ROLE OF ADENOSINE AND STEROIDS IN MAST CELL BIOCHEMISTRY

腺苷是一种强有力的冠状动脉血管扩张的内源性介质， 血小板聚集抑制和类固醇激素生成，其水平升高 在活体和面对肺缺氧或抗原挑战时明显 并在体外用几种促分泌剂刺激肥大细胞。它 也被证明能增强抗原刺激的大鼠血清肥大细胞 通过作用于细胞表面的腺苷受体来释放介质。 皮质类固醇是一种有效的抗炎激素，由 慢性前列腺癌后抑制肥大细胞介质释放的肾上腺皮质 活体给药。要探索其重要性和作用机制 腺苷和类固醇在肥大细胞分泌过程中的作用 肥大细胞介体增强剂和抑制剂的比较 大鼠浆膜和小鼠骨的释放、功能和药理研究 骨髓肥大细胞将在这些试剂存在的情况下进行培养。 将评估腺苷的释放和细胞内ATP含量的波动 肥大细胞培养上清液和颗粒的高效液相色谱分析 茶碱、地塞米松和色甘酸钠。肥大细胞腺苷 受体将直接通过放射性配基结合利用来表征 (3H)腺苷或更特异的标记腺苷激动剂 对腺苷脱氨酶耐药。潜在的生化改变 腺苷及其类似物引起的磷脂变化， 环磷酸腺苷、花生四烯酸代谢以及磷脂酶A2 以及C和蛋白激酶活性，将被研究。解离 脱颗粒与白三烯和前列腺素生成之间的关系 将通过仔细比较这两种调解人的途径来探索 花生四烯酸代谢物的释放和精确定量。 皮质类固醇诱导磷脂酶--脂调节蛋白的产生 抑制蛋白。肥大细胞磷脂酶A2和C的活性 长期应用类固醇后磷脂代谢的变化 和二酰甘油的水平将被评估。确定具体步骤 皮质类固醇对肥大细胞分泌发挥作用的地方将是 尝试添加外源花生四烯酸代谢物和融合素 磷脂酶产物逆转介质释放的抑制作用。一个 对腺苷和类固醇生物化学的进一步认识 与肥大细胞介体释放有关可能有助于药物的发展 在治疗哮喘和过敏方面很有用。

Adenosine is a potent endogenous mediator of coronary vasodilation, platelet aggregation inhibition, and steroidogenesis, whose levels increase markedly in vivo and in the face of pulmonary hypoxia or antigen challenