produced in ECs and is a potent vasoconstrictor. In addition to inhibiting platelet and white blood cell
activation, NO also maintains vascular smooth muscle cells
in a non-proliferative state [12] (Fig.22.3).
Denition ofEndothelial Dysfunction
Endothelial cell structure, property, and function are quite
diverse resulting in a heterogeneous endothelial environment
in which organ systems vary greatly in their capacity to accomplish different functions [3]. Of note this heterogeneity in regulation of vascular tone, molecule transportation, coagulation,
and hormone metabolism can be observed between organ systems and within endothelial cells of the same organ. Therefore,
endothelial dysfunction is dened as an aberration in the physical integrity and/or functional processes of ECs. EC dysfunction
© Springer Nature Switzerland AG 2021
C. S. Scher et al. (eds.), Essentials of Blood Product Management in Anesthesia Practice,
https://doi.org/10.1007/978-3-030-59295-0_22
217
218
https://t.me/medicina_free
Fig. 22.1 Schematic diagram
of endothelial cell
embryogenesis. (Modied
from image from Dr. Samuel
Onyewu)
S. C. Onyewu et al.
Fig. 22.2 Endothelial cell lining a vessel lumen. (Modied from Stijn
AI.Ghesquiere. University of Maastricht. Nov 2005)
often results in alterations in vasoreactivity, increased propensity to thrombus and plaque formation, and leukocyte adhesion along with inammatory changes [8–10]. EC dysfunction
occurs either as a principal determinant of the pathophysiologic
mechanism of a disease or as a vestige of collateral damage [1,
5]. EC activation and/or dysfunction may arise from otherwise
adaptive responses which may be excessive, sustained, spatial,
or temporally misplaced [13] (Fig. 22.4). ECs may be in an
activated state yet not dysfunctional [8].
In summary, EC dysfunction affects multiple organ systems and is involved in many disease processes [1, 5]. Hence,
ECs will serve as a reliable conduit in the understanding and
possible management of different pathologic conditions. In
the subsequent parts of this chapter, we will be discussing
the various disease processes associated with EC dysfunction and its anesthetic implications and management.
22 Vascular Endothelial Dysfunction andInammatory States
https://t.me/medicina_free
Table 22.1 Endothelial cell characteristics and physiologic functions
Maintenance of cell membrane integrity
Fibronectin
Laminin
Collagen
Proteoglycans
Proteases
Lipid metabolism
Lipoprotein lipase receptor
Anticoagulant molecules elaboration and regulator
Heparin
Prostacyclin
Thrombomodulin
Plasminogen activator
Procoagulant molecules elaboration
Von Willebrand factor
Plasminogen activator inhibitor
Thromboxane A2
Factor V
Thromboplastin
Platelet activator factor
Vasoconstrictor factors
Angiotensin-converting enzyme
Thromboxane A2
Leukotrienes
Endothelin
Vasodilator factors
Nitric oxide
Prostacyclin
Immunity and inammatory regulators
Interleukins 1, 6, 8
Major histocompatibility complex II
Adhesion molecules: E-selectin, P-selectin
Regulation of growth factors
Insulin growth factor
Transforming growth factor
Colony stimulating factor
Table created by Dr. Samuel Onyewu
219
Pathophysiology ofEndothelial Dysfunction
Endothelial dysfunction is known to be associated with multiple pathologic conditions [14]. It is directly implicated in
the pathogenesis and clinical course of cardiovascular conditions, diabetes mellitus, renal dysfunction, Alzheimer’s
disease, erectile dysfunction, and osteoporosis [15–23].
Endothelial dysfunction may result from various etiologies
such as direct injury to the endothelium, infections, reactive
or immunologic causes, aging, and disease states.
Etiologies ofEndothelial Dysfunction
Iatrogenic
Direct injury alters the morphological architecture of the vascular ECs increasing the likelihood of thrombosis and concentric intimal thickening. Direct injury may occur following
iatrogenic procedures performed to correct an underlying
pathology. These include angioplasty and stent placement to
improve the patency of stenosed vessels [24] (Fig.22.5).
Infectious
Viruses and bacteria have also been implicated to EC activation [25]. Other inducers of the endothelium include lipid
products, complement components, advanced glycosylation
end products, hypoxia, laminar blood ow, and growth factors. See Fig. 22.4. Activated ECs secrete cytokines, chemokines, growth factors, procoagulants, and anticoagulant
molecules.
