e3 103 Meyer T, Brinck U Differential distribution of serotonin and tryp tophan hydroxylase in the human gastrointestinal tract Digestion 1999;60 63 68 104 Fan L, Iseki S Immunohistochemical localizat[.]
e3 103 Meyer T, Brinck U Differential distribution of serotonin and tryptophan hydroxylase in the human gastrointestinal tract Digestion 1999;60:63-68 104 Fan L, Iseki S Immunohistochemical localization of vascular endothelial growth factor in the globule leukocyte/mucosal mast cell of the rat respiratory and digestive tracts Histochem Cell Biol 1999;111:13-21 105 Deleted in review 106 Revelly JP, Tappy L, Berger MM, et al Early metabolic and splanchnic responses to enteral nutrition in postoperative cardiac surgery patients with circulatory compromise Intensive Care Med 2001;27:540-547 107 Kliegman RM, Pittard WB, Fanaroff AA Necrotizing enterocolitis in neonates fed human milk J Pediatr 1979;95:450-453 108 Cahill P, Redmond E, Sitzmann JV Endothelial dysfunction in cirrhosis and portal hypertension Pharmacol Ther 2001;89:273-293 109 Pannen BH, Bauer M, Noldge-Schomburg GF, et al Regulation of hepatic blood flow during resuscitation from hemorrhagic shock: role of NO and endothelins Am J Physiol 1997;272:H2736-H2745 110 Clemens MG Nitric oxide in liver injury Hepatology 1999;30:1-5 111 Shah V, Lyford G, Gores G, Farrugia G Nitric oxide in gastrointestinal health and disease Gastroenterology 2004;126:903-913 112 Matheson PJ, Spain DA, Harris PD, et al Glucose and glutamine gavage increase portal vein nitric oxide metabolite levels via adenosine A2b activation J Surg Res 1999;84:57-63 113 Watkins CC, Sawa A, Jaffrey S, et al Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy J Clin Invest 2000;106:373-384 114 Russo A, Fraser R, Adachi K, et al Evidence that nitric oxide mechanisms regulate small intestinal motility in humans Gut 1999;44:72-76 115 Perner A, Andresen L, Normark M, et al Expression of nitric oxide synthases and effects of L-arginine and L-NMMA on nitric oxide production and fluid transport in collagenous colitis Gut 2001;49:387-394 116 Burgener D, Laesser M, Treggiari-Venzi M, et al Endothelin-1 blockade corrects mesenteric hypoperfusion in a porcine low cardiac output model Crit Care Med 2001;29:1615-1620 117 Ozel SK, Yuksel M, Haklar G, et al Nitric oxide and endothelin relationship in intestinal ischemia/reperfusion injury (II) Prostaglandins Leukot Essent Fatty Acids 2001;64:253-257 118 Guzman JA, Rosado AE, Kruse JA Dopamine-1 receptor stimulation attenuates the vasoconstrictive response to gut ischemia J Appl Physiol 2001;91:596-602 119 Jakob SM, Ruokonen E, Takala J Effects of dopamine on systemic and regional blood flow and metabolism in septic and cardiac surgery patients Shock 2002;18:8-13 120 Clemmesen JO, Galatius S, Skak C, et al The effect of increasing blood pressure with dopamine on systemic, splanchnic, and lower extremity hemodynamics in patients with acute liver failure Scand J Gastroenterol 1999;34:921-927 121 LeDoux D, Astiz ME, Carpati CM, Rackow EC Effects of perfusion pressure on tissue perfusion in septic shock Crit Care Med 2000;28:2729-2732 122 Dworkin LD, Sun AM, Brenner BM The renal circulations In: Brenner BM, ed The Kidney 6th ed Philadelphia: WB Saunders Company; 2000:277-318 123 Myers BD, Deen WM, Brenner BM Effects of norepinephrine and angiotensin II on the determinants of glomerular ultrafiltration and proximal tubule fluid reabsorption in the rat Circ Res 1975;37:101110 124 Naicker S, Bhoola KD Endothelins: vasoactive modulators of renal function in health and disease Pharmacol Ther 2001;90:61-88 125 Shipley RE, Study RS Changes in renal blood flow, extraction of inulin, glomerular filtration rate, tissue pressure and urine flow with acute alterations of renal artery blood pressure Am J Physiol 1951;167:676-688 126 Bidani AK, Griffin KA, Williamson G, et al Protective importance of the myogenic response in the renal circulation Hypertension 2009;54:393-398 127 Cupples WA Interactions contributing to kidney blood flow autoregulation Curr Opin Nephrol Hypertens 2007;16:39-45 128 Loutzenhiser R, Griffin K, Williamson G, Bidani A Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms Am J Physiol Regul Integr Comp Physiol 2006;290:R1153-R1167 e4 Abstract: When delivering critical care, one must understand the specific properties that characterize the various regional circulations because therapies that benefit one region may be detrimental to another Vascular tone is influenced by (1) innervation and neural processes, (2) circulating endocrine and neuroendocrine mediators, (3) local metabolic