l-663536 and Hyperplasia

Given the importance of leukotrienes in vascular inflammation induced by local tissue injury, this study investigated the role for 5-lipoxygenase (5-LO) in monocytes in the development of intimal hyperplasia. As a mechanistic study, the importance of monocyte 5-LO in monocyte-macrophage differentiation with subsequent infiltration in neointima was evaluated. In a mouse model of wire-injured femoral artery, intimal hyperplasia started as early as 2wks after injury, and luminal area and blood flow were reduced due to increased neointima formation. Time-dependent increases in macrophage infiltration were observed in neointima and showed a positive relationship with neointima volume. In 5-LO-deficient (KO) mice or wild-type (WT) mice treated with an inhibitor of 5-LO activating protein (MK886, 1 and 10mg/kg), intimal hyperplasia and macrophage infiltration into neointima were reduced, but monocyte adhesion to injured luminal surface was not inhibited, which suggested 5-LO participates in monocyte-macrophage differentiation. In an in vitro study, monocyte-macrophage differentiation was found to be increased by high mobility group box 1 protein (HMGB1), but this effect was attenuated in cells isolated from 5-LO-KO mice. Furthermore, macrophage infiltration and intimal hyperplasia were more prominent in 5-LO-KO mice transplanted with monocytes from WT mice than in 5-LO-KO mice transplanted with monocytes from 5-LO-KO mice. Taken together, it was suggested that 5-LO in monocytes played a pivotal role in monocyte-macrophage differentiation and subsequent infiltration of macrophage in neointima, leading to vascular remodeling after vascular injury.

Topics: Animals; Arachidonate 5-Lipoxygenase; Cell Differentiation; Femoral Artery; HMGB1 Protein; Hyperplasia; Indoles; Lipoxygenase Inhibitors; Macrophages; Mice; Mice, Knockout; Monocytes; Neointima; Tunica Intima; Vascular Remodeling

Intimal thickening is a major complication following percutaneous transluminal coronary angioplasty, which leads to restenosis and requires reoperation. We have investigated the effect of a 5-lipoxygenase inhibitor, MK-886, a leukotriene B4 (LTB4) receptor antagonist, ONO-4057 or a LTC4 and LTD4 receptor antagonist, ONO-1078, on intimal thickening. Photochemical reaction between green light and systemically administered Rose Bengal produced intimal thickening in the rat femoral artery. Each drug was administered orally, once a day for 7 days, starting just after the endothelial injury. Both MK-886 administration, 10 mg/kg, and ONO-4057 administration, 100 mg/kg, suppressed intimal thickening level examined three weeks after endothelial injury, while similarly administered ONO-1078 did not. In cultured rat-derived smooth muscle cells, LTB4, an active metabolite of 5-lipoxygenase whose biosynthesis in air pouch exudate was suppressed by MK-886, stimulated cell migration. Based on these observations, the 5-lipoxygenase may have a key role in intimal thickening via its metabolites such as LTB4.

Topics: Animals; Cell Division; Cell Movement; Endothelium, Vascular; Femoral Artery; Hyperplasia; Indoles; Lipoxygenase Inhibitors; Male; Photolysis; Rats; Rats, Wistar; Tunica Intima

In mouse skin in vivo the irritant and hyperplasiogenic tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) strongly increased the epidermal content of the cysteinyl leukotrienes LTC4, LTD4 and LTE4, but not of leukotriene LTB4. This effect was completely suppressed by the selective leukotriene biosynthesis inhibitor MK-886. Intragastric administration of MK-886 prevented phorbol ester-induced ear edema, but not epidermal hyperproliferation and tumor promotion. These data indicate that leukotrienes are involved in the pro-inflammatory effects of the phorbol ester, whereas its hyperproliferative and tumor-promoting activities do not depend on 5-lipoxygenase-catalyzed leukotriene formation. This action differs from several non-selective inhibitors of lipoxygenases that were found to inhibit tumor promotion in initiated mouse skin.

Topics: Animals; Ear, External; Edema; Epidermis; Female; Hyperplasia; Indoles; Inflammation; Leukotriene B4; Mice; Skin Neoplasms; SRS-A; Tetradecanoylphorbol Acetate