Fig. 22.3 Schematic diagram
showing the functions of
endothelial nitric oxide
synthetase (eNOS) function,
its inducers and inhibitors
220
https://t.me/medicina_free
Fig. 22.4 Schematic
representation of factors
associated with endothelial
cell activation and
dysfunction. (Modied from
image from Dr. Samuel
Onyewu)
Fig. 22.5 Schematic diagram
of endothelial cell injury.
(Modied from: Sharfuddin
A, Molitoris BA.Endothelial
cell injury. In: Vincent JL,
Hall JB, editors; 2012)
S. C. Onyewu et al.
Reactive Substrates
Nicotine from chronic cigarette smoking is a burgeoning
etiology for cardiovascular diseases, which accounts for a
third of the deaths in cigarette smokers [26–29]. Nicotine
causes morphological alterations of ECs and vascular
smooth muscles inducing functional changes associated with
the pathogenesis of cardiovascular diseases [30–33]. A proposed mechanism of action of nicotine-associated endothelial dysfunction is an imbalance in vascular tone, increased
expression of ET-1, inducible NOS, and reduced expression
of eNOS [34, 35] (Fig.22.6).
Nicotine reduces the production and bioavailability of
nitric oxide (NO), by decreasing the expression of endothelial nitric oxide synthetase (eNOS). Nicotine also causes
alteration in the functional integrity of the endothelium
resulting in vasospasm, stimulation of leukocytes and platelet adhesion, and thus thrombus formation [36].
Aging
Aging is an integral factor in the development of atherosclerosis, vasculopathies, and cardiovascular disease. Age-
22 Vascular Endothelial Dysfunction andInammatory States
https://t.me/medicina_free
Fig. 22.6 Schematic diagram
of nicotine-related endothelial
dysfunction. (Modied from
image from Dr. Samuel
Onyewu)
Fig. 22.7 Schematic diagram
showing endothelial
dysfunction related to aging.
(Modied from Rodella LF,
Rezzani R.Endothelial and
vascular smooth cell
dysfunction: a comprehensive
appraisal; 2012)
221
related dysfunction of both endothelial and vascular smooth
muscle cells has been attributed to vasospasm, thrombosis,
cellular growth, oxidative stress, and inammation [20].
Some report that aging deteriorates the balance between
vasodilator and vasoconstrictor substances produced by the
endothelium [20, 37–40]. Senescent ECs have attenuated
angiogenic and regenerative capacity, hence limited ability to form new vascular structures [20]. Furthermore, EC
senescence may alter the physiologic functions of the endothelium by altering secretion of cytokines, growth factors,
and proteases in the vascular wall [41] (Fig.22.7).
Clinical Presentation ofEndothelial
Dysfunction andInammatory States
Atherosclerosis
Atherosclerosis is a chronic inammatory response triggered
in attempt to mitigate vascular endothelial cell dysfunction, lipid accumulation and oxidation, and thrombosis [42].
Endothelial cell dysfunction along with formation of a fatty
streak in which proliferation of intima vascular smooth muscle cells and extracellular matrix (ECM) deposition occurs
creates an atherosclerotic atheroma (Fig.22.8). The atheroma
is an intima layer lesion that protrude into vascular lumen.
Atherosclerosis is responsible for hypertension, cardiovascular, cerebrovascular, coronary artery, and peripheral
222
https://t.me/medicina_free
Fig. 22.8 Schematic diagram
showing a well-developed
atheroma constricting blood
vessel lumen. (Modied from
Glagov etal. [43])
S. C. Onyewu et al.
Table 22.2 Risk factors for atherosclerosis
Modiable Non-modiable
Hypertension Age
Diabetes mellitus Gender
Hyperlipidemia Family history
Cigarette smoking Genetics
C-reactive protein
Table created by Dr. Samuel Onyewu
vascular diseases. In combination these diseases have been
attributed to half of all deaths in the western world [16, 24].
The prevalence and severity of atherosclerosis are related to
several risk factors which can be divided into modiable and
non-modiable risk factors (Table22.2).
Risk factors have a multiplicative effect. The presence of
two risk factors result in a fourfold likelihood of having an
ischemic heart event. Meanwhile, the presence of three risk
factors result in a seven fold likelihood of having an ischemic
heart event [24].
