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Kuesioner Pra Skrining Perkembangan KPSP
Kuesioner Pra Skrining Perkembangan KPSP
Kuesioner Pra Skrining Perkembangan KPSP
Academic Unit of Anaesthesia & Intensive Care, School of Medicine, University of Aberdeen AB25 2ZD,
Scotland UK
*Corresponding author. E-mail: n.r.webster@abdn.ac.uk
In the past, the endothelium was considered to be inert, described as a `layer of nucleated
cellophane', with only non-reactive barrier properties, such as presentation of a non-thrombo-
genic surface for blood ¯ow and guarding against pro-in¯ammatory insults. However, it is now
A single layer of endothelial cells lines the entire vascular different surface antigens and receptors but can generate
system. In adults, approximately ten trillion (1013) cells different responses to the same stimulus.20 Even cells from
form an almost 1 kg `organ'. Endothelial cell structure and the same part of the vasculature can have varied responses.
functional integrity are important in the maintenance of the It is also important to note that responses of cultured
vessel wall and circulatory function, but the endothelium is endothelial cells may not re¯ect responses seen in the same
by no means inert. As a barrier, the endothelium is semi- cells in vivo, and the immortalized endothelial cell lines
permeable and regulates the transfer of small and large used in many laboratory studies may, in particular, have
molecules. Endothelial cells are dynamic and have both altered expression patterns of key markers compared with
metabolic and synthetic functions (Fig. 1). They exert cells studied in vivo.21
signi®cant autocrine, paracrine and endocrine actions and Endothelial cells have a role in maintaining a non-
in¯uence smooth muscle cells, platelets and peripheral thrombogenic blood±tissue interface and regulate throm-
leucocytes. bosis, thrombolysis, platelet adherence, vascular tone and
Endothelial cells and haematopoietic cells arise from blood ¯ow. The endothelium is indispensable for body
haemangioblasts, blast-like bipotential cells.9 Precursor homeostasis; an uncontrolled endothelial cell response is
cells are thought to arise from the ventral ¯oor of the dorsal involved in many disease processes, including atherosclero-
aorta within the aorto±gonad±mesonephros region. sis, hypertension, pulmonary hypertension, sepsis and
Splanchnopleuric mesoderm transforms into mesenchymal in¯ammatory syndromes. These diseases are related to
cells, which differentiate into the haemangioblasts. The endothelial injury, dysfunction and activation.
haemangioblast then becomes an intermediate pre-endo-
thelial cell, which can further differentiate into either a
committed haematopoietic cell line, or an endothelial cell. Selected functions of endothelial cells
Endothelial cells can also transdifferentiate into mesen-
chymal cells and intimal smooth muscle cells. Endothelium transport functions
It is important to point out that there is marked The endothelium is an important barrier to the free passage
phenotypic variation between endothelial cells in different of molecules and cells from the blood to the underlying
parts of the vascular system, such that cells from interstitium and cells. Speci®c transport mechanisms trans-
different locations in the same person not only express port essential circulating blood macromolecules across
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2004
Galley and Webster
106
Physiology of the endothelium
Fig 2 Caveolae are responsible for transcellular transport in endothelial cells. Caveolae are carriers of albumin. Albumin binding proteins (albumin
binding glycoprotein, gp60) initiate endocytosis of albumin by associating with the scaffolding protein caveolin-1 (A) and activating the kinase Src.
Vascular tone
Fig 3 Nitric oxide synthase (NOS) type III catalyses the production of
The endothelium produces a number of vasodilator and nitric oxide from the cationic amino acid L-arginine. The enzyme is
vasoconstrictor substances which regulate vasomotor tone activated via changes in intracellular calcium in response to changes in
and the recruitment and activity of in¯ammatory cells, and shear forces or via a receptor-mediated process. Released nitric oxide
regulate thrombosis.55 activates soluble guanylate cyclase (GC) in smooth muscle cells,
converting GTP to cGMP. This activates a protein kinase which leads to
Nitric oxide the inhibition of calcium in¯ux into the smooth muscle cell, and
Endothelial cells have a major role in the regulation of decreased calcium±calmodulin stimulation of myosin light chain kinase.
This in turn decreases the phosphorylation of myosin light chains,
vascular tone, through production of several vasoactive decreasing smooth muscle tension development and causing
mediators. Nitric oxide, prostacyclin, endothelin (ET) and vasodilatation.
endothelial-derived hyperpolarizing factor are powerful
vasoactive substances released from the endothelium in
response to both humoral and mechanical stimuli, and can
profoundly affect both the function and structure of the
underlying vascular smooth muscle. Nitric oxide is a Nuclear factor kappa B (NFkB) is a redox-sensitive
profound vasodilator. Constitutive production of nitric transcription factor which regulates, in part, gene expression
oxide by the endothelium maintains the vasculature in a of many cytokines, growth factors, adhesion molecules and
state of vasodilatation. Both type II (cytokine-inducible) and enzymes involved in immune and in¯ammatory respon-
type III (endothelial constitutive) NOS, which catalyse the ses.52 It is maintained in a non-activated state in the
conversion of L-arginine to nitric oxide (Fig. 3), have been cytoplasm by association with an inhibitor subunit, IkB
found in endothelial cells. Caveolae play an integral part in (Fig. 4). Proteolysis of IkB in response to activation stimuli,
regulating the activity of endothelial NOS. In addition, including lipopolysaccharide (LPS, endotoxin) and cyto-
pro-in¯ammatory cytokines also increase the activity of kines with a common redox-sensitive step, reveals a nuclear
GTP-cyclohydrolase, the rate-limiting enzyme for tetra- recognition site. This then prompts the NFkB to move into
hydobiopterin production, which is a cofactor for NOS.27 the nucleus, where it binds to target DNA and results in
The y+ amino acid transporter channels are co-located with mRNA expression. Constitutive nitric oxide production by
NOS on caveolae, and re-circulation of L-arginine from endothelial cells inhibits adhesion molecule expression
L-citrulline mediated by cytokines has also been described through stabilization of IkB, thus attenuating pro-
in vascular endothelial cells.34 in¯ammatory responses.
