Endothelial Surface Receptors Research Articles

Activated protein C versus protein C in severe sepsis.

To delineate critical differences between activated protein C (APC) and its precursor, protein C, with regard to plasma levels in health and in severe sepsis, and to discuss the implications of these differences as they relate to treatment strategies in patients with severe sepsis. DATA SOURCE/STUDY SELECTION: Published literature including abstracts, manuscripts, and review articles reporting studies in both experimental animal models and humans that provide an understanding of the relationship and the critical differences between circulating levels of APC and protein C. The protein C pathway represents one of the major regulatory systems of hemostasis, exhibiting antithrombotic, profibrinolytic and anti-inflammatory properties. This pathway also plays a critical role in the pathophysiology of severe sepsis. Central to this pathway is the vitamin K-dependent serine protease, APC, and its precursor, protein C. The conversion of protein C to APC is dependent on the complex of thrombin and thrombomodulin, an integral endothelial surface receptor. The conversion of protein C to APC is further augmented by another endothelial surface protein, the endothelial protein C receptor. There are limited published data on APC levels in health and disease, probably due to the complexity of the assay methodology for measuring APC and the absence of commercially available diagnostic kits. In animals and humans with normal functioning endothelium, circulating levels of APC (1-3 ng/mL) are positively correlated with protein C (4000-5000 ng/mL) concentration and the amount of thrombin generated. In patients with severe sepsis, there is a generalized endothelial dysfunction, contributing to multiple organ failure with increased morbidity and mortality. Persistently low protein C levels are related to poor prognosis. Key to understanding the treatment strategy with APC or protein C is knowledge of the functional status of the endothelium and, specifically, whether the microvasculature in patients with severe sepsis can support the conversion of protein C to APC. To date, only APC (drotrecogin alfa [activated]) has been shown to reduce mortality in severe sepsis in a large, phase 3, placebo-controlled, double-blind international trial. In contrast, no data, other than open-label case studies, are available for evaluation of the effects of protein C in the treatment of severe sepsis. The limited data available indicate that lower levels of protein C in sepsis occur in the absence of appreciable conversion to APC. These observations indicate that treatment with APC may be more efficacious than protein C in severe sepsis, where generalized endothelial dysfunction may impair conversion of protein C to APC. Additional research is required to confirm these observations.

Association between the Molecular Pathobiology of Essential Hypertension and Thrombotic Diseases

Association between the Molecular Pathobiology of Essential Hypertension and Thrombotic Diseases

The neutrophil and preeclampsia.

Endothelial injury is common to all pathological features of preeclampsia. Neutrophil activation has been implicated in the pathophysiology of preeclampsia and requires binding and transmigration of neutrophils through the endothelium. This occurs via an interaction of endothelial adhesion molecules and surface receptors on neutrophils. Upon activation, neutrophil granules are released, the contents of which are capable of mediating vascular damage. In addition, leukotrienes are synthesized, and superoxide is generated in a respiratory burst. These products also provoke vascular damage. Neutrophil recruitment to the endothelium involves express of P-selectin and released of platelet activating factor from the endothelium. In preeclampsia there is evidence of an increase in neutrophil activation with up-regulation of neutrophil integrin expression and increased regulation of the protease elastase. Furthermore, these markers of neutrophil activation correlate with established markers of disease severity. The primary mechanism of neutrophil activation is unknown, but neutrophils in preeclampsia appear to have normal motor activity. Several potential mechanisms of neutrophil activation have been identified. They include up-regulation of cellular adhesion molecules on the endothelial surface, increased generation of tumor necrosis factor-alpha, and endothelial activation from hyperlipidemia. In additional to activation of neutrophils in preeclampsia, there may be involvement of the interleukin-6 and endothelin-1 in "priming" neutrophils for subsequent superoxide production. Activated neutrophils are likely to play a large part in the arteriopathy and endothelial damage associated with preeclampsia, but it is unclear whether neutrophil activation is the cause or the consequence of endothelial damage.