Non-modiable risk factors – Age, gender, and genetics. Age greater than 45years have been shown to have a
higher likelihood of the presence of atherosclerotic lesions
[42]. Men are more likely than pre-menopausal women to
have atherosclerotic disease. This protective effect has been
attributed to estrogen. However, the protective effect has
not been shown in post-menopausal women on hormonal
therapy [44]. Genetics play a signicant role and has been
implicated in atherosclerosis and ischemic heart disease
(IHD). A few genetic disorders like familial hypercholesterolemia have a higher propensity of causing atherosclerosis.
However, the association is likely multifactorial in nature
and related to inherited genetic polymorphism and other
established risk factors of familial clustering such as hypertension or diabetes [45].
Modiable risk factors – Hyperlipidemia, hypertension,
cigarette smoking, and diabetes (Table22.2). Hyperlipidemia
mostly hypercholesterolemia is responsible for the formation
of atherosclerosis. Low-density lipoprotein (LDL) transports
cholesterol to peripheral vascular tissues, while high-density
lipoprotein (HDL) transports cholesterol from tissues into the
liver where the cholesterol is excreted in the bile. High intake
of cholesterol and saturated fat from egg yolks, animal fat, and
butter increase plasma level of cholesterol. Trans- unsaturated
fat used in confectionery and margarine adversely affect cholesterol prole. On the other hand, omega-3 fatty acid, found
in sh oil, exercise, and moderate alcohol intake improve
cholesterol prole. Hypertension both systolic and diastolic
levels are important in atherosclerosis. Hypertension on its
own increases the risk for IHD by 60% [16, 24]. Prolonged
cigarette smoking of a pack or more a day doubles the rate
of death from IHD, while smoking cessation signicantly
reduces the risk [24]. The nicotine released from cigarette
smoking increases release of platelet-derived growth factors,
ICAM-1 and VCAM-1 expression inducing EC dysfunction
and atherosclerotic lesion formation [46, 47]. Diabetes mellitus induces hypercholesterolemia and markedly increases the
risk of atherosclerosis. Diabetics compared to non-diabetics
have a hundred-fold increase in peripheral vessel disease,
and two fold increase in myocardial infarction along with
increased risk of cerebral vascular accidents.
Twenty percent of cardiovascular events happen in the
absence of hyperlipidemia, hypertension, cigarette smoking,
and diabetes [42]. Therefore, inammation, hyperhomocysteinemia, metabolic syndrome, dyslipidemia, lipoprotein a,
and hemostatic factors increase the risk for atherosclerosis.
Inammation is present in all stages of atherogenesis, and it
is closely linked to atherosclerotic plaque formation and rupture. Multiple inammatory markers have been associated
with IHD.C-reactive protein (CRP) has emerged as the most
sensitive inammatory markers [48]. CRP is an acute phase
reactant produced in the liver that opsonizes bacteria and activates complements. When CRP is secreted from cells within
the atherosclerotic intima, CRP activates local endothelial
cells inducing a prothrombotic state and increases adhesiveness of EC to leukocytes. CRP is an independent predictor
of myocardial infarction, cerebral vascular accident, periph-
22 Vascular Endothelial Dysfunction andInammatory States
https://t.me/medicina_free
223
eral arterial disease, and sudden cardiac death among healthy
individuals [42]. Smoking cessation, exercise, weight loss
and statins reduce CRP levels, although reduction in CRP
level has not been proven to reduce cardiovascular risk [24].
Hyperhomocysteinemia is associated with coronary artery
disease, peripheral vascular disease, stroke, and venous
thrombosis [49]. Elevated homocysteine can be found in low
intake of folate and vitamin B12; however, vitamin supplementation has not shown to preclude cardiovascular disease.
Metabolic syndrome is characterized by conditions associated with insulin resistance [50]. The syndrome is also associated with hypertension, dyslipidemia, and central obesity.
