The pathophysiology of atherosclerotic cardiovascular disease (CVD) is highlighted by vascular dysfunction and low-grade vascular inflammation. Furthermore, the site-specific distribution of atherosclerosis throughout the arterial vasculature is primarily determined by local hemodynamic force. Therefore, this dissertation outlines three experiments designed to investigate the role of acute mental and physical (i.e., aerobic exercise), and vascular wall shear stress (SS) on the inflammatory aspects of atherosclerosis. Chapter 2 examines the effect of acute laboratory-induced mental stress on intracellular pro-inflammatory signaling pathways in peripheral blood mononuclear cells. Chapter 3 investigates the impact of acute laboratory-induced mental stress and maximal aerobic exercise on the concentration of soluble VCAM-1 (sVCAM-1) and CX3CL1/fractalkine (sCX3CL1) in human serum. Lastly, Chapter 4 examines the role of short- (30 min) and long-term (24 hr) low-to-negative oscillating SS (LOSS) and high laminar SS (HLSS) on the expression and secretion (i.e., cleavage) of cell-membrane VCAM-1 and CX3CL1 by human umbilical vein endothelial cell cultures in vitro. Together, these experiments provide evidence that acute psychological stress, maximal aerobic exercise, and HLSS influence vascular inflammation and adhesive properties of the vessel wall. More specifically, the results from Chapter 2 provide evidence that acute mental stress promotes the immune-cell mediated synthesis of pro-inflammatory cytokines in circulation. In addition, Chapter 3 and Chapter 4 demonstrate that the elevations in blood flow and hemodynamic force associated with maximal aerobic exercise, and unidirectional high SS may have the capacity to alter the expression of endothelial-bound cellular adhesion molecules, in part by eliciting their release from the vessel wall.

<p>Diss. (sammanfattning) Umeå : Umeå universitet, 1996, härtill 6 uppsatser</p> / digitalisering@umu

Yes / Alterations of Endothelial cells (ECs) play a critical role in different pathogenesis of many serious human diseases, and dysfunction of the vascular endothelium is an indicator for human disorders. Endothelial dysfunction is considered to be an early indicator for atherosclerosis, which is characterised by overexpression of adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Hydrogen peroxide (H2O2) released via neutrophils is an important mediator of endothelial cell function. Ambient production of superoxide anion (O2−) and subsequently H2O2 at low levels is critical for regulating endothelial cell functions and proliferation. In this study, we investigated the effects of H2O2 on the expression of adhesion molecules VCAM-1 and ICAM-1 in cultured human umbilical vein endothelial cells (HUVECs). Intracellular superoxide anion production was detected by using p-Nitro Blue Tetrazolium (NBT) assay. Our results showed that administration of 100μM of H2O2 on HUVECs for 2, 6, 12 and 24 h induced a time-dependent increase in ICAM-1 and VCAM-1 mRNA and protein expression levels with a significant increase observed from 6 h. HUVECs exposed to H2O2 exhibit increased O2−, suggesting that H2O2 induced oxidative stress may be a reasonable for atherosclerosis. This increase can be reduced by the flavonoid, N-acetyl cysteine (NAC). The modulation of endothelial cell function through this mechanism may underlie the contribution of H2O2 to the development of vascular disease.

