sepsis and the kidney.pdf - SASSiT
sepsis and the kidney.pdf - SASSiT
sepsis and the kidney.pdf - SASSiT
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<strong>sepsis</strong> <strong>and</strong> <strong>the</strong> <strong>kidney</strong> 215<br />
NOS, by inhibiting leukocyte interactions with endo<strong>the</strong>lial cells <strong>and</strong> inhibiting<br />
platelet aggregation [17].<br />
Soluble <strong>and</strong> local mediators<br />
Endo<strong>the</strong>lins<br />
The production of endo<strong>the</strong>lins, which are potent vasoconstrictors, by endo<strong>the</strong>lial,<br />
mesangial <strong>and</strong> tubular cells is stimulated by proinflammatory cytokines,<br />
including TNF. The vasoconstrictors vasopressin <strong>and</strong> angiotensin II also<br />
stimulate endo<strong>the</strong>lin release. Endo<strong>the</strong>lins cause vigorous constriction of <strong>the</strong><br />
afferent <strong>and</strong> efferent arterioles, <strong>and</strong> mesangial cell contraction. The effects of<br />
endo<strong>the</strong>lin may be secondary to its induction of platelet-activating factor (PAF)<br />
syn<strong>the</strong>sis in <strong>the</strong> mesangium or thromboxane A 2 by <strong>the</strong> endo<strong>the</strong>lium. Additionally,<br />
endo<strong>the</strong>lin induces some vasodilators, counteracting its vasoconstricting effect,<br />
including prostacyclin, NO, <strong>and</strong> prostagl<strong>and</strong>in E 2 . Two endo<strong>the</strong>lin receptors are<br />
active in <strong>the</strong> renal parenchyma: <strong>the</strong> endo<strong>the</strong>lin-A receptor is found mainly in <strong>the</strong><br />
vascular compartment, <strong>and</strong> <strong>the</strong> endo<strong>the</strong>lin-B receptor is found mainly in <strong>the</strong><br />
tubular compartment. In an animal model of glycerol-mediated toxic renal injury,<br />
selective antagonism of <strong>the</strong> endo<strong>the</strong>lin-A receptor lessened <strong>the</strong> reduction in glomerular<br />
filtration rate [18]. Preliminary evidence suggested that <strong>the</strong> endo<strong>the</strong>lin-B<br />
receptor was integral to clearing endo<strong>the</strong>lin-1, <strong>and</strong> probably plays a beneficial<br />
role in ischemia. Studies of selective endo<strong>the</strong>lin-A receptor blockade <strong>and</strong><br />
nonselective endo<strong>the</strong>lin receptor blockade (both endo<strong>the</strong>lin-A receptor <strong>and</strong><br />
endo<strong>the</strong>lin-B receptor) demonstrated improved outcomes only for <strong>the</strong> selective<br />
blockade in a chronic ischemia animal model, fur<strong>the</strong>r supporting <strong>the</strong> beneficial<br />
effects of intact endo<strong>the</strong>lin-B receptor function [19].<br />
Tumor necrosis factor <strong>and</strong> interleukin-1<br />
Major mediators of cytokine-induced renal injury include TNF <strong>and</strong> IL-1, both<br />
of which promote fur<strong>the</strong>r cytokine release, induce vasoconstriction, neutrophil<br />
aggregation, production of reactive oxygen species, <strong>and</strong> induction of tissue<br />
factor <strong>and</strong> promotion of thrombosis [20]. When infused into animal models, TNF<br />
<strong>and</strong> IL-1 result in renal damage <strong>and</strong> decrease RBF <strong>and</strong> glomerular filtration rate<br />
[21]. TNF is produced <strong>and</strong> circulated systemically, whereas IL-1 is expressed in<br />
<strong>the</strong> glomerular endo<strong>the</strong>lial cells early in animal models of <strong>sepsis</strong>. These pleiotropic<br />
cytokines are capable of inducing mesangial <strong>and</strong> endo<strong>the</strong>lial production<br />
of PAF, endo<strong>the</strong>lin, adenosine, NO, <strong>and</strong> prostagl<strong>and</strong>in E 2 . The migration of<br />
activated neutrophils into <strong>the</strong> <strong>kidney</strong> in <strong>the</strong> setting of up-regulation of adhesion<br />
molecule expression by activated endo<strong>the</strong>lial cells leads to fur<strong>the</strong>r endo<strong>the</strong>lial<br />
damage <strong>and</strong> is likely a seminal event in <strong>the</strong> pathogenesis of ARF. Ischemic<br />
animal models of ARF demonstrate a protective effect of monoclonal antibodies<br />
to adhesion molecules [22].