products, (4) blood gas composition, (5) endothelial-derived factors, and (6) myogenic processes The cerebral circulation is characterized by a blood-brain barrier Regulation of myocardial perfusion is tailored to match regional myocardial oxygen supply to demand over the widest possible range of cardiac workload Critically ill patients are at risk for impaired splanchnic blood flow that can impair the two chief functions of the gastrointestinal system: (1) digestion and absorption of nutrients and (2) maintenance of a barrier to the translocation of enteric antigens Renal blood flow remains constant over a wide range of renal artery perfusion pressures, but urinary flow rate is a function of renal perfusion pressure Key words: vascular tone, endothelium, cerebral circulation, myocardial blood flow, renal blood flow, splanchnic circulation 25 Endothelium and Endotheliopathy YVES OUELLETTE • Until recently, scientists and clinicians considered the endothelium, the cell layer that lines the blood vessels, as an inert barrier separating the various components of blood and the surrounding tissues The vascular endothelium is now recognized as a highly specialized and metabolically active organ performing a number of critical physiologic, immunologic, and synthetic functions These functions include regulation of vascular permeability, fluid and solute exchange between the blood and interstitial space, vascular tone, cell adhesion, homeostasis, and vasculogenesis.1 The normal vascular endothelium is only one cell layer thick, separating the blood and vascular smooth muscle The endothelium responds to physical and biochemical stimuli by releasing regulatory substances affecting vascular tone and growth, thrombosis and thrombolysis, and platelet and leukocyte interactions with the endothelium Because normal endothelial function plays a central role in vascular homeostasis, it is logical to conclude that endothelial dysfunction contributes to disease states characterized by vasomotor dysfunction, abnormal thrombosis, or abnormal vascular proliferation The endothelium lies between the lumen and vascular smooth muscle, where it is uniquely positioned to “sense” changes in hemodynamic forces or blood-borne signals by membrane receptor mechanisms The endothelial cells can respond to physical and chemical stimuli by synthesis or release of a variety of vasoactive and thromboregulatory molecules and growth factors The vascular endothelium possesses numerous enzymes, receptors, and transduction molecules, and interacts with other vessel wall constituents and circulating blood cells In addition to these universal functions, the endothelium may have organ-specific roles that are differentiated for various parts of the body, such as gas exchange in the lungs, control of myocardial function in the heart, or phagocytosis in the liver and spleen 218 • Because of their location, endothelial cells have the ability to interact with blood components, such as flow, soluble factors, and other cells Endothelial cells integrate these signals into a cohesive regulation of vascular responses The endothelium controls the vascular tone of the underlying smooth muscle cells through the production of vasodilator and vasoconstrictor mediators • • PEARLS Endothelial cell activation in response to inflammation changes endothelial cellular physiology and alters vascular function A large number of endothelial cell–active molecules are potential biomarkers for the early diagnosis of sepsis Normal Endothelial Function Endothelial Cell Heterogeneity Many vascular diseases appear to be restricted to specific vascular beds For example, thrombotic events are often localized to single vessels It is also common for certain vasculitides to specifically affect certain arteries, veins, or capillaries or to affect certain organs Tumor cells often metastasize more commonly within particular vascular beds The basis for this variability in vascular disease is poorly understood but may be explained by the heterogeneity of endothelial cells There has been a greater understanding of how endothelial cell heterogeneity may contribute both to the maintenance of organ-specific function and to the development of disorders restricted to specific vascular beds.1–3 The cell biology of capillary endothelium from different vascular beds may explain differences in tissue function For example, the brain microcirculation is lined by endothelial cells connected by tight junctions that maintain the blood-brain barrier By contrast, sinusoids found in the liver, spleen, and bone marrow are lined by endothelial cells