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PubMed1982

Role of the vascular endothelium.

A possible explanation for the non-thrombogenic effect of the endothelium is the presence of prostacyclin, (PGI2), the potent inhibitor of platelet aggregation and adherence, which is produced and released by the endothelium in response to various stimuli. Removal of PGI2 from the endothelium did not increase baseline platelet adherence, but did increase thrombin-induced platelet adherence from 4 to 60%. Additions of exogenous PGI2 at low concentrations reversed the enhanced thrombin-induced platelet adherence under these conditions. Although it is unlikely that prostacyclin is the sole factor regulating platelet adherence to the endothelium, it appears to play a major role in the interaction of platelets with components of the blood vessel wall. Conditions which predispose to adherence of platelets to the vessel wall may involve entrapment of tumor cells and lead to metastasis formation. Whether prostacyclin and other factors involved in the non-thrombogenic character of the vascular endothelium provide a significant defense against attachment of tumor cells is not known, but the potential for such a primary or secondary role clearly exists. In our studies, prostacyclin did not appear to influence the adherence of Raji lymphoma cells to the endothelium. Additional studies are indicated to correlate adherence of tumor cells to the vascular wall with their potential for formation of metastatic lesions.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Pathology of anterior chamber angle in diabetic neovascular glaucoma: extension of corneal endothelium onto iris surface.

The purpose of this study is to elucidate the extension of the corneal endothelium onto the iris surface, a condition which has been found in the eyes with rubeosis iridis in various ocular disorders. Histopathology of the anterior chamber angle was studied by electron microscopy in 6 eyes with neovascular glaucoma occurring in the advanced stage of diabetic retinopathy. Histopathological findings embraced extensive peripheral anterior synechiae occluding the filtration angle and fibrovascular tissue on the anterior surface of the iris. In addition, formation of a continuous layer of endothelium was observable on the surface of the iris facing the anterior chamber in the 6 eyes. The newly formed endothelium was continuous with the corneal endothelium at the pseudo-angle formed by the attachment of peripheral anterior synechiae. Two types of corneal endothelial cells were found near the pseudoangle, one type with degenerative changes and the other apparently engaged in normal metabolic activity. It may be assumed from these findings that, while the corneal endothelium undergoes degeneration, new cells of unknown origin proliferate on the posterior corneal surface to replace the disrupted corneal endothelium and extend onto the iris surface.

Adult↗
PubMedDate not supplied

Role of endothelium in conversion of angiotensin I to angiotensin II in rabbit aorta.

Rabbit aortic rings with either an intact endothelium or a disrupted endothelium were used to generate dose response curves to angiotensin I (AI) in the presence (ED50 = 3 X 10(-7) M) and absence (ED50 = 1.7 X 10(-8) M) of 10 micrograms/ml teprotide, a converting-enzyme inhibitor. Treatment with teprotide did not alter responses to angiotensin II (AII). Comparable dose-dependent responses were obtained with AII regardless of endothelial integrity. Contraction velocities in response to angiotensin I (10(-7) M) and AII (10(-7) M) were also measured. Angiotensin II produced a significantly greater contraction velocity (p less than 0.001) than that produced by AI. The amount of conversion to AII by both intact rabbit aortic rings and rings following removal of the endothelium was determined using 125I-AI and 125I-AII. Waters C18 SEP-PAK columns were used to separate AI and AII. During the first 3 to 4 minutes after the addition of AI, contraction velocity measurements and conversion were greater in intact rings than rings without endothelium. Conversion of AI to AII in endothelial-disrupted rings was the same as in intact rings by 5 minutes after the addition of AI. Conversion of AI to AII was inhibited by 30 micrograms/ml teprotide at all times measured, and there was no evidence of an alternate route of metabolism. Angiotensin I contraction velocity measurements after 10 micrograms/ml teprotide also demonstrated impaired efficiency of conversion of AI to AII. Thus, it was established that a lack of endothelium attenuated the rate of conversion of AI to AII initially, and formation of AII with or without endothelium was blocked by teprotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗
PubMed1983

Evidence for cell death in the vascular endothelium in vivo and in vitro.

