Selective Inhibition of Adhesion Molecule Expression by Edelf osine (ET-18-OCH&lt;sub&gt;3&lt;/sub&gt;) on Human Umbilical Vein or Microvascular Endothelium

Bosse, Diane; Parker, Jackson; Vogler, William R.; Ades, Edwin W.

doi:10.1159/000163941

Cited by 8 publications

(3 citation statements)

References 8 publications

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“…Neutrophils are the cornerstone cell type in inflammation, and our data indicate that edelfosine acts on early neutrophil-dominated stages of inflammation. In addition, edelfosine has been reported to inhibit the expression of adhesion molecules in endothelial cells (Bosse et al, 1995), thus further supporting an anti-inflammatory role for this drug by abating neutrophil-endothelium interaction. The anti-inflammatory activity of edelfosine seems to be underlain by its effects on adhesion molecules, thus preventing inflammatory cells from crossing blood vessel walls to reach affected organs.…”

Section: Discussionmentioning

confidence: 85%

Novel Anti-Inflammatory Action of Edelfosine Lacking Toxicity with Protective Effect in Experimental Colitis

Mollinedo

Gajate²,

Morales³

et al. 2009

J Pharmacol Exp Ther

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Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine; ) is an antitumor alkyl-lysophospholipid analog that binds lipid rafts, altering their protein composition (J Exp Med 200:353-365). Because L-selectin locates in lipid rafts and plays a crucial role in the recruitment of leukocytes into inflamed tissues, we hypothesized that edelfosine might affect inflammation by modulating L-selectin and inflammatory cell migration. Here, we have found that edelfosine inhibited neutrophil-endothelium interaction through L-selectin shedding. Oral treatment of edelfosine diminished inflammation in two murine animal models. Edelfosine showed a higher antiinflammatory effect than the nonsteroidal anti-inflammatory drug (NSAID) indomethacin in the bentonite mouse-paw edema model. Using a rat model of experimental colitis, edelfosine oral administration ameliorated the clinical and histopathologic severity of the inflammatory colitis with a dramatic decrease in mucosal damage and neutrophil infiltration. Colon sections from edelfosine-treated rats showed a remarkable reduction in ulcer formation, edema, and inflammatory cell infiltration. Edelfosine enhanced lipopolysaccharide-induced expression of anti-inflammatory interleukin-10 in mouse macrophages. Edelfosine oral treatment in rats, at doses 8-fold higher than those displaying anti-inflammatory action, lacked toxicity. Edelfosine treatment showed no any significant cardiotoxicity, hepatotoxicity or renal toxicity. Unlike NSAIDs, edelfosine did not inhibit prostaglandin E 2 synthesis in gastrointestinal mucosal biopsies, and no histologic alteration in gastrointestinal tract was detected after drug treatment. Thus, edelfosine shows a potent in vitro and in vivo anti-inflammatory activity while sparing gastric mucosa. Our data identify edelfosine as a novel anti-inflammatory drug by abating neutrophil infiltration through L-selectin shedding and may provide a new therapeutic approach for inflammatory bowel disease free from toxicity.

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Section: Discussionmentioning

confidence: 85%

Novel Anti-Inflammatory Action of Edelfosine Lacking Toxicity with Protective Effect in Experimental Colitis

Mollinedo

Gajate²,

Morales³

et al. 2009

J Pharmacol Exp Ther

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“…Synthetic alkylphospholipids (APLs) are structurally derived from PAF (Berkovic, 1998). Prototypes are edelfosine (ET-18-OCH 3 ) (Bosse et al, 1995;Mollinedo et al, 1997;Arthur and Bittman, 1998;Gajate and Mollinedo, 2001) and miltefosine (hexadecylphosphocholine) (Schön et al, 1996;Clive et al, 1999). Owing to their chemical structure, alkylphospholipids become incorporated into cell membranes where they interfere with signaling events and influence proliferation, survival, adhesion, migration, and cytokine production (Mollinedo et al, 1997;Arthur and Bittman, 1998;Wieder et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Inositoylated Platelet-Activating Factor (Ino-C2-PAF) Modulates Dynamic Lymphocyte–Endothelial Cell Interactions and Alleviates Psoriasis-Like Skin Inflammation in Two Complementary Mouse Models

Forkel

Schön

Hildmann

et al. 2014

Journal of Investigative Dermatology

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Psoriasis, a tumor necrosis factor alpha (TNFα)-governed inflammatory disorder with prominent dysregulation of cutaneous vascular functions, has evolved into a model disorder for studying anti-inflammatory therapies. We present experimental in vitro and in vivo data on 1-O-octadecyl-2-O-(2-(myo-inositolyl)-ethyl)-sn-glycero-3-(R/S)-phosphatidyl-choline (Ino-C2-PAF), the lead compound of a class of synthetic glycosylated phospholipids, in anti-inflammatory therapy. Ino-C2-PAF strongly induced apoptosis only in TNFα-stimulated, but not in untreated human vascular endothelial cells. Moreover, TNFα-induced endothelial adhesion molecules that mediated the rolling and firm adhesion of leukocytes (vascular cell adhesion protein-1 (VCAM-1), E-selectin, and ICAM-1) were selectively downregulated by Ino-C2-PAF. Similarly, expression of L-selectin, VCAM-1 receptor α4β1 integrin , and lymphocyte function-associated antigen-1 on human peripheral blood mononuclear cells was reduced without induction of apoptosis. Functionally, these changes were accompanied by significant impairment of rolling and adhesion of human peripheral blood lymphocytes on TNFα-activated endothelial cells in a dynamic flow chamber system. When the therapeutic potential of Ino-C2-PAF was assessed in two complementary mouse models of psoriasis, K5.hTGFβ1 transgenic and JunB/c-Jun-deficient mice, Ino-C2-PAF led to significant alleviation of the clinical symptoms and normalized the pathological cutaneous changes including vascularization. There were no overt adverse effects. These findings suggested that Ino-C2-PAF is a potential candidate in the therapy of inflammatory skin diseases that include abnormal vascular functions.

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“…Cell Adhesion Molecule-1, PECAM-1) und CD54 (ICAM-1) auf HMEC-1 (human microvascular endothelial cell line) in vitro durch Et-18-OCH 3 beschrieben (Bosse et al 1995). Zusätzlich fand sich eine Reduktion von CD62L auf humanen neutrophilen Granulozyten (Mollinedo et al 2009).…”

Section: Schließlich Wurde Die Herunterregulation Der Adhäsionsmolekü...unclassified

Anti-inflammatorische Wirkung des inositoylierten Plättchen-aktivierenden Faktors (Ino-C2-PAF) in vitro und in vivo

Forkel¹

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Selective Inhibition of Adhesion Molecule Expression by Edelf osine (ET-18-OCH<sub>3</sub>) on Human Umbilical Vein or Microvascular Endothelium

Cited by 8 publications

References 8 publications

Novel Anti-Inflammatory Action of Edelfosine Lacking Toxicity with Protective Effect in Experimental Colitis

Novel Anti-Inflammatory Action of Edelfosine Lacking Toxicity with Protective Effect in Experimental Colitis

Inositoylated Platelet-Activating Factor (Ino-C2-PAF) Modulates Dynamic Lymphocyte–Endothelial Cell Interactions and Alleviates Psoriasis-Like Skin Inflammation in Two Complementary Mouse Models

Anti-inflammatorische Wirkung des inositoylierten Plättchen-aktivierenden Faktors (Ino-C2-PAF) in vitro und in vivo

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