that allow transcellular trafficking between intercellular gaps Similarly, fenestrated endothelial cells found in the intestinal villi, endocrine glands, and kidneys facilitate selective permeability, which is required for efficient absorption, secretion, and filtering.4 Another example of endothelial cell heterogeneity lies in the expression of cell surface receptors involved in cell-to-cell signaling and cell trafficking For example, in the mouse, lung-specific endothelial cell adhesion molecules are exclusively expressed by pulmonary postcapillary endothelial cells and some splenic venules Similarly, specific mucosal cell adhesion molecules are expressed primarily on endothelial venules in the Peyer patches of CHAPTER 25 Endothelium and Endotheliopathy the small intestine.5,6 Tumor cells may show clear preferential adhesion to the endothelium of specific organs paralleling their in vivo metastatic propensities.7 Endothelial Progenitor Cells A significant amount of literature has shown that maintenance and repair of vasculature in ischemic diseases may be at least partially mediated through recruitment of endothelial progenitor cells (EPCs) from the bone marrow to areas of vascular injury An EPC is a specific subtype of hematopoietic stem cell that has been isolated from circulating mononuclear cells, bone marrow, and cord blood EPCs migrate from the bone marrow to the peripheral circulation, where they contribute to vascular repair.8,9 When injected into animal models of ischemia, EPCs are incorporated into sites of neovascularization8,10,11 and have contributed to improved outcomes in patients with ischemic vascular disorders.12 In addition, there has been accumulating evidence for the function of EPCs in critical illnesses such as sepsis Recruitment of EPCs to areas of endothelial and vascular damage may have prognostic implications and could be associated with clinical outcome The pathophysiologic changes associated with critical illness—notably, sepsis and sepsis-related organ dysfunction—may lead to apoptosis and necrosis of endothelial cells from the vasculature and recruitment of EPCs from the bone marrow In various models of vascular injury and organ dysfunction, only a few studies have emerged regarding EPCs in particular as a therapeutic strategy Transplanted EPCs have been shown to improve survival of mice following liver injury.13 Infusion of EPCs also restored blood flow in a mouse model of hind limb ischemia.9 A prospective randomized trial compared the effects of EPC transplantation in patients with idiopathic pulmonary arterial hypertension versus conventional therapy and showed that after 12 weeks, patients who had received EPCs had a significant improvement in their 6-minute walk test, mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac output.14 Coagulation and Fibrinolysis A normal physiologic function of the endothelium is to provide an antithrombotic surface inhibiting platelet adhesion and clotting, facilitating normal blood flow Under pathophysiologic conditions, the endothelium transforms into a prothrombotic surface A dynamic equilibrium exists between both states that permits a rapid response to an insult and a rapid recovery.15 Anticoagulant Mechanisms The endothelium has anticoagulant, antiplatelet, and fibrinolytic properties.16 Endothelial cells are the major sites for anticoagulant reactions involving thrombin Thrombin plays a key role in coagulation, including the activation of platelets, activation of several coagulation enzymes and cofactors, and stimulation of procoagulation pathways on the endothelial cell surface In the normal state, there is little thrombin enzyme activity The surrounding endothelial cell matrix contains heparin sulfate and related glycosaminoglycans that activate antithrombin III In addition, the subendothelial cell matrix contains dermatan sulfate, which promotes the antithrombin activity of heparin cofactor II Furthermore, microvascular endothelial cells release a tissue factor pathway inhibitor that inhibits the factor VIIa/tissue factor complex and further contributes to anticoagulation (Fig 25.1) 219 Thrombin activity is also modulated by endothelial cell synthesis of thrombomodulin.17,18 The binding of thrombin to thrombomodulin facilitates the enzyme’s activation of the anticoagulant protein C Activated protein C (APC) activity is enhanced by cofactor C, also called protein S, which is synthesized by endothelial cells as well as by other cells (see Fig 25.1) APC inhibits factor Va and factor VIIIa Thrombomodulin (TM) also inhibits prothrombinase activity indirectly by binding factor Xa (Fig 25.2) Protein C has a special receptor on the endothelial cells: endothelial cell protein C receptor (EPCR) EPCR augments protein C activation approximately 20-fold in vivo by binding protein C and presenting it to the thrombin-TM activation complex Both EPCR and TM can be found in plasma as soluble proteins APC retains its ability to bind EPCR; this complex appears to be involved in some of the cellular signaling mechanisms that downregulate inflammatory cytokine formation (tumor necrosis factor [TNF], interleukin-6) In addition, platelet adhesion to endothelial cells is markedly inhibited by endothelium-derived prostacyclin.19 The interactions between platelets and endothelium regulate platelet function, coagulation cascades, and local vascular tone Microvascular endothelial cells may secrete tissue plasminogen activator (t-PA), the powerful thrombolytic agent in frequent clinical use for treatment of coronary thrombotic occlusion.20 t-PA release is stimulated in vivo by norepinephrine, vasopressin, or stasis within the vessel lumen Thrombin may also stimulate t-PA release, providing a further endothelium-mediated safeguard against uncontrolled coagulation Procoagulant Mechanisms The expression and release of tissue factor is the pivotal step in transforming the endothelium from an anticoagulant to a procoagulant surface.21,22 Tissue factor accelerates factor VIIadependent activation of factors X and IX (see Fig 25.1) The synthesis of tissue factor is induced by a number of agonists— including thrombin, endotoxin, several cytokines, shear stress, Tissue factor Tissue factor inhibitor Factor VIIa Factor VII TF Factor VIIIa Factor X Factor Xa Prothrombin Thrombin Fibrinogen Antithrombin Fibrin Thrombomodulin Endothelium Factor VIII Factor Va Activated protein C Protein C • Fig 25.1 Endothelium control of the coagulation cascade An inflamma- tory stimulus upregulates the interaction of tissue factor (TF) with factor VII, which generates activated factor VII (factor VIIa) The TF–factor VIIa complex then leads to the conversion of factor X to factor Xa The interaction of factors Xa and Va results in the conversion of prothrombin to thrombin and the conversion of fibrinogen to fibrin Three key anticoagulant pathways can inhibit this process Protein C is activated through its interaction with cell-surface thrombomodulin and inhibits the activities of factors Va and VIIIa Antithrombin blocks the activation of multiple factors, including factor X and thrombin Tissue factor pathway inhibitor interferes directly with the tissue factor–factor VIIa complex 220 S E C T I O N I V Pediatric Critical Care: Cardiovascular PROTEIN C PATHWAY C4bp Endotoxins Cytokines Coagulation Inhibition of fVa and fVIIIa L-arg + PC APC sTM Prot C receptor Thrombin TM TAFI Endothelial cell Membrane Inflammation • ↓ Cytokine production • ↓ Leukocyte adherence • ↓ Apoptosis, etc Fibrinolysis Inhibition of PAI-1 • Fig 25.2 The interaction of the protein C system with the endothelium: Thrombin bound to thrombomodulin (TM) modifies protein C bound to the endothelial protein C (Prot C) receptor on the cell surface to generate activated protein C (APC) APC acts as a natural anticoagulant by inactivating activated factors V (fVa) and VIII (fVIIIa), modulating inflammation by downregulating the synthesis of proinflammatory cytokines, leukocyte adherence, and apoptosis and enhancing fibrinolysis by inhibiting thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor type-1 (PAI-1) C4Bbp, C4b binding protein (binds protein S); 1PS, in the presence of protein S; sEPCR, soluble endothelial cell protein C receptor; sTM, soluble thrombomodulin (Modified from Hazelzet J Pathophysiology of pediatric sepsis In: Nadel S Infectious Diseases in the Pediatric Intensive Care Unit London: Springer; 2008.) hypoxia, oxidized lipoproteins, and other endothelial insults Once endothelial cells expressing tissue factor are exposed to plasma, prothrombinase activity is generated and fibrin is formed on the surface of the cells Tissue factor can also be found in plasma as a soluble protein Its role there is not well understood, but it probably plays a role in the initiation of coagulation Endothelium-Derived Vasodilators The important role that the endothelium plays in controlling vascular tone has only recently been appreciated Clinicians and researchers have come to appreciate that the endothelium controls underlying smooth muscle tone in response to certain pharmacologic and physiologic stimuli This response involves a number of luminal membrane receptors and complex intracellular