Leukocyte rolling and firm adhesion at the venular endothelium are two discrete events in the cellular inflammatory response mediated via selectin and integrin adhesion molecules, respectively. The dependency of chemoattractant-induced firm leukocyte adhesion on the preceding rolling interaction was investigated in rat mesenteric microvessels through use of intravital microscopy. Leukocyte rolling was dose-dependently inhibited by systemic treatment with the sulphated polysaccharide fucoidin. The firm leukocyte adhesion following stimulation with the chemotactic peptide fMLP was similarly inhibited when fMLP challenge was performed subsequent to inhibition of leukocyte rolling by fucoidin. Thus, based on paired observations in single venules before and after fucoidin treatment, reduced rolling leukocyte flux prior to fMLP challenge was paralleled over a wide range by a proportional decrease in fMLP-induced leukocyte adhesion. The results demonstrate quantitatively a close relationship between the extent of leukocyte rolling and the magnitude of the subsequent firm adhesion response, and, that an initial rolling interaction is a precondition for firm adhesion to occur at physiological blood flow rates in vivo.

Inflammatory recruitment of leukocytes into the cerebrospinal fluid (CSF) during bacterial meningitis has been shown to contribute significantly to the neurological damage commonly associated with this serious disease. In this study we tested whether or not inhibition of leukocyte rolling, a precondition for firm leukocyte adhesion to vascular endothelium in vivo, may reduce CSF leukocyte recruitment and associated inflammatory changes in rabbits with experimental meningitis. As documented by intravital microscopy of small venules in the rabbit mesentery and tenuissimus muscle, leukocyte rolling was rapidly and profoundly reduced by intravenous treatment with the polysaccharide fucoidin, a homopolymer of sulfated L-fucose known to block the function of the leukocytic "rolling receptor" L-selectin. Moreover, fucoidin treatment dramatically reduced the accumulation of both leukocytes and plasma protein in the CSF of rabbits challenged intrathecally with pneumococcal antigen. These main findings thus illustrate that inhibition of leukocyte rolling, an early and obligatory step in the process of leukocyte extravasation, may be an effective therapeutic approach to attenuate leukocyte-dependent central nervous system damage in bacterial meningitis. (J. Clin. Invest. 1994. 93:929-936.)

Intravital microscopy and determination of in vivo histamine release revealed that the cyclooxygenase inhibitor indomethacin reduced antigen-induced vasodilation while enhancing plasma extravasation, leukocyte accumulation, and histamine release in cheek pouches of immunized hamsters. Topical application of prostaglandin E2 (PGE2, 30 nM) totally reversed the indomethacin-induced potentiation of the inflammatory reaction to antigen challenge and suppressed both the histamine release and plasma leakage also in the absence of indomethacin. On the other hand, PGE2, which per se caused vasodilation, markedly potentiated the postcapillary leakage of plasma induced by histamine or leukotriene C4, as well as the leukocyte activation and subsequent plasma extravasation evoked by leukotriene B4. Taken together, the data indicate that PGE2 reduced the antigen response by suppression of mediator release from the numerous mast cells present in the cheek pouch. Moreover, the PGE2-sensitive potentiation by indomethacin of the antigen response suggests that endogenous vasodilating prostaglandins (possibly PGE2) predominantly were antiinflammatory.The potent vasodilator prostaglandin E2 (PGE2) is released at sites of inflammation, causes a wheal and flare reaction when injected into skin, and enhances the effects of pain-and edema-producing stimuli (cf. ref. 1). Moreover, nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the fatty acid cyclooxygenase, which catalyzes the initial steps in the biosynthesis of PGE2 from arachidonic acid (cf. ref. 1). Hence, PGE2 is considered to be an inflammatory mediator. Nevertheless, PGE2 and related compounds also exhibit antiinflammatory activities (2-8), and NSAIDs sometimes augment inflammation (9, 10). These conflicting observations complicate understanding of the functional role of PGE2 in inflammation.In the present study, intravital microscopy of the hamster cheek pouch was used to characterize the influence of PGE2 and the prototype of NSAIDs, indomethacin, on microcirculatory dynamics during acute mast cell-dependent inflammation evoked by antigen challenge. Supported also by in vivo measurements of antigen-induced histamine release from the cheek pouch and analysis of the microvascular interactions between exogenous inflammatory mediators and PGE2, we conclude that endogenous cyclooxygenase products predominantly inhibit acute allergic inflammation via local suppression of inflammatory mediator release.MATERIALS AND METHODS Drugs and Chemicals. Leukotrienes B4 and C4 (LTB4, LTC4) were provided by J. Rokach (Merck Frosst Labs, Pointe Claire, PQ) and PGE2 by J. Pike (Upjohn). Arachidonic acid was from Nu Chek Prep. Stock solutions of LTB4, PGE2, and arachidonic acid were stored at -20°C in ethanol, and LTC4 was stored similarly in ethanol/water, 1:1. Concentrations and purity of the icosanoids were checked before use by appropriate methods (UV spectrometry, reverse-phase HPLC, and thin-layer chromatography). Acetylcholine chloride, fluorescein isothiocyanate-conjugated dextr...

Background: Heparin given intravenously has shown beneficial effects in the treatment of refractory ulcerative colitis in open trials. Low molecular weight heparin (LMWH) offers advantages in the method of administration but have not been evaluated in inflammatory bowel disease conditions.Aim: To assess the tolerability and safety of subcutaneous self‐administered LMWH in outpatients with refractory ulcerative colitis and to evaluate any potential adjuvant therapeutic effect.Patients and Methods: Twelve patients with mild to moderately active ulcerative colitis were included in the trial. The patients had either responded poorly to treatment with conventional therapy, including oral and/or rectal glucocorticosteroids, or had experienced a rapid relapse during or shortly after GCS therapy. Dalteparin sodium 5000 units s.c. injection was administered twice daily for 12 weeks. Patients were monitored for possible adverse events and changes in clinical symptoms, and endoscopic and histological scores were analysed. Leucocyte scanning was performed at inclusion and at the end of the study.Results: Tolerability and compliance were excellent and no serious adverse events occurred. Eleven patients improved symptomatically and six (50%) attained complete remission after 12 weeks of treatment. Endoscopic, scintigraphic and histological scores were found to be significantly improved.Conclusion: Self‐administered LMWH given s.c. may be a safe adjuvant therapy for patients with active, glucocorticosteroids‐refractory ulcerative colitis. A controlled trial should be undertaken to confirm the positive effects found in this study.

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