Dyslipidemia leads to endothelial cell dysfunction secondary
to increased oxidative stress and a systemic pro-inammatory state that leads to vascular thrombosis. Lipoprotein (a)
is an altered form of LDL. Lipoprotein (a) contains apolipoprotein B-100 portion of LDL linked to apolipoprotein
A. Lipoprotein (a) levels are associated with an elevated
risk of coronary and cerebrovascular disease, independent
of total cholesterol and LDL levels [44]. Plasminogen activator inhibitor 1 and thrombin both have procoagulant and
pro-inammatory effect. Plasminogen activator inhibitor 1,
thrombin, and platelet-derived growth factors are major predictors of vascular pathology in atherosclerosis [42].
The pathogenesis of atherosclerosis is based on a composite of two theories known as the intimal cell proliferation
or repetitive formation and organization of thrombi [51, 52],
which is summarized as the response to injury hypothesis
[53]. According to the model, atherosclerosis is produced
by the following pathologic events: endothelial injury which
causes increased vascular permeability, leukocyte adhesion,
and thrombosis. This leads to accumulation of lipoproteins
especially oxidized LDL in the vessel walls; monocytes
adhere to the endothelium, followed by its migration to the
intima and nally its transformation to macrophages and
foam cells. Foam cells are composed of platelet adhesion,
factors released from activated platelets, macrophages, and
vascular wall cells. These induce smooth muscle wall cells
of blood vessel wall media which lead to smooth muscle
cell proliferation and ECM production. Lipids accumulate
both extracellularly and within the cells (macrophages and
smooth muscle cells) (Fig.22.9).
The clinical presentation of atherosclerosis depends on
the organ system affected and the severity of the atherosclerotic lesion. Its manifestation includes coronary artery disease, stroke, peripheral artery disease, hypertension, or renal
failure. Sequelae of an atheromatous plaque include hemorrhage, rupture, and thrombus formation and migration with
possible microemboli. The more detrimental sequelae are
ischemia and aneurysm formation.
Hypertension
Hypertension is a major risk factor for atherosclerosis and
other conditions such as multi-infarct dementia, aortic dissection, renal failure, and hypertensive heart disease [54]
(Table22.3).
Idiopathic (essential) hypertension accounts for 95% of
the cases, while the remaining 5% are associated with secondary diseases of the renal or endocrine systems. Idiopathic
hypertension is associated with short-term problems and
is compatible with longevity especially when blood pressure is adequately controlled. However, uncontrolled
Fig. 22.9 Evolution of
atheromatous plaque
formation. (Modied from
Story HC etal. Circulation.
92:1355–1379; 1995)
224
S. C. Onyewu et al.
https://t.me/medicina_free
hypertension causes death within 1–2 years if not treated
promptly. Systolic BP of 200mmHg and diastolic pressures
>120mmHg is associated with end-organ damage such as
retinal damage and exudates with or without papilledema,
renal failure, and cerebral hemorrhage. Recent BP criteria
developed by the American Heart association are intended to
decrease the related complications [54].
Table 22.3 Types and major causes of hypertension (systolic and
diastolic)
Essential hypertension (idiopathic accounts for 90–95% of cases)
Secondary hypertension is primarily due to renal or endocrine
disorders
Renal
Glomerulonephritis
Chronic kidney disease
Renal artery stenosis
Polycystic kidney disease
Renal vasculitis
Renin producing tumors
Endocrine
Adrenocortical hyper function: Cushing’s syndrome, primary
hyperaldosteronism, congenital adrenal hyperplasia, licorice
ingestion
Exogenous hormones: Glucocorticoid therapy, estrogen,
sympathomimetic, tyramine containing food, monoamine oxidase
inhibitors
Pheochromocytoma
Acromegaly
Hypothyroidism (myxedema)
Hyperthyroidism (thyrotoxicosis)
Pregnancy induced
Neurologic
Raised intracranial pressure
Sleep deprivation
Surgical stress from pain
Cardiovascular
Coarctation of the aorta
Polyarteritis nodosa
Volume overload
Table created by Dr. Samuel Onyewu
Regulation of blood pressure is dependent on renal autoregulation through glomerular ultraltration, renin angiotensin aldosterone system, sodium intake, uid homeostasis,
exercise, stress, obesity, and smoking. Adequate blood pressure monitoring is imperative in preventing atherosclerosis
and other cardiovascular risk factors.