Focal, spontaneous cell death in the rat aortic endothelium was demonstrated by cytochemistry. Cells with intracellular calcium deposits, indicating cell death with mitochondrial calcification, were identified by chlorotetracycline fluorescence. The same cells also contained cytoplasmic IgG, which binds to cytoskeletal components of the dead cell. The immunocytochemical detection of IgG in en face preparations was used as a quantitative method for detecting cell death in the aortic endothelium. The use of an indirect immunoperoxidase technique and "Häutchens" of paraformaldehyde-fixed tissue provided high sensitivity and cellular recovery with low background. A cell death frequency of 0.19% +/- 0.04% was observed in 5-month-old Sprague-Dawley rats. When compared with the replication rate of aortic endothelium in these animals, the data suggest that dead cells remain in the endothelium for more than 24 hours. This conclusion was supported by in vitro studies. Confluent cultures of bovine aortic endothelium were pulsed with trypan blue, and the residence time of blue cells was 3.5-4 days in non-flow culture system. Time-lapse video microscopy showed a prolonged cell death process with a phase of rapid intracellular movements, followed by undermining by surrounding cells and fragmentation of the dead cell. Migration of surrounding cells rapidly covered partial detachments of the dead cell, so that no holes could be detected in the monolayer when the dead cell finally detached. It is concluded that the normal turnover of cells in the aortic endothelium involves a prolonged phase of in situ cell death and finally detachment with very little or no exposure of subendothelial structures.

Animals↗
PubMed1983

Inactivation of thrombin by the aortic endothelium.

The aim of the investigation was to clarify the uptake of thrombin on vascular endothelium and the inhibition of thrombin on the endothelium in the presence or absence of plasma. Segments of porcine aorta were used. Thrombin was labelled with 125I and its enzymatic activity was assayed amidolytically using a specific chromogenic substrate. After exposure to the endothelium both enzymatic activity and radioactivity disappeared from the thrombin solution and were recovered as surface bound activities. The enzyme activity confined to the endothelium rapidly disappeared in the presence of plasma but no activity was recovered in the plasma. The surface confined radioactivity, however, decreased slowly and was quantitatively recovered in the plasma. In the absence of plasma, i.e. in the presence of a balanced Ringer's solution, only slow disappearance of thrombin enzymatic activity occurred although the rate of disappearance was higher than that of release of radioactivity. It is concluded that thrombin, taken up on the endothelium, is almost instantaneously inhibited by an interaction mechanism with plasma and then released in an inactive state. The endothelium itself, however, seems to slowly inhibit bound thrombin and then release it.

Animals↗
PubMed1981

Prostacyclin release from cultured and ex vivo bovine vascular endothelium. Studies with thrombin, arachidonic acid, and ionophore A23187.

Prostacyclin release from systemic and pulmonary endothelium has been evaluated in cultured cell monolayers and in an ex vivo vascular segment model in which the endothelium remains in contact with subendothelial structures. The effect of exposure to arachidonic acid, ionophore A23187, and thrombin on prostacyclin release has been assessed. Arachidonic acid elicited prostacyclin release in a dose-dependent fashion. Ionophore also stimulated bovine systemic endothelium to release prostacyclin. Thrombin-endothelial cell interactions have been examined extensively. Unlike umbilical venous endothelium, systemic and pulmonary bovine endothelium did not release prostacyclin following exposure to thrombin. Exposure to thrombin also failed to evoke the release of tritiated arachidonate metabolites from the bovine endothelial cell preparations. The presence of high affinity binding sites for thrombin (KD = 9.5 X 10(-9) M) on the bovine endothelium suggests that either thrombin binding is causally unrelated to prostacyclin release or that the bovine cells lack mediators required for thrombin to exert its effect.