INTRODUÇÃO: Eventos vasculares e imunológicos são centrais na patogênese da granulomatose com poliangeíte (GPA). Moléculas de adesão celular tem papel fundamental no recrutamento de células inflamatórias do sangue para os tecidos. Diferentes leitos vasculares apresentam particularidades na expressão de moléculas de adesão celular explicando talvez parte da especificidade da GPA por determinados órgãos. A elevação no nível sérico de moléculas de adesão celular e aumento da expressão destas em amostras de biópsia renal já foram demonstrados em pacientes com vasculite ANCA associada. No entanto, o fenômeno ainda não foi estudado in situ no pulmão. OBJETIVO: O objetivo deste estudo foi analisar o padrão de expressão endotelial pulmonar de três moléculas de adesão celular na GPA, in situ: molécula de adesão intercelular 1 (ICAM-1), molécula e adesão vascular 1 (VCAM-1) e E-selectina. MÉTODOS: Examinou-se a expressão endotelial de ICAM-1, VCAM-1, E-selectina usando marcação imuno-histoquímica em secções de pulmão fixadas e parafinadas de lesões de GPA (n = 8 casos, 90 secções transversais de vasos analisados). Foram também analisados controles positivos: amostras de pulmão de doença intersticial associada à esclerodermia (SScl) (n = 8 casos, 96 secções transversais de vasos analisados) e controles negativos (n = 9 casos, 90 secções transversais de vasos analisados). A quantificação imuno-histoquímica foi realizada no aumento de 400x usando a técnica de point-counting. RESULTADOS: ICAM-1: A expressão endotelial mediana de ICAM-1 esteve aumentada de forma semelhante na GPA e na SScl (81% and 73%, respectivamente; p = 0.97). A comparação com o grupo controle (26.3%) revelou diferença estatisticamente significativa entre controle e GPA (p <0.001) quanto entre controle e SScl (p = 0.017). VCAM-1: A expressão mediana de VCAM-1 esteve significativamente aumentada na GPA se comparada a SScl (79.5% vs 41.4%; p = 0.012), no entanto, a expressão endotelial de VCAM-1 nos controles também esteve moderadamente aumentada (49.8%) e não houve diferença estatística entre SScl e controles ( p = 0.549) ou entre GPA e controles (p = 0.242). E-selectina: A expressão endotelial mediana de E-selectina esteve aumentada de forma semelhante na GPA e SScl (100% e 88.2%, respectivamente; p = 0.272). A comparação com o grupo controle (13.8%) revelou diferença estatisticamente significativa entre controle e GPA (p < 0.001) e controle e SScl (p = 0.045). CONCLUSÃO: Esses achados evidenciam o fenômeno de ativação endotelial pulmonar in situ em lesões de GPA. O perfil de expressão de moléculas de adesão parece ter particularidades em diferentes doenças a exemplo da maior expressão de VCAM-1 na GPA em relação à SScl. Essas observações contribuem para o conhecimento fisiopatogênico na GPA. / INTRODUCTION: Vascular and immunologic processes are central to the pathogenesis of granulomatosis with polyangiitis (GPA). Endothelial cellular adhesion molecules have a central role in recruiting leukocytes to sites of inflammation. Moreover, different vascular beds are phenotypically and functionally distinct with regard to expression of cellular adhesion molecules. They have been shown to be elevated in sera and in renal biopsies of patients with active ANCA-associated vasculitis. Despite of that, the expression of cellular adhesion molecules has not been studied in situ in the lungs. OBJECTIVE: Within this context, the aim of this study was to analyze the in situ pulmonary endothelial immunohistochemical pattern of expression of three cellular adhesion molecules in GPA: intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin . METHODS: For such, we examined formalin-fixed, paraffin-embedded sections of lung lesions of GPA (n = 8 cases, 90 transverse sections of pulmonary vessels), negative controls which were obtained from autopsies ( n = 9 cases, 90 transverse sections of pulmonary vessels analyzed) and positive controls