Holger Ulbrich

Neutrophil-Derived Heparin-Binding Protein (HBP/CAP37) Deposited on Endothelium Enhances Monocyte Arrest under Flow Conditions

In acute inflammation, infiltration of neutrophils often precedes a second phase of monocyte invasion, and data in the literature suggest that neutrophils may directly stimulate mobilization of monocytes via neutrophil granule proteins. In this study, we present a role for neutrophil-derived heparin-binding protein (HBP) in monocyte arrest on endothelium. Adhesion of neutrophils to bovine aorta endothelial cells (ECs) or HUVEC-triggered secretion of HBP and binding of the protein to the EC surface. Blockade of neutrophil adhesion by treatment with a mAb to CD18 greatly reduced accumulation of HBP. In a flow chamber model, immobilized recombinant HBP induced arrest of human monocytes or monocytic Mono Mac 6 (MM6) cells to activated EC or plates coated with recombinant adhesion molecules (E-selectin, P-selectin, VCAM-1). However, immobilized recombinant HBP did not influence arrest of neutrophils or lymphocytes. Treatment of MM6 cells with recombinant HBP evoked a rapid and clear-cut increase in cytosolic free Ca2+ that was found to be critical for the HBP-induced monocyte arrest inasmuch as pretreatment with the intracellular calcium chelating agent BAPTA-AM abolished the evoked increase in adhesion. Thus, secretion of a neutrophil granule protein, accumulating on the EC surface and promoting arrest of monocytes, could contribute to the recruitment of monocytes at inflammatory loci.

Synthesis and anti-inflammatory evaluation of some pyrazolo[3,4-b]pyridines

Novel series of pyrazolo[3,4-b]pyridines with basic skeleton different from the known COX inhibitors were synthesized from 5-amino-1-[4-(aminosulfonyl)phenyl]-3-phenyl-1H-pyrazole, which in turn was prepared by the condensation of (4-sulfamoylphenyl)hydrazine with α-cyanoacetophenone. All the newly synthesized compounds were tested for their in vivo anti-inflammatory activity by carrageenan-induced rat paw edema assay. Some of the most potent compounds were evaluated in different COX and LOX assays. Some of the new compounds were found to possess moderate anti-inflammatory activity.

Diaryl-dithiolanes and -isothiazoles: COX-1/COX-2 and 5-LOX-inhibitory, *OH scavenging and anti-adhesive activities.

Three series of non-steroidal anti-inflammatory drugs (NSAIDs) inhibiting the cyclooxygenase/5-lipoxygenase (COX/5-LOX) pathways as such as formation of hydroxyl radicals and adhesion were prepared: 4,5-diaryl isothiazoles, 4,5-diaryl 3H-1,2-dithiole-3-thiones and 4,5-diaryl 3H-1,2-dithiole-3-ones. The aim of the present study was to develop substances which can intervene into the inflammatory processes via different mechanisms of action as multiple target non-steroidal anti-inflammatory drugs (MTNSAIDs) with increased anti-inflammatory potential. The current lead 11a was evaluated in COX-1/2, 5-LOX and (*)OH scavenging in vitro assays and in a static adhesion assay where it proved to inhibit adhesion. Moreover, 11a treatment attenuated expression of macrophage adhesion molecule-1 (Mac-1) on extravasated polymorphonuclear leukocytes (PMNs) which indicates that the activation was reduced. The assays used are predictive for the in vivo efficacy of test compounds as shown for 11a in a peritonitis model of acute inflammation in mice. Thus, the novel 5-LOX/COX and (*)OH inhibitor 11a possesses anti-inflammatory activity that, in addition to COX/5-LOX inhibition, implicates effects on leukocyte-endothelial interactions.

Investigations Concerning the Correlation of COX-1 Inhibitory and Hydroxyl Radical Scavenging Activity

The aim was to study the COX‐1 inhibiting efficacy in context with hydroxyl radical scavenging properties of compounds bearing a carboxylic acid and ester function, respectively. In general, the acids are more potent radical scavengers than the corresponding esters but there is no clear correlation with their COX‐1 inhibiting potencies. A feasible scavenging mechanism of carboxylic acids is discussed.

NSAR: Klassifizierung und Wirkspektrum: Eine heterogene Arzneistoffklasse

NSAR sind etablierte Arzneistoffe zur Behandlung entzundlicher Erkrankungen wie z.B. der rheumatoiden Arthritis, der Osteoarthritis und der Arthrose. In den letzten Jahren ist durch die Entwicklung von selektiven COX-2-Hemmstoffen der Arzneischatz bereichert worden. Allerdings gibt es immer mehr Anhaltspunkte, dass mit den selektiven COX-2-Hemmern hinsichtlich der Vertraglichkeit keine den klassischen NSAR deutlich uberlegene Substanzgruppe erhalten wurde.So mahnte die amerikanische Arzneimittelbehorde FDA den Rofecoxib (Vioxx ®)-Hersteller wegen „falscher, unausgewogener oder irrefuhrender Aussagen” ab, nachdem sich herausgestellt hatte, dass Daten zur Unvertraglichkeit in den publizierten Studien, wie z.B. grosere Haufigkeit des Auftretens von schweren unerwunschten Wirkungen unter der Therapie mit Vioxx ® im Vergleich zu Naproxen, unerwahnt blieben [53, 43, 46].Der endgultige Stellenwert dieser Substanzen wird sich erst nach mehrjahriger klinischer und ambulanter Anwendung unter Einbeziehung multimorbider Patienten abschatzen lassen. Bei der Therapie mit NSAR sollte weiterhin berucksichtigt werden, dass diese uber zusatzliche Mechanismen wirksam werden konnen, wie z.B. Hemmung der Aktivierung des Nuclear Factor-κB (NF-κB), Inhibition der IL-1-induzierten Matrix-Metalloproteinkinasenexpression oder Eingriff in die Adhasionskaskade der Leukozyten. Untersuchungen im Hinblick auf die genannten Mechanismen konnten das weit gefacherte Spektrum der Wirkungen von NSAR erklaren und zu einer Optimierung der Therapie beitragen.