Animals↗
PubMed1982

The control of hemostasis. Role of endothelium in the regulation of inhibitory and catabolic pathways.

The role of the microvascular endothelium in the integration of inhibitory and catabolic pathways of hemostasis is discussed in light of recent findings of direct biochemical links between endothelium and regulatory plasma proteins. These findings include the following: (1) On the vascular endothelium, a cofactor for antithrombin III (with an activity comparable to stationary phase heparin) catalyzes thrombin inhibition in vivo. (2) A second cofactor on endothelium binds thrombin in a manner that enhances by several orders of magnitude the ability of thrombin to activate protein C. (3) Activated protein C has both anticoagulant and catabolic activities; anticoagulant activity results from the susceptibility of factors Va and VIIIa to inactivation by activated protein C, whereas catabolic activity arises from the stimulation by activated protein C of the release from endothelium of fibrin-dependent plasminogen activator. (4) Because it requires fibrin as a cofactor, the plasminogen activator lyses clots without provoking fibrinogenolysis. Location of these activities on endothelium separates coagulation in time and space from catabolic pathways, and provides for their expression after the initiation of hemostasis.

Antithrombins↗
PubMed1977

Repair in arterial tissue. The role of endothelium in the permeability of a healing intimal surface. Vital staining with Evans blue and silver-staining of the aortic intima after a single dilatation trauma.

The role of the endothelium as a factor determining the permeability of a healing aortic intima after a severe mechanical lesion in the rabbit was studied by vital staining with Evans blue, by surface light microscopy after silver-staining, fluorescence microscopy and by other methods. Endothelium to develop from pre-existing endothelium in the mouths of intercostal arteries and at the borders of the lesion, remained unstained by vital staining, whereas denuded surfaces as well as pseudo-endothelium, probably derived from smooth muscle cells in the neointima, were intensely coloured. There was a general tendency towards a decreasing permeability of the aortic wall throughout an experimental period of 6 months. The determinant factor in the decreasing permeability was the presence of genuine endothelium, but changes in the endothelium, probably in the form of differentiation of intercellular junctions and changes in the connective tissue in the deeper layers, seemed to be additional factors which influenced the permeability.

Animals↗
PubMed1995

Endothelium-dependent vascular hyporesponsiveness without detection of nitric oxide synthase induction in aortas of cirrhotic rats.

The present experiments were designed to test if induction of nitric oxide synthase (NOS) plays a role in the systemic vasodilation observed in hepatic cirrhosis. Because endotoxin levels are elevated in cirrhosis, and endotoxin stimulates inducible nitric oxide synthase (iNOS) expression in several cell lines, aortas of carbon tetrachloride-induced cirrhotic rats with ascites were evaluated for iNOS expression. Endotoxin-treated rats were studied as positive controls. Phenylephrine contraction was decreased in aortic rings with endothelium from both endotoxin-treated and cirrhotic rats as compared with controls. However, after endothelium denudation, the reduced contractility persisted in endotoxin-treated rats but disappeared in cirrhotic rats. L-Nitro-arginine-methylester (L-NAME), a nonselective inhibitor of NOS, potentiated the phenylephrine contraction of aortic rings with and without endothelium from endotoxin-treated rats but only rings with endothelium from cirrhotic rats. Moreover, aminoguanidine (AG), a preferential inhibitor of iNOS, did not affect phenylephrine contraction of rings with or without endothelium from cirrhotic rats but reversed the blunted response in endotoxin-treated rats. Northern analysis detected iNOS RNA (mRNA) expression in aortas of endotoxin-treated rats but did not detect it from cirrhotic rats. In summary, although several previous studies provide evidence for in vivo overproduction of nitric oxide in cirrhosis, the present results do not support iNOS induction as the source of nitric oxide in aortas of cirrhotic rats. Rather, because the aortic vascular hyporesponsiveness in cirrhosis is endothelium-dependent, overexpression or overstimulation of the endothelial constitutive isoform of NOS appears to be involved.

