Leech M, Hutchinson P, Holdsworth S R, Morand E F
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Melbourne, Australia.
Clin Exp Immunol. 1998 Jun;112(3):383-8. doi: 10.1046/j.1365-2249.1998.00601.x.
Pharmacologic glucocorticoids are powerful inhibitors of the inflammatory response at many levels, including leucocyte trafficking and function. The adhesion molecule P-selectin is a key participant in polymorphonuclear neutrophil (PMN) migration to sites of inflammation. The extent to which endogenous glucocorticoids influence PMN migration and activation is not clear. We used the glucocorticoid receptor antagonist RU486 to examine the effect of endogenous glucocorticoid blockade on PMN migration and function in carrageenan monoarthritis in the rat. Arthritis was induced by intraarticular injection of carrageenan and disease severity measured by PMN count in synovial lavage fluid. Decalcified frozen sections of injected joints were analysed for expression of P-selectin by immunohistochemistry. Adrenal glucocorticoid action was blocked in vivo with RU486 20 mg/kg. PMN phagocytosis and reactive oxygen species synthesis were measured by flow cytometry. Carrageenan injection was associated with severe arthritis (synovial lavage PMN 5.9 +/- 0.7 x 10(6), P < 0.01 versus control) which was dose-dependent. P-selectin was not detected in normal joints but was abundant in joints injected with 500 microg carrageenan. RU486 resulted in exacerbation of carrageenan arthritis (9.7 +/- 0.8 x 10(6), P < 0.05). RU486 also altered the threshold for disease induction, in that most RU486-treated animals were susceptible to arthritis at a dose of carrageenan (2.5 microg) which did not induce arthritis in most control-treated animals (P < 0.05), denoting an altered threshold for arthritis induction. RU486 treatment was associated with increased synovial P-selectin expression. Activation status as measured by PMN phagocytic and oxidative function were not influenced by endogenous glucocorticoid blockade. These findings suggest that endogenous glucocorticoids selectively influence PMN migration to inflamed joints via P-selectin expression, but have no effect on PMN activation status.
药理糖皮质激素在许多层面都是炎症反应的强力抑制剂，包括白细胞的运输和功能。黏附分子P-选择素是多形核中性粒细胞（PMN）迁移至炎症部位的关键参与者。内源性糖皮质激素对PMN迁移和激活的影响程度尚不清楚。我们使用糖皮质激素受体拮抗剂RU486来研究内源性糖皮质激素阻断对大鼠角叉菜胶单关节炎中PMN迁移和功能的影响。通过关节内注射角叉菜胶诱导关节炎，并通过滑膜灌洗液中的PMN计数来衡量疾病严重程度。通过免疫组织化学分析注射关节的脱钙冰冻切片中P-选择素的表达。用20mg/kg的RU486在体内阻断肾上腺糖皮质激素的作用。通过流式细胞术测量PMN吞噬作用和活性氧合成。注射角叉菜胶与严重关节炎相关（滑膜灌洗PMN为5.9±0.7×10⁶，与对照组相比P<0.01），且呈剂量依赖性。在正常关节中未检测到P-选择素，但在注射500μg角叉菜胶的关节中大量存在。RU486导致角叉菜胶性关节炎加重（9.7±0.8×10⁶，P<0.05）。RU486还改变了疾病诱导的阈值，因为大多数接受RU486治疗的动物在角叉菜胶剂量（2.5μg）下易患关节炎，而该剂量在大多数对照治疗动物中不会诱发关节炎（P<0.05），这表明关节炎诱导阈值发生了改变。RU486治疗与滑膜P-选择素表达增加有关。通过PMN吞噬和氧化功能测量的激活状态不受内源性糖皮质激素阻断的影响。这些发现表明，内源性糖皮质激素通过P-选择素表达选择性地影响PMN向炎症关节的迁移，但对PMN激活状态没有影响。