Vascular Aneurysm andDissection
An aneurysm is a localized abnormal dilation of a blood vessel or the heart [54]. The aneurysms are either congenital or
acquired, true or false. A true aneurysm is one that has all
the layers of the blood vessel or the heart intact. Examples of
true aneurysms are atherosclerotic, syphilitic, and congenital
or ventricular aneurysm that occur following a transmural
myocardial infarction. A false aneurysm is an aneurysm that
has a defect in the vessel wall causing an extravascular hematoma which freely communicates with an intravascular space
(pulsating hematoma). An example of a false aneurysm is
a ventricular rupture contained in a pericardial adhesion or
an arterial leak at the anastomosis site of a synthetic graft
with a native artery. Aneurysms are also classied by shape
and size. A fusiform aneurysm is a diffuse circumferential
dilation of a long (up to 20 cm) vascular segment. A saccular aneurysm is a spherical outpouching that is between 5
and 20cm, and they often contain a thrombus. A dissection
on the other hand is a hematoma or hemorrhage within the
walls of a blood vessel. Dissections are often but not always
aneurysmal (Fig.22.10).
The pathogenesis of an aneurysm is related to the alteration in the structure and/or function of the vessel wall connective tissue. Risk factors include intrinsic deciency of
the connective tissue wall commonly seen in Marfan’s and
Loeys-Dietz syndromes, Ehlers-Danlos, and vitamin C
deciencies. In Marfan’s there is defect in the synthesis of
brillin which leads to abnormal transforming growth factor
Fig. 22.10 Diagram of
Aortic aneurysm and
dissection. (Modied from
Pinard [55])
22 Vascular Endothelial Dysfunction andInammatory States
https://t.me/medicina_free
225
beta (TGF-B) activity, resulting in progressive weakness of
elastic tissue in the aorta. In Loeys-Dietz syndrome, mutation in TGF-B receptors leads to abnormal elastin and collagen I and III.Aneurysms in individuals with Loeys-Dietz
syndrome rupture easily even at small sizes [56]. EhlersDanlos is also associated with defective collagen III synthesis. Vitamin C deciency is associated with altered collagen
cross-link.
Another etiology leading to aneurysm formation is the
imbalance between collagen synthesis and degradation
secondary to local inammatory inltrates and proteolytic
enzymes. Metalloproteinases (MMP) from macrophages
in atherosclerotic plaques and vasculitis have been implicated in aneurysm development [57]. MMP has the ability
to degrade all the components (collagens, elastin, proteoglycans, laminin, bronectin) of ECM in arterial walls. Also,
there may be loss of smooth muscle cells or synthesis of
non- collagenous or non-elastic ECM. This can occur due
to ischemia in the media layer secondary to atherosclerotic
thickening in the intima. Demand ischemia occurs due to the
increased distance of oxygen and nutrients travel to supply
the smooth muscles. Systemic hypertension can also occur
due to narrowing of the vasa vasorum. Histologically this
change is described as cystic medial degeneration. The two
most important disorders that predispose to aortic aneurysms
are atherosclerosis and hypertension. The symptoms of an
aortic aneurysm depend on the location. It ranges from chest
or abdominal pain secondary to obstruction, compression or
ischemia, pulsating mass, hemorrhage with shock, and death
following exsanguination.
Vascular dissection occurs when blood nds its way
through the walls of an aorta. Dissection commonly occurs
in middle aged (40–60-year-old) men with an underlying
history of hypertension. In younger individuals the history
of Marfan’s disease is usually present. Dissection can also
occur following aortic cannulation during cardiopulmonary
bypass and cardiac catheterization. The major pathogenesis
of dissection is hypertension. Hypertensive patients have
medial hypertrophy of the vasa vasorum. Medial hypertrophy is associated with degenerative changes of the aortic media and variable loss of medial smooth muscle cells.
Vascular dissections are also associated with inherited or
acquired connective tissue disorder (Marfan’s, EhlersDanlos, vitamin C deciency, and copper deciency). Types
of dissection depends on the involvement of the ascending
aorta. Type A and B or DeBakey I/II or III (Fig.22.11). The
presentation of vascular dissection depends on the area of
involvement. Therefore, symptoms may include chest pain
radiating between the scapulae, and back pain from transverse myelitis if the spinal arteries are affected. Prognosis
has improved over the years, and the main goal of treatment
is blood pressure control.