Animals↗
PubMed1994

Aberrant expression of membrane cofactor protein and decay-accelerating factor in the endothelium of patients with systemic sclerosis. A possible mechanism of vascular damage.

BACKGROUND: One of the main features of systemic sclerosis (SSc) is vascular damage, the mechanism of which is not understood. The aim of this study was to investigate if complement (C) regulatory molecules, membrane cofactor protein (MCP), decay-accelerating factor (DAF), and CD59, which normally protect endothelial cells from damage by autologous C, are absent or down-regulated in vascular endothelium of patients with SSc. A deficiency or persistent down-regulation of the above molecules is likely to render vascular endothelium of these patients susceptible to damage by physiologically or pathologically activated C. From this point of view, expression of MCP, DAF, and CD59 was tested on endothelium of skin of normal subjects and patients with diffuse and limited forms of SSc. EXPERIMENTAL DESIGN: Punch biopsies of normal skin (N = 11) and lesional and non-lesional skin of patients with diffuse (N = 5) and limited (N = 5) forms of SSc were obtained and serial sections prepared. Immunoperoxidase staining of these sections was carried out using four monoclonal antibodies (MoAbs) directed to different epitopes of DAF, four to different epitopes of MCP, one to CD59 and one to von Willebrand factor. von Willebrand factor served as a marker of endothelial cells. Besides normal skin, lesional skin of systemic lupus erythematosus and several inflammatory and proliferative diseases, described below, served as controls. RESULTS: The endothelium of normal skin strongly expressed all the three proteins. However, the endothelium of lesional and nonlesional skin of all the 10 patients with diffuse or limited forms of the disease tested, expressed either decreased or undetectable amounts of MCP and DAF. CD59 expression was normal in some patients and lower than normal in others. Aberrant expression of MCP, DAF, or CD59 was not found in other control inflammatory, connective tissue and proliferative diseases studied. CONCLUSIONS: In view of the common function of MCP and DAF to protect self cells from autologous C, their decrease or virtual absence from the endothelium of patients with SSc strongly suggests that this deficiency may contribute to vascular damage, resulting in intima proliferation and, finally, fibrosis.

Antibodies, Monoclonal↗
PubMed1994

P-selectin mediates the interaction of circulating leukocytes with platelets and microvascular endothelium in response to oxidized lipoprotein in vivo.

BACKGROUND: Oxidized low density lipoprotein (oxLDL) has been demonstrated to stimulate leukocyte/endothelium interaction, an early feature of atherogenesis. Using the skinfold chamber model for intravital microscopy in hamsters and mice, we have shown that oxLDL-induced leukocyte adhesion to microvascular endothelium shares many characteristics with leukocyte adhesion during inflammation and ischemia/reperfusion, including the involvement of beta 2 integrin adhesion molecules. In light of the two-step model of leukocyte adhesion, we have examined the contribution of P-selectin to oxLDL-induced leukocyte/endothelium interaction. P-selectin is an inducible adhesion molecule on platelets and endothelium, mediating the initial steps of leukocyte margination and rolling along the endothelial lining, as well as of aggregate formation between platelets and leukocytes. EXPERIMENTAL DESIGN: For our studies, we used the dorsal skinfold chamber model for intravital fluorescence microscopy on awake Syrian golden hamsters. Hamsters were treated 10 minutes before oxLDL-injection (oxidized by Cu2+, 4 mg/kg body weight, intravenously) with blocking antibodies to P-selectin (2 mg/kg body weight intravenously, N = 7). RESULTS: In seven control animals (pretreated with an irrelevant IgG antibody), oxLDL injection elicited leukocyte rolling and adhesion on both venular and arteriolar endothelium, and also the formation of aggregates tumbling down the microvessels and firmly adhering to the microvascular endothelium. The aggregates consisted of leukocytes and activated, dendritic platelets, as assessed by scanning electron microscopy of the buffy coat isolated by density gradient centrifugation of whole blood taken from hamsters 15 minutes after injection of oxLDL. Leukocyte adhesion to venular and arteriolar endothelium, as well as the formation of leukocyte/platelet aggregates were significantly reduced by pretreatment of the animals with anti-P-selectin antibodies. CONCLUSIONS: These data emphasize the similarities between leukocyte adhesion in response to oxLDL and in other pathophysiologic conditions, identifying P-selectin as a crucial player in the interaction between leukocytes and microvascular endothelium as well as in the formation of circulating leukocyte/platelet aggregates.