which were cases of interstitial lung disease associated with systemic sclerosis (SScl) (n = 8 cases, 96 transverse sections of pulmonary vessels). The quantification of the immunohistochemical staining was performed at x400 magnification using the technique of point-counting, previously described. RESULTS: ICAM-1: Median endothelial expression of ICAM-1 was similarly enhanced in GPA and SScl (81% and 73%, respectively; p = 0.97). When compared to controls (26.3%), both GPA (p <0.001) and SScl (p = 0.017) had significantly higher endothelial expression of ICAM-1. VCAM-1: Median endothelial expression of VCAM-1 was significantly enhanced in GPA when compared to SScl (79.5% vs 41.4%; p = 0.012), however the endothelial expression of VCAM-1 in the controls was also moderately enhanced (49.8%) and no statistically significant difference was found between SScl and controls ( p = 0.549) or between GPA and controls (p = 0.242). E-selectin: Median endothelial expression of E-selectin was similarly enhanced in GPA and SScl (100% and 88.2%), respectively; p = 0.272. When compared to controls (13.8%), both GPA (p < 0.001) and SScl (p = 0.045) had significantly higher endothelial expression of E-selectin. CONCLUSION: These observations are evidence of in situ pulmonary endothelial activation in lesions of GPA. The profile of expression of cellular adhesion molecules seems to be particular for each disease state and timing as evidenced by the enhanced expression of VCAM-1 in GPA when compared to SScl. These observations add information to the pathogenetic knowledge of GPA

INTRODUÇÃO: Eventos vasculares e imunológicos são centrais na patogênese da granulomatose com poliangeíte (GPA). Moléculas de adesão celular tem papel fundamental no recrutamento de células inflamatórias do sangue para os tecidos. Diferentes leitos vasculares apresentam particularidades na expressão de moléculas de adesão celular explicando talvez parte da especificidade da GPA por determinados órgãos. A elevação no nível sérico de moléculas de adesão celular e aumento da expressão destas em amostras de biópsia renal já foram demonstrados em pacientes com vasculite ANCA associada. No entanto, o fenômeno ainda não foi estudado in situ no pulmão. OBJETIVO: O objetivo deste estudo foi analisar o padrão de expressão endotelial pulmonar de três moléculas de adesão celular na GPA, in situ: molécula de adesão intercelular 1 (ICAM-1), molécula e adesão vascular 1 (VCAM-1) e E-selectina. MÉTODOS: Examinou-se a expressão endotelial de ICAM-1, VCAM-1, E-selectina usando marcação imuno-histoquímica em secções de pulmão fixadas e parafinadas de lesões de GPA (n = 8 casos, 90 secções transversais de vasos analisados). Foram também analisados controles positivos: amostras de pulmão de doença intersticial associada à esclerodermia (SScl) (n = 8 casos, 96 secções transversais de vasos analisados) e controles negativos (n = 9 casos, 90 secções transversais de vasos analisados). A quantificação imuno-histoquímica foi realizada no aumento de 400x usando a técnica de point-counting. RESULTADOS: ICAM-1: A expressão endotelial mediana de ICAM-1 esteve aumentada de forma semelhante na GPA e na SScl (81% and 73%, respectivamente; p = 0.97). A comparação com o grupo controle (26.3%) revelou diferença estatisticamente significativa entre controle e GPA (p <0.001) quanto entre controle e SScl (p = 0.017). VCAM-1: A expressão mediana de VCAM-1 esteve significativamente aumentada na GPA se comparada a SScl (79.5% vs 41.4%; p = 0.012), no entanto, a expressão endotelial de VCAM-1 nos controles também esteve moderadamente aumentada (49.8%) e não houve diferença estatística entre SScl e controles ( p = 0.549) ou entre GPA e controles (p = 0.242). E-selectina: A expressão endotelial mediana de E-selectina esteve aumentada de forma semelhante na GPA e SScl (100% e 88.2%, respectivamente; p = 0.272). A comparação com o grupo controle (13.8%) revelou diferença