Biomedical subjects

Michael W J Boehme

Publications and source records attributed to Michael W J Boehme.

3 recordsLinked to original sources

PubMed2005

Decrease in circulating endothelial cell adhesion molecule and thrombomodulin levels during oral iloprost treatment in rheumatoid arthritis patients: preliminary results.

OBJECTIVE: Rheumatoid arthritis is a chronic inflammatory autoimmune disease with proinflammatory cytokines involved in its pathogenesis. Recently in vitro as well as in vivo studies have shown that iloprost, a stable prostacyclin analogue, can reduce the release of these cytokines. This study was performed to further investigate the anti-inflammatory effects of iloprost by determining plasma adhesion molecules as markers of endothelial cell activation, and plasma thrombomodulin as a parameter of endothelial cell injury in patients with rheumatoid arthritis receiving oral iloprost therapy. METHODS: Plasma thrombomodulin levels and the values of the plasma adhesion molecules VCAM-1 (vascular cell adhesion molecule 1), E-selectin (CD62E), and ICAM-1 (intercellular adhesion molecule 1, CD 54) were measured by ELISA during a 7-day period of treatment with orally-administered iloprost in 14 patients with active rheumatoid arthritis. Finally, the same parameters were determined at the end of the observation period (1 week after the end of therapy). In addition, the disease activity was measured using the DAS (disease activity score) as well as the patients' self-assessed pain severity, and correlated with the changes of plasma adhesion molecule and thrombomodulin levels. RESULTS: The plasma levels of all three adhesion molecules as well as of thrombomodulin significantly decreased under therapy with oral iloprost. After 1 week (day 7 of therapy), the mean percent changes from day 0 were -20.1% for VCAM-1 (p = 0.008), -21.2 for ICAM-1 (p = 0.003), -24.6% for E-selectin (p = 0.001), and -21.7% for thrombomodulin (p = 0.003). This decrease lasted up to 1 week after the end of therapy in the case of VCAM-1 (p = 0.023) and ICAM-1 (p = 0.001). Further analysis of the results revealed additional significant correlations between different parameters of clinical disease activity, thrombomodulin and adhesion molecules. CONCLUSION: This study showed hints towards clinical effects in patients with rheumatoid arthritis receiving oral iloprost therapy. Pathophysiologically, the decrease of adhesion molecules points at an immunomodulating effect of iloprost. The observed thrombomodulin-lowering effect of iloprost may indicate stabilisation of endothelial cell function by diminishing endothelial cell injury.

Administration, Oral↗

PubMed2002

A 7-day oral treatment of patients with active rheumatoid arthritis using the prostacyclin analog iloprost: cytokine modulation, safety, and clinical effects.

OBJECTIVE: The purpose of this study was to investigate the plasma levels of tumor necrosis factor (TNF)-alpha, its soluble p55 and p75 receptors, ex vivo lipopolysaccharide (LPS)-stimulated TNF-alpha production, and plasma levels of interleukin 6, interleukin 1, and interleukin 10 during a 7-day oral administration of iloprost in patients with active rheumatoid arthritis. METHODS: During oral 7-day administration of the prostacyclin analog iloprost, the plasma levels of TNF-alpha, soluble p55, and p75 TNF-alpha receptors, IL-1, IL-6, and IL-10 and C-reactive protein (CRP) in serum were determined on days -1, 1, 3, 4, 6, and 8 and after a treatment-free follow-up on day 15. In addition, the ex vivo TNF-alpha production in whole blood under LPS-stimulated and -unstimulated conditions were measured. Fifteen patients with active rheumatoid arthritis and baseline TNF-alpha plasma levels of > or =2 pg/ml were included in independent groups receiving 50 microg, 100 microg, or 150 microg iloprost per day in addition to their conventional antirheumatic therapy. The respective dose was given once daily from days 1 to 3 and doubled from days 4 to 7. The tender and swollen joint count (28 joints) and the patients' assessments of pain severity and general feeling (10-cm visual analog scale) were performed on days -1, 4, and 8 (end of treatment) and after a 7-day follow-up. RESULTS: The patients showed decreased TNF-alpha levels during iloprost administration. The decrease in the ex vivo LPS-stimulated TNF-alpha production and plasma levels of the p75 TNF receptor were found to be associated with a decrease in the number of tender joints. Additionally, IL-6 was downregulated. CONCLUSION: A 7-day oral administration of iloprost resulted in a change of in vivo and ex vivo cellular cytokine production, with reductions in TNF-alpha and p75 TNF receptor plasma levels. These changes were associated with clinical improvements in active rheumatoid arthritis.

Administration, Oral↗

PubMed2002

Kinetics of thrombomodulin release and endothelial cell injury by neutrophil-derived proteases and oxygen radicals.

Thrombomodulin is a transmembranous glycoprotein of endothelial cells. In vitro it is a marker of endothelial cell injury. In vivo the levels of serum thrombomodulin are regarded as a parameter of activity in vasculitides. The latter are pathophysiologically determined by neutrophil-derived inflammation and endothelial cell injury caused by secretion of proteases and hydrogen peroxide. It was the objective of this study to determine whether thrombomodulin is only a late marker of advanced endothelial cell injury or whether it indicates also earlier stages of cell alterations. Over 24 hr endothelial cell cultures were incubated with hydrogen peroxide or the neutrophil proteases proteinase-3, elastase and cathepsin G. The time-dependent increase of thrombomodulin in the supernatant was determined by enzyme-linked immunosorbent assay and immunoblot. In addition the viability (eosin, tetrazolium dye assay), detachment (crystal-violet assay), and apoptosis (4',6-diamine-2'-phenylindole-dihydrochloride assay) of the respective endothelial cells were determined for adherent and non-adherent cells. A rapid thrombomodulin increase was found under all experimental conditions. The additional immunoblotting analysis showed the pattern of proteolytic cleavage caused by the protease reactivity. In case of hydrogen peroxide the thrombomodulin increase was closely correlated with the loss of cell viability and lysis. The incubation of endothelial cells with the different proteases resulted in a time-dependent detachment of primarily viable cells. In addition to cell necrosis apoptotic cell death was found in the subgroup of detached endothelial cells after prolonged incubation over 24 hr with proteinase-3 (23%), elastase (31%), and cathepsin G (19%). In contrast, still adhering cells did not show any signs of necrosis or apoptosis. In summary these studies confirm in vitro that soluble thrombomodulin is not only a parameter of advanced endothelial cell destruction itself but also in addition an early marker of initial endothelial cell membrane changes induced by neutrophil derived proteases and oxygen radicals.

Apoptosis↗