Animals↗
PubMed1994

Potentiation by trandolaprilat of the endothelium-dependent hyperpolarization induced by bradykinin.

In canine coronary arteries, bradykinin evokes endothelium-dependent relaxations that are mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). The converting-enzyme inhibitor trandolaprilat potentiates the endothelium-dependent relaxations evoked by bradykinin in this tissue. The present experiments were designed to determine whether or not facilitated release of EDHF contributes to the augmented response to bradykinin in the presence of trandolaprilat. Organ-chamber studies were performed to measure changes in isometric tension in rings of canine coronary arteries. In the presence of nitro-L-arginine, an inhibitor of NO synthase, trandolaprilat augmented the endothelium-dependent relaxations evoked by bradykinin. These relaxations were not inhibited by the K(+)-channel inhibitors tetraethylammonium, 4-aminopyridine, or glibenclamide, but were abolished in high-potassium solution. The membrane potential in individual smooth-muscle cells of coronary artery was measured by means of glass microelectrodes. Trandolaprilat potentiated the endothelium-dependent hyperpolarizations evoked by a subthreshold concentration of bradykinin, and these endothelium-dependent hyperpolarizations were inhibited by high-potassium solution. These experiments demonstrate that EDHF contributes to the relaxation evoked by bradykinin in the canine coronary artery and that trandolaprilat potentiates the release of this factor. This effect of trandolaprilat may contribute to its vasodilator properties.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Double-stranded RNA induces sickle erythrocyte adherence to endothelium: a potential role for viral infection in vaso-occlusive pain episodes in sickle cell anemia.

Vaso-occlusive pain episodes in sickle cell anemia are hypothesized to be precipitated by adherence of sickle erythrocytes to vascular endothelium in the microcirculation. Febrile episodes, thought to be viral in etiology, are frequently associated with vaso-occlusion; however, a direct link between viral infection and vascular occlusion has not yet been established. Many pathogenic viruses contain double-stranded RNA or replicate through double-stranded RNA intermediates. Double-stranded RNA has been shown to induce vascular cell adhesion molecule-1 (VCAM-1) protein expression on endothelial cells. Recently, a new adhesion pathway has been described between VCAM-1 expressed on cytokine stimulated endothelium and the alpha 4 beta 1 integrin complex expressed on sickle reticulocytes. Based on these observations, the hypothesis was developed that viral infection, through double-stranded RNA intermediates, increases endothelial VCAM-1 expression leading to sickle erythrocyte adhesion to endothelium via an alpha 4 beta 1-VCAM-1--dependent mechanism. In support of this hypothesis, endothelial cells exposed to the synthetic double-stranded RNA poly(I:C) or the RNA virus parainfluenza 1 (Sendai virus) express increased levels of VCAM-1 and support increased sickle erythrocyte adherence under continuous flow at 1.0 dyne/cm2 shear stress as compared with unstimulated endothelium. Blocking antibodies directed against either VCAM-1 on the endothelium or alpha 4 beta 1 on sickle erythrocytes inhibit nearly all of the increased sickle cell adherence caused by poly(I:C) or Sendai virus. These results support the hypothesis that viruses, through double-stranded RNA elements, can induce sickle erythrocyte adherence to endothelium through alpha 4 beta 1-VCAM-1--mediated adhesion and provide a potential link between viral infection and microvascular occlusion precipitating sickle cell pain episodes.