estatisticamente significativa entre controle e GPA (p < 0.001) e controle e SScl (p = 0.045). CONCLUSÃO: Esses achados evidenciam o fenômeno de ativação endotelial pulmonar in situ em lesões de GPA. O perfil de expressão de moléculas de adesão parece ter particularidades em diferentes doenças a exemplo da maior expressão de VCAM-1 na GPA em relação à SScl. Essas observações contribuem para o conhecimento fisiopatogênico na GPA. / INTRODUCTION: Vascular and immunologic processes are central to the pathogenesis of granulomatosis with polyangiitis (GPA). Endothelial cellular adhesion molecules have a central role in recruiting leukocytes to sites of inflammation. Moreover, different vascular beds are phenotypically and functionally distinct with regard to expression of cellular adhesion molecules. They have been shown to be elevated in sera and in renal biopsies of patients with active ANCA-associated vasculitis. Despite of that, the expression of cellular adhesion molecules has not been studied in situ in the lungs. OBJECTIVE: Within this context, the aim of this study was to analyze the in situ pulmonary endothelial immunohistochemical pattern of expression of three cellular adhesion molecules in GPA: intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin . METHODS: For such, we examined formalin-fixed, paraffin-embedded sections of lung lesions of GPA (n = 8 cases, 90 transverse sections of pulmonary vessels), negative controls which were obtained from autopsies ( n = 9 cases, 90 transverse sections of pulmonary vessels analyzed) and positive controls which were cases of interstitial lung disease associated with systemic sclerosis (SScl) (n = 8 cases, 96 transverse sections of pulmonary vessels). The quantification of the immunohistochemical staining was performed at x400 magnification using the technique of point-counting, previously described. RESULTS: ICAM-1: Median endothelial expression of ICAM-1 was similarly enhanced in GPA and SScl (81% and 73%, respectively; p = 0.97). When compared to controls (26.3%), both GPA (p <0.001) and SScl (p = 0.017) had significantly higher endothelial expression of ICAM-1. VCAM-1: Median endothelial expression of VCAM-1 was significantly enhanced in GPA when compared to SScl (79.5% vs 41.4%; p = 0.012), however the endothelial expression of VCAM-1 in the controls was also moderately enhanced (49.8%) and no statistically significant difference was found between SScl and controls ( p = 0.549) or between GPA and controls (p = 0.242). E-selectin: Median endothelial expression of E-selectin was similarly enhanced in GPA and SScl (100% and 88.2%), respectively; p = 0.272. When compared to controls (13.8%), both GPA (p < 0.001) and SScl (p = 0.045) had significantly higher endothelial expression of E-selectin. CONCLUSION: These observations are evidence of in situ pulmonary endothelial activation in lesions of GPA. The profile of expression of cellular adhesion molecules seems to be particular for each disease state and timing as evidenced by the enhanced expression of VCAM-1 in GPA when compared to SScl. These observations add information to the pathogenetic knowledge of GPA

Les phospholipases A2 sécrétées (sPLA2) font partie d’une grande famille d’enzymes impliquées dans la synthèse d’écosanoïdes, de chimiokines et dans l’expression de molécules d’adhérence. Ce groupe comprend dix isoformes différentes (sPLA2-IB, -IIA, -IIC, -IID, -IIE, -IIF, -III, -V, -X et XII) dont la majorité sont surexprimées en présence de molécules pro-inflammatoires telles que l’interleukine-1β (IL-1 β) et le lipopolysaccharide bactérien (LPS). La sPLA2-IIA fut longtemps considérée comme la principale sPLA2 associée à l’inflammation. Toutefois, un nombre grandissant d’études suggère l’implication d’autres isoformes dans la réponse inflammatoire. Étant donné la similarité structurelle des différentes isoformes de sPLA2, la majorité des inhibiteurs présentement