107
Galley and Webster
Host defence
Endothelial cells are in a unique strategic position as key
players in host defence and in¯ammation. Orchestration of
immune and in¯ammatory responses depends on com-
munication between cells by soluble molecules given the
generic terms cytokines; these include chemokines, colony
stimulating factors (CSF), IL, growth factors and interferons
(IFN). They are low-molecular-weight proteins that regulate
both the amplitude and duration of the immune and
in¯ammatory responses. Endothelial cells produce and
react to a variety of cytokines and other mediators.
Chemokines
The chemokine repertoire of endothelial cells includes a
108
Physiology of the endothelium
to endothelium by expression of CD154 on activated some important homeostatic anticoagulant effects as well as
platelets, which binds to CD40 on endothelial cells. This pro-coagulant activity. It binds to thrombomodulin expres-
induces expression of leucocyte adhesion molecules and sed on the endothelial cell surface, which is the major
tissue factor on the endothelial surface. Thrombin or physiological buffer for the pro-coagulant effects of
histamine stimulation selectively induces endothelial cell thrombin in normal vessels. Because thrombomodulin
P-selectin while cytokines and LPS stimulation leads to binds to the same site on thrombin that would normally
E-selectin expression. Movement of the adherent cells bind to ®brinogen, platelets or factor V, all of these
between tightly adjacent endothelial cells and into the functions are blocked. Instead, the thrombin±thrombo-
tissues to the site of infection or injury occurs via complex modulin complex activates protein C (through a different
and tightly regulated sequential activation steps, allowing site on the thrombin molecule), resulting in initiation of the
the integrity of the endothelium itself to be maintained activated protein C pathway.14 This process is augmented
whilst at the same time allowing the movement of activated by the endothelial protein C receptor (EPCR). Activated
in¯ammatory cells out of the circulation to the site in protein C must dissociate from EPCR before it can bind to
infection or injury. protein S and function as an effective anticoagulant through
109
Galley and Webster
Cytokines, growth factors, lipids and enzymes modulate cell vasodilatation may simultaneously involve augmented ET
function, leading to lipid accumulation, vasoconstriction activity in disease states, including atherosclerosis. In a
and promotion of thrombosis. Active endothelial participa- mouse model of atherosclerosis, chronic ETA receptor
tion is required for monocyte adhesion and migration to the blockade restored nitric-oxide-mediated endothelial func-
sub-endothelium. In addition, endothelin is a profound tion and inhibited atherosclerotic plaque development.2
chemoattractant for monocytes. The endothelium oxidizes
native low-density lipoprotein (LDL); the accumulation of
monocytes could represent an attempt to remove the sub- Infection and in¯ammation
endothelial oxidized LDL. The activated monocytes secrete Severe infection with Gram-negative organisms leads to the
TNFa and IL-1, with secondary up-regulation of growth appearance of endotoxin or LPS in the bloodstream, which
factors by endothelial and smooth muscle cells. Oxidised interacts with LPS-binding protein (LBP) and binds to
LDL stimulates both endothelin and E-selectin production. CD14 receptors, transducing signals via Toll-like receptors
Lipids (particularly LDL) and oxidant stress play a major (TLR), which culminate in the activation of NFkB. NFkB
role in impairing endothelial function by reducing the activation leads to increased gene expression of several
110
Physiology of the endothelium
cytokines, including TNFa and IFNg, induce increased hypertensive rats however, ET-1 in vascular tissue did
permeability of some cells through effects on tight junction correlate with systemic arterial pressure which was reduced
proteins and increased VEGF expression.49 When T cells by endothelin antagonists.56 The involvement of endo-
are activated as part of the host defence process, they genous ET-1 in mild-to-moderate hypertension remains
express their own tight junction proteins to make the controversial but it may be implicated in some more severe
transendothelium process smooth.1 types of hypertension.
Anatomical damage to the endothelium occurs during Pulmonary hypertension however, has been shown to be
septic shock, and a single injection of LPS in animals associated with increased ET-1 production both in animal
denudes endothelium.47 Endothelial cells become detached models and in patients.60
and sub-endothelial oedema occurs. Cellular damage is
apparent as early as 15 min after LPS injection, with nuclear
vacuolization, cytoplasmic swelling and protrusion, cyto-
Thrombosis
plasmic fragmentation and detachment of the endothelium There are a number of inherited or acquired thrombotic
from its underlying layer.33 In a caecal ligation and puncture disorders of endothelium-derived and regulated proteins.18
111
Galley and Webster
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