Anemia, Sickle Cell↗
PubMed1995

Influence of endothelium on responses of isolated dog coronary artery to beta-adrenoceptor agonists.

AIM: To study the role of the endothelium in mediating the response of the coronary arteries to adrenoceptor agonists. METHODS: Endothelium intact and denuded dog epicardial coronary artery rings were used. The contractile responses were recorded on forcetransducer and a pen recorder. RESULTS: In all ring segments, norepinephrine (NE) and isoproterenol (Iso) produced concentration-dependent relaxation in the presence and absence of phentolamine. Endothelium-removal decreased this relaxation and depressed the maximal response. Inhibition of nitric oxide synthesis by N omega-nitro-L-arginine-methyl ester induced the same influences as endothelium-removal. CONCLUSION: beta-adrenoceptor agonists produce relaxation of dog coronary artery by both endothelium-dependent and independent mechanisms, endothelium-dependent relaxation induced by beta-adrenoceptor agonists is mediated by nitric oxide.

Adrenergic beta-Agonists↗
PubMed1995

An interferon-inducible molecule on brain endothelium which controls lymphocyte adhesion mediated by integrins.

We undertook a search for cytokine-inducible molecules present on brain endothelium and which are involved in the control of lymphocyte adhesion. We screened 39 monoclonal antibodies (mAb) against rat brain endothelium in vitro, and identified five recognizing cytokine-inducible molecules. None of the 39 antibodies blocked lymphocyte adhesion, but one antibody (4A2), produced a 400% enhancement of lymphocyte binding. The 4A2 antigen is induced on brain endothelium by interferon-gamma (INF-gamma) but not tumour necrosis factor-alpha (TNF-alpha), at 6-48 hr. It is preferentially expressed near inter-endothelial cell junctions, but it also expressed on all lymphocytes and weakly on aortic endothelium in vitro. In vivo, it is not detectable on cells in the normal central nervous system (CNS), however it appears in the CNS during T-cell mediated immune reactions. Triggering of cells via this molecule enhances integrin-mediated adhesion of lymphocytes to brain endothelium, primarily via LFA-1. Unlike ICAM-1, 4A2 antigen is induced on endothelium of both Lewis and PVG strains. Although, it has some functional properties of human CD31, the 4A2 antigen is not rat CD31. The cellular localization of this molecule, its actions on integrin-mediated adhesion and its induction by IFN-gamma, all indicate that the 4A2 antibody recognizes a molecule involved in the control of lymphocyte migration into the brain.

Animals↗
PubMed1994

The endothelium and control of blood vessel function in health and disease.

The endothelium is critically involved in the regulation of vascular function through its barrier role, via interaction with circulating cells such as platelets, which then release vasoactive or growth regulating agents, through production of substances which may modulate vascular tone and smooth muscle cell growth and also exert anti-thrombotic effects. The release of serotonin, adenosine diphosphate (ADP), or growth factors from platelets adhering to damaged endothelium, the release of endothelium-derived relaxing or contracting factors (nitric oxide, prostanoids, endothelin), the production of growth factors, all of which exert their effects in paracrine or even autocrine fashion, are some of the mechanisms whereby the endothelium influences vascular tone and growth and platelet aggregation. In different conditions such as hypertension, atherosclerosis, diabetes, heart failure, ischemic heart disease, sepsis, and shock, dysfunction of the endothelium plays an important pathophysiological role through reduction or enhancement of the release of these different products with significant hemodynamic and trophic effects. Therapeutic interventions targeting the endothelium hold promise in the treatment and prevention of some cardiovascular diseases and their complications.

Blood Coagulation↗
PubMed1994

DNA synthesis in isolated arteries of normotensive and hypertensive rats: effects of the endothelium.