disponibles sont non spécifiques et bloquent simultanément plus d’une sPLA2. De ce fait, encore peu de choses sont connues quant au rôle précis de chacune des sPLA2 dans la réponse inflammatoire. Ayant accès à des souris génétiquement modifiées n’exprimant pas la sPLA2-V (sPLA2-V-/-), nous avons donc investigué le rôle spécifique de la sPLA2-V dans le recrutement leucocytaire induit par le LPS, ainsi que sa capacité à moduler l’expression de certaines molécules d’adhérence. Pour ce faire, nous avons utilisé le modèle inflammatoire de la poche d’air sous-cutanée. L’administration de LPS dans la poche d’air de souris contrôles (WT) entraîne un recrutement leucocytaire important. Cet appel de cellules inflammatoires est cependant significativement diminué chez les souris sPLA2-V-/-. De plus, l’expression des molécules d’adhérence VCAM-1 et ICAM-1 est également diminuée chez les souris sPLA2-V-/- comparativement aux souris WT. Nos résultats démontrent donc le rôle important de la sPLA2-V dans le recrutement leucocytaire et l’expression de molécules d’adhérence induits par le LPS, confirmant ainsi l’implication de cette enzyme dans le processus inflammatoire. / Secretory phospholipases A2 (sPLA2s) are well known for their contribution in the biosynthesis of inflammatory eicosanoids. These enzymes also participate in the inflammatory process by regulating chemokine production and protein expression of adhesion molecules. The majority of sPLA2 isoforms are up-regulated by proinflammatory stimuli such as bacterial lipopolysaccharide (LPS), which predominantly increases the expression of group V sPLA2 (sPLA2-V). Furthermore, it has recently been shown that sPLA2-V is a critical messenger in the regulation of cell migration during allergic airway responsiveness. Herein, we investigated the effect of sPLA2-V on LPS-mediated leukocyte recruitment and its capacity to modulate adhesion molecule expression. We conducted our study in the murine air pouch model, using sPLA2-V null mice (sPLA2-V-/-) and control wild-type (WT) littermates. We observed that LPS (1 μg/mL)-mediated leukocyte migration in sPLA2-V-/- was attenuated by 52 and 86% after 6 and 12 hours of treatment, respectively, as compared to WT mice. In WT mice, treatment with the cell-permeable sPLA2 inhibitor (12-epi-scalaradial; SLD) reduced LPS-mediated leukocyte recruitment by 67%, but had no additional inhibitory effect in sPLA2-V-/- mice. Protein analyses from the air pouch skin were carried out upon LPS-challenge, and the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 were both significantly reduced in sPLA2-V-/- mice as compared to control WT mice. Together, our data demonstrate the role of sPLA2-V in LPS-induced ICAM-1 and VCAM-1 protein overexpression and leukocyte recruitment, supporting the contribution of sPLA2-V in the development of inflammatory innate immune responses.

Les phospholipases A2 sécrétées (sPLA2) font partie d’une grande famille d’enzymes impliquées dans la synthèse d’écosanoïdes, de chimiokines et dans l’expression de molécules d’adhérence. Ce groupe comprend dix isoformes différentes (sPLA2-IB, -IIA, -IIC, -IID, -IIE, -IIF, -III, -V, -X et XII) dont la majorité sont surexprimées en présence de molécules pro-inflammatoires telles que l’interleukine-1β (IL-1 β) et le lipopolysaccharide bactérien (LPS). La sPLA2-IIA fut longtemps considérée comme la principale sPLA2 associée à l’inflammation. Toutefois, un nombre grandissant d’études suggère l’implication d’autres isoformes dans la réponse inflammatoire. Étant donné la similarité structurelle des différentes isoformes de sPLA2, la majorité des inhibiteurs présentement disponibles sont non spécifiques et bloquent simultanément plus d’une sPLA2. De ce fait, encore peu de choses sont connues quant au rôle précis de chacune des sPLA2 dans la réponse inflammatoire. Ayant accès à des souris génétiquement modifiées n’exprimant pas la sPLA2-V (sPLA2-V-/-), nous