Prescott M F, McBride C K, Venturini C M, Gerhardt S C
Research Department, Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
J Cardiovasc Pharmacol. 1989;14 Suppl 6:S76-81.
This investigation tested the effect of anti-inflammatory agents acting at different levels of the arachidonic acid cascade on leukocyte migration into the vessel wall. An animal model of vasculitis was used in which leukocytes stimulate migration of smooth muscle cells from the media into the intima resulting in formation of intimal lesions. In this model, an endotoxin-soaked thread is implanted in the adventitia along the ventral side of the rat femoral artery. At 2 days, subendothelial and medial leukocyte accumulation occurs exclusively in the ventral half of the vessel. At 14 days, intimal lesions composed primarily of smooth muscle cells are localized to the ventral half of the vessel. Treatment with neither the lipoxygenase inhibitor L-651,392 nor the dual cyclooxygenase and lipoxygenase inhibitor BW755C affected leukocyte migration into the vessel wall or subsequent lesion formation. Treatment with the cyclooxygenase inhibitor diclofenac sodium greatly reduced both leukocyte accumulation and lesion formation, whereas leukocyte migration and lesion formation were nearly totally inhibited by treatment with dexamethasone. Thus, it has been demonstrated that although leukocyte accumulation in the vessel wall stimulates intimal lesion formation, pharmacologic inhibition of leukocyte accumulation prevents lesion formation.
本研究测试了作用于花生四烯酸级联反应不同水平的抗炎剂对白细胞迁移至血管壁的影响。采用了一种血管炎动物模型，其中白细胞刺激平滑肌细胞从血管中层迁移至内膜，导致内膜病变形成。在该模型中，将一根浸泡过内毒素的线沿大鼠股动脉腹侧植入外膜。2天时，内皮下和中层白细胞聚集仅发生在血管腹侧半部分。14天时，主要由平滑肌细胞组成的内膜病变局限于血管腹侧半部分。使用脂氧合酶抑制剂L-651,392或双环氧合酶和脂氧合酶抑制剂BW755C治疗均不影响白细胞向血管壁的迁移或随后的病变形成。使用环氧合酶抑制剂双氯芬酸钠治疗可大大减少白细胞聚集和病变形成，而使用地塞米松治疗几乎完全抑制了白细胞迁移和病变形成。因此，已证明尽管血管壁中的白细胞聚集刺激内膜病变形成，但药物抑制白细胞聚集可预防病变形成。