Vasculitis
Vasculitis is dened as inammation of the vascular wall of
arteries, veins, and capillaries. The presence of these vessels in various organ systems allows vasculitis to occur in
all organs resulting in an overall general clinical presenta-
Fig. 22.11 Diagrammatic
representations of the types of
dissection. (Modied from
Matthews JP, Swaminathan
M, Ayoub CM. Clinical
manual and review of
transesophageal
echocardiography. 2nd ed.
www.accessanesthesiology.
com
)
226
https://t.me/medicina_free
S. C. Onyewu et al.
tion. Approximately 20 primary types of vasculitis are recognized. Efforts have been made to classify them based on
the vasculature involved, the size of the vessel they affect,
associated organs implicated, pathologic mechanism, morphologic characteristic at presentation, and even patient
demographics [58]. Although, this is still an evolving process, the Chapel-Hill nomenclature remains the most widely
accepted classication approach [59] (Fig.22.12).
Vasculitis is often immune mediated or caused by infection. Infectious etiologies can also lead to non-infectious
vasculitis by indirectly inducing immune complexes and
causing cross-reactivity. Treatment modality may be counterproductive if the etiology is not identied. Other causes
of vasculitis include radiation, mechanical trauma, and biochemical toxins. Non-infectious vasculitis is initiated by
immune complex deposition, antineutrophil cytoplasmic
antibodies (ANCA), and anti-endothelial cell antibodies.
Immune complex associated vasculitis has many similarities
of other immune complex conditions such as Arthus reaction
and serum sickness [60]. Examples of immune complex vasculitis include systemic lupus erythematosus (SLE), polyarteritis nodosa (PAN), and drug hypersensitivity vasculitis
(penicillin and streptokinase). For patients with SLE, there
is a DNA-anti-DNA complex which bind to vascular walls.
About 30% of PAN patients have circulating HBsAg-anti
HBsAg antibody complex [61]. Drug hypersensitivity vasculitis occurs when a drug (penicillin) binds to serum proteins. Drug hypersensitivity vasculitis can also occur when
foreign protein (streptokinase) binds to antibodies and form
circulating immune complexes (See Fig.22.12). The temporal sequence of antigen-antibody complex formation is yet
to be fully understood. Antineutrophil cytoplasmic antibodies (ANCAs) are described as antibodies that react against
constituents (mainly enzymes) of neutrophil. Reactivity is
primarily to granules, monocytes, lysosomes, and endothelial cells. ANCA can be divided into anti-myeloperoxidase
(MPO-ANCA) formerly known as perinuclear ANCA
(p-ANCA) and anti-proteinase- 3 (PR-3 ANCA), formerly
known as cytoplasmic ANCA (c-ANCA). MPO is a lysosomal granule that produces free oxygen radicals and is
induced by agents, such as propylthiouracil. PR-3 is a neutrophil azurophilic granule constituent [61, 62]. PR-3 ANCA
are seen in Wegener granulomatosis, while MPO-ANCA
are common with microscopic polyangiitis and ChurgStrauss syndrome. ANCAs are useful markers for diagnosis
of ANCA vasculitis. The mechanism of action is activation
of neutrophils which synthesize free radicals and proteolytic enzymes. The ensuing neutrophil-endothelial interaction leads to endothelial cell damage. Anti-endothelial cell
antibodies are antibodies to endothelial and smooth muscle
cells predisposing patients to Kawasaki disease [63, 64].
Infectious vasculitis occurs following localized invasion
of bacteria and fungi. Hematogenous spread from distant
infectious site following septicemia or embolization from
infective endocarditis can also cause vasculitis. Organisms
commonly involved are Aspergillus and Mucor. These fungi
can lead to aneurysm, thrombosis, or infarction.
Diabetes Mellitus
Diabetes mellitus is a condition that is associated with
impaired glucose utilization by cells. EC dysfunction associated with type 1 diabetes aka insulin-dependent diabetes is
predominantly caused by the metabolic changes seen with
hyperglycemia and microvascular complications prominently
in retinal and renal vessels [65]. Non-insulin-dependent
(type 2) diabetes is associated with obesity and metabolic
Fig. 22.12 Diagrammatic
schema of the various types of
vasculitis and vasculature
affected. (Modied from
Imboden JB, Hellmann DB,
Stone JH. Current diagnosis
and treatment; Rheumatology.
3rd ed. www.accessmedicine.
com)
Соседние файлы в папке Библиотека им академика М.И. Перельмана