avons donc investigué le rôle spécifique de la sPLA2-V dans le recrutement leucocytaire induit par le LPS, ainsi que sa capacité à moduler l’expression de certaines molécules d’adhérence. Pour ce faire, nous avons utilisé le modèle inflammatoire de la poche d’air sous-cutanée. L’administration de LPS dans la poche d’air de souris contrôles (WT) entraîne un recrutement leucocytaire important. Cet appel de cellules inflammatoires est cependant significativement diminué chez les souris sPLA2-V-/-. De plus, l’expression des molécules d’adhérence VCAM-1 et ICAM-1 est également diminuée chez les souris sPLA2-V-/- comparativement aux souris WT. Nos résultats démontrent donc le rôle important de la sPLA2-V dans le recrutement leucocytaire et l’expression de molécules d’adhérence induits par le LPS, confirmant ainsi l’implication de cette enzyme dans le processus inflammatoire. / Secretory phospholipases A2 (sPLA2s) are well known for their contribution in the biosynthesis of inflammatory eicosanoids. These enzymes also participate in the inflammatory process by regulating chemokine production and protein expression of adhesion molecules. The majority of sPLA2 isoforms are up-regulated by proinflammatory stimuli such as bacterial lipopolysaccharide (LPS), which predominantly increases the expression of group V sPLA2 (sPLA2-V). Furthermore, it has recently been shown that sPLA2-V is a critical messenger in the regulation of cell migration during allergic airway responsiveness. Herein, we investigated the effect of sPLA2-V on LPS-mediated leukocyte recruitment and its capacity to modulate adhesion molecule expression. We conducted our study in the murine air pouch model, using sPLA2-V null mice (sPLA2-V-/-) and control wild-type (WT) littermates. We observed that LPS (1 μg/mL)-mediated leukocyte migration in sPLA2-V-/- was attenuated by 52 and 86% after 6 and 12 hours of treatment, respectively, as compared to WT mice. In WT mice, treatment with the cell-permeable sPLA2 inhibitor (12-epi-scalaradial; SLD) reduced LPS-mediated leukocyte recruitment by 67%, but had no additional inhibitory effect in sPLA2-V-/- mice. Protein analyses from the air pouch skin were carried out upon LPS-challenge, and the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 were both significantly reduced in sPLA2-V-/- mice as compared to control WT mice. Together, our data demonstrate the role of sPLA2-V in LPS-induced ICAM-1 and VCAM-1 protein overexpression and leukocyte recruitment, supporting the contribution of sPLA2-V in the development of inflammatory innate immune responses.

No description available.

1 Cardiovascular risks in chronic airway disease in childhood The aim of this thesis was to evaluate cardiovascular risk by using a combined diagnostic approach by measuring RHI and specific biochemical markers in patients with chronic respiratory disease, where we could assume a possible risk of CVD. A total of 119 probands were examined, including 22 patients with cystic fibrosis (CF) and 52 asthma patients. We evaluated RHI using a new plethysmographic method that has a number of advantages over the ultrasonographic methods used in other studies, including non-invasiveness, high sensitivity, low biological variability and objectivity due to automatic processing. Of the biochemical parameters, we measured 4 biomarkers in relation to endothelial dysfunction (ED): hsCRP, ADMA, E-selectin, and VCAM-1. We compared RHI and biomarkers in CF and asthma patients with healthy controls and sought mutual correlations. We did not prove a statistically significant difference in RHI between the test groups with CF children but we confirmed the decreasing trend of RHI since adolescence and significantly lower RHI values in CF adults, confirming the progressive development of atherogenesis and worsening of ED with age. Biochemical parameters showed significantly higher levels of hsCRP, sVCAM-1 and E-selectin in CF...