Role of the Endothelium in the Flow Regulation of Vascular Tone

The strategic location of the endothelium between the flowing intraluminal blood and the vascular smooth muscle cells in the blood vessel wall implies that it should play a crucial role in the blood flow regulation of vascular tone. However, the nature of many of the cellular mechanisms involved in this inter-relationship remain speculative and controversial. The author's hypothesis is that flow can initiate two responses as the result of shear stress activation of a common sensor -the characteristic response is dilation but constriction occurs at lower and can also occur at higher tone levels. At lower levels of tone, flow-contraction and -dilation interact influencing wall tone towards a balance point. Current theories of flow sensing include deformation of viscoelastic molecules attached to the lumenal surface of the endothelium, deformation of the lumenal surface of endothelial cells and flow-dependent, endogenous agonist -lumenal endothelial surface receptor interaction. There are a number of ways in...

Recombinant soluble human thrombomodulin: A randomized, blinded assessment of prevention of venous thrombosis and effects on hemostatic parameters in a rat model

Thrombomodulin is an endothelial surface receptor that binds thrombin and accelerates the activation of protein C. We compared the effects of a recombinant thrombomodulin analog (TME), recombinant hirudin (r-HIR), heparin sodium (HEP), and normal saline (Control) on thrombus formation, activated partial thromboplastin time (APTT), thrombin time (TT), platelet aggregation and tail transection bleeding time (BT) in a rat model of vena cava thrombosis. Results: TM E, r-HIR and HEP prevented venous thrombosis in this model in a dose-dependent manner. At the dose required to reduce vena cava thrombosis by 50% (ED 50), TM E did not prolong the APTT or TT as did HEP and r-HIR. Platelet aggregation in response to thrombin was not effected by TME but was inhibited by both r-HIR and HEP. BT did not differentiate the agents tested. Conclusion: TM E inhibited venous thrombosis in a rat vena cava model with less effect on hemostatic variables than HEP or r-HIR.

Modeling of palmitate transport in the heart

Transport of palmitate from the albumin-palmitate complex in the plasma to inside mitochondria where it undergoes beta-oxidation is a multistep process. Albumin's large size prevents permeation via interendothelial clefts. Palmitate dissociation from albumin in solution is too slow to provide an adequate supply of the unbound palmitate. The discovery that the dissociation occurs upon albumin binding to an endothelial surface receptor resolves the conundrum. Palmitate transport across the luminal surface membrane may be either carrier-mediated or passive. Fatty-acid binding protein inside endothelial and cardiac muscle cells facilitates diffusion through cytosol while maintaining the unbound palmitate concentration at a very low level. Within the interstitium, albumin is again the palmitate carrier. Still controversial is whether or not there is a saturable sarcolemmal transporter or simply passive exchange. Inside the myocyte palmitate is again bound to the fatty acid binding protein which buffers the free palmitate concentration, facilitates diffusion, and may facilitate further intracellular reactions.

Endothelium dependence of dilation of pial arterioles in mouse brain by calcium ionophore.

Previous studies have shown that local selective in situ injury of pial arteriolar endothelium eliminates the dilations produced by acetylcholine or bradykinin. One means of producing such injury employs a helium-neon laser in the presence of intravascular Evans blue. Since the endothelium-dependent dilations produced by acetylcholine or bradykinin may be initiated by interaction with endothelial surface receptors, it is possible that the light simply inactivates or destroys these receptors. We used calcium ionophore A-23187, another dilating agent known from in vitro studies of large arteries to be endothelium-dependent, which moves calcium into endothelial cells rather than interacting with surface receptors. Our data in 10 mice show that before injury, 10(-5)M A-23187 dilated arterioles to 109 +/- 2% of control diameter. After selective endothelial injury by helium-neon laser, dilation was essentially abolished (101 +/- 1% of baseline diameter; p less than 0.01, Wilcoxon test). Undamaged sites along the arteriole still dilated to A-23187. Our data indicate that the laser must do more than inactivate surface receptors and are the first in vivo microvascular (vessels of less than 100 micron diameter) data showing endothelium dependence of the response to A-23187.