pathways and the synthesis and release of a variety of relaxing and constricting substances Nitric Oxide Furchgott and Zawadzki first postulated the existence of an endothelium-derived relaxing factor (EDRF) in 1980, when they noticed that the presence of endothelium was essential for rabbit aortic rings to relax in response to acetylcholine.21 Later, it was determined that the biologic effects of EDRF are mediated by nitric oxide (NO).23 NO is generated from the conversion of L-arginine to NO and L-citrulline by the enzyme nitric oxide synthase (NOS).24 There are two general forms of NOS: constitutive and inducible In the unstimulated state, NO is continuously produced by constitutive NO synthase (cNOS) The activity of cNOS is modulated by calcium that is released from endoplasmic stores in response to the Ca2+ + iNOS cNOS NO + Cit +PS sEPCR Shearing forces CaM + Ca2+ Vasoactive agents + R Endothelial cell NO + GTP GC cGMP-PK cGMP cGMP-P Smooth muscle cell • Fig 25.3 Nitric oxide (NO) is generated from L-arginine (L-arg) by the action of nitric oxide synthase (NOS) In the resting state, constitutive NOS (cNOS) is modulated by intracellular Ca21 and calmodulin (CaM) Stored Ca21 is released in response to vasoactive agents (e.g., acetylcholine and bradykinin) and other external stimuli, such as shearing forces Activation of endothelial cells by cytokines and endotoxins increases expression of inducible NOS (iNOS) Citrulline (Cit) is a byproduct of NO production NO has a half-life of only a few seconds in vivo and quickly diffuses to surrounding cells, such as smooth muscle cells NO stimulates the production of the intracellular mediator cyclic GMP (cGMP) Increased cGMP activates a series of cGMP-dependent protein kinases (cGMP-PKs) and cGMP-dependent phosphatases (cGMP-Ps) activation of certain receptors Substances such as acetylcholine, bradykinin, histamine, insulin, and substance P stimulate NO production through this mechanism Similarly, shearing forces acting on the endothelium are another important mechanism regulating the release of NO The inducible form of NOS (iNOS) is not calcium dependent but instead is stimulated by the actions of cytokines (e.g., TNF-a, interleukins) or bacterial endotoxins (e.g., lipopolysaccharide) iNOS occurs over several hours and results in NO production that may be more than a thousandfold greater than that produced by cNOS This is an important mechanism in the pathogenesis of inflammation (Fig 25.3) Inhibition of NOS using competitive analogs of L-arginine drastically reduces endothelium-dependent relaxation in vitro, particularly in large conduit arteries, thereby evoking vasoconstriction Chronic treatment of animals with NOS inhibitors or suppression of the cNOS gene is reported to induce hypertension.25–27 Once NO is formed by an endothelial cell, it readily diffuses out of the cell and into adjacent smooth muscle cells where it binds and activates the soluble form of guanylyl cyclase, resulting in the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate.28 cGMP, in turn, activates a number of cGMP-modulated enzymes (see Fig 25.3) Increased cGMP activates a kinase that subsequently leads to the inhibition of calcium influx into the smooth muscle cell and decreased calcium-calmodulin stimulation of myosin light chain kinase This, in turn, decreases the phosphorylation of myosin light chains, decreasing smooth muscle tension development and causing vasodilation There is also some evidence that increases in cGMP can lead to myosin light chain dephosphorylation by activating the phosphatase In addition, cGMP-dependent protein kinase phosphorylates potassium ion (K1) channels to induce hyperpolarization, thereby inhibiting vasoconstriction.29,30 Interestingly, NO inhibition of platelet aggregation is also related to the increase in cGMP Drugs that inhibit the breakdown of cGMP, such as inhibitors of cGMP-dependent phosphodiesterase (e.g., sildenafil), potentiate the effects of NO-mediated actions on the target cell ... or to affect certain organs Tumor cells often metastasize more commonly within particular vascular beds The basis for this variability in vascular disease is poorly understood but may be explained... adhesion, homeostasis, and vasculogenesis.1 The normal vascular endothelium is only one cell layer thick, separating the blood and vascular smooth muscle The endothelium responds to physical and... prospective randomized trial compared the effects of EPC transplantation in patients with idiopathic pulmonary arterial hypertension versus conventional therapy and showed that after 12 weeks,