OBJECTIVES: To compare DNA synthesis in isolated arteries of normotensive and hypertensive rats and to evaluate whether removal of the endothelium affects this process. DESIGN: Carotid and renal artery segments were isolated from normotensive Wistar, Wistar-Kyoto (WKY) and Sprague-Dawley rats, and from spontaneously hypertensive rats (SHR), transgenic Sprague-Dawley rats harbouring the mouse Ren-2 gene and from WKY rats rendered hypertensive by aortic coarctation. METHODS: Artery segments were exposed in vitro to serum with or without previous gentle removal of the endothelium. Nuclear incorporation of the thymidine analogue 5-bromo-2'-deoxyuridine was visualized by immunocytochemistry and the percentage of labelled medial nuclei was determined. RESULTS: In both types of artery, obtained from 6-week-old WKY rats and from 6-week-old SHR, removal of endothelium increased the percentage of 5-bromo-2'-deoxyuridine-labelled medial nuclei (L%). Also, in the arteries of 20-week-old Wistar rats, WKY rats and WKY rats rendered hypertensive by aortic coarctation and in vessels of 11-week-old Sprague-Dawley rats and Sprague-Dawley rats harbouring the mouse Ren-2 gene, removal of endothelium increased L%. Conversely, in the arteries of 20-week-old SHR removal of the endothelium did not alter L%. Furthermore, maximally stimulated DNA synthesis was considerably smaller in de-endothelialized arteries of adult SHR than in denuded vessels from the other strains and models. CONCLUSION: These findings confirm that the endothelium can reduce DNA synthesis in the intact rat arterial smooth muscle. This effect is not modified by hypertension, but is selectively reduced in the arteries of adult SHR.

Animals↗
PubMed1994

15-Hydroxyeicosatetraenoic acid inhibits neutrophil migration across cytokine-activated endothelium.

15-hydroxyeicosatetraenoic acid (15-HETE) is an eicosanoid, formed by the actions of 15-lipoxygenase, epoxygenases, and cyclooxygenases on arachidonic acid, whose tissue levels are often elevated during inflammation. The present study demonstrates that 15(S)-HETE is a potent inhibitor of polymorphonuclear neutrophil (PMN) migration across cytokine-activated endothelium in vitro. 15(S)-HETE is rapidly esterified into PMN phospholipids, and we report that 15-(S)-HETE-remodeled PMN displayed blunted adhesion to, and migration across, human endothelial cells that had been activated with either interleukin-1 beta or tumor necrosis factor-alpha Several lines of evidence suggested that 15(S)-HETE inhibited PMN transmigration by attenuating PMN responsiveness to endothelial cell-derived platelet-activating factor (PAF). The inhibitory action of 15(S)-HETE on transmigration was not restricted by the profile of adhesion molecules expressed by cytokine-activated endothelium. Interleukin-1 beta and tumor necrosis factor-alpha induce PAF production by endothelium, and PMN migration across cytokine-activated endothelium was inhibited by a PAF receptor antagonist. PMN migration across endothelium in response to exogenous PAF was dramatically inhibited following exposure of PMN to 15(S)-HETE. Furthermore, 15(S)-HETE-remodeled PMN displayed impaired cytoskeletal and adhesion responses when stimulated by exogenous PAF, two pivotal events in PMN migration across activated endothelium. 15(S)-HETE seemed to attenuate PMN responsiveness to PAF by inhibiting membrane-associated signal transduction events. In keeping with this interpretation, remodeling of PMN phospholipids with 15(S)-HETE was associated with a sixfold reduction in the affinity of specific high-affinity PAF receptors for their ligand and impaired PAF-triggered IP3 generation. In contrast, PMN adhesion responses stimulated by calcium ionophore or activators of protein kinase C remained intact. These results provide further evidence that 15(S)-HETE may be an important endogenous inhibitor of PMN-endothelial cell interaction that serves to limit or reverse neutrophil-mediated inflammation in vivo.

Cell Adhesion↗