Einführung - Periphere Blutmonozyten spielen eine Rolle in der Pathogenese der Arteriosklerose. Bei spontan hypertensiven Ratten wurden im Vergleich zu normotonen Wistar-Kyoto-Ratten signifikant erhöhte Zahlen aktivierter Monozyten beobachtet [Liu 1996]. Wir untersuchten Monozyten von Patienten mit essentieller Hypertonie und von gesunden Probanden hinsichtlich möglicher Unterschiede in der Aktivierung anhand ihrer Adhäsion an von uns kultivierte (HAEC) und isolierte (HSVEC, HUVEC, HUAEC) humane Endothelzellen. Wir bestimmten die Adhäsionsmoleküle ICAM-1, VCAM-1 sowie E-Selektin und analysierten die Superoxidfreisetzung von humanem Endothel und Monozyten. Methoden - Humane periphere Blutmonozyten wurden mittels Dichtegradienten-zentrifugation und Plastikadhärenz isoliert und mit LPS, Angiotensin II (Ang II), und Ang II nach Vorinkubation mit dem AT1-Antagonisten Eprosartan stimuliert. Die Monozyten wurden auf einschichtigem Endothel ausgesät und die Adhäsion als Prozentsatz der initial gesäten Zellen erfasst. Die durch PMA induzierte Superoxidfreisetzung des Endothels oder der Monozyten wurde mittels Chemilumineszenz bestimmt. Ergebnisse - Monozyten von Patienten mit essentieller Hypertonie hefteten sich im Vergleich zu gesunden Probanden spontan und nach Stimulation mit Ang II signifikant verstärkt an HAEC und HUVEC-Monolayer an. Die Spiegel von ICAM-1 und VCAM-1 waren bei Patienten mit arterieller Hypertonie im Vergleich zu den gesunden Kontrollpersonen signifikant erhöht. Die Chemilumineszenzaktivität postkonfluenter Endothelzellen erhöhte sich nach Stimulation mit Ang II im Vergleich zur Messung ohne vorherige Stimulierung. Nach Stimulation mit PMA oder mit Ang II wurden bei Hypertonikern signifikant höhere Werte für die Chemilumineszenzaktivität der Monozyten gemessen als bei gesunden Kontrollpersonen. Schluss - Mit diesen Versuchen an humanen Monozyten und Endothelzellen wurde ein weiterer Beweis für die Aktivierung der Monozyten von Patienten mit essentieller Hypertonie erbracht. Meine Ergebnisse unterstützen die Sicht einer Monozytenbeteiligung an der Pathogenese atherosklerotischer Läsionen, die mit arterieller Hypertonie in Zusammenhang stehen. / Introduction - Peripheral blood monocytes are involved in the pathogenesis of atherosclerosis. Significantly elevated numbers of activated monocytes were observed in spontaneously hypertensive rats compared to those in normotensive Wistar-Kyoto rats [Liu 1996]. We isolated and cultivated human endothelial cells and examined monocytes from patients with arterial hypertension and healthy volunteers to identify possible differences in their adhesion behavior to human endothelial cells (HAEC, HSVEC, HUVEC, HUAEC). We determined the levels of ICAM-1, VCAM-1 and E-selectin, and we analyzed superoxide release by human endothelium and human monocytes. Methods - Peripheral blood monocytes were isolated by density gradient centrifugation and plastic adherence. Subsets of the samples were stimulated with LPS, Angiotensin II, Angiotensin II following preincubation with the AT1-antagonist eprosartan or left without a stimulant. After incubation, monocytes were seeded onto confluent monolayers of human aortic endothelial cells and the adhesion was determined as the percentage of the initially seeded cells. Oxygen species release induced by PMA was analyzed for endothelium and monocytes in suspension by chemiluminescence. Results - Peripheral blood monocytes of patients with essential hypertension performed a significantly increased spontaneous adhesion and adhesion following stimulation with Angiotensin II to HAEC- and HUVEC-monolayers. Levels of human soluble adhesion molecules ICAM-1 and VCAM-1 were significantly raised in hypertensive patients. Chemiluminescence activity of post confluent endothelial cells was increased after stimulation with Angiotensin II compared to the measurement before stimulation. Following stimulation with PMA or Angiotensin II, significantly higher chem-iluminescence levels were measured in hypertensive patients compared to healthy volunteers. Conclusion - These data indicate that monocytes of patients with essential hypertension may be preactivated. My results support the view of a monocyte involvement in the pathogenesis of atherosclerotic lesions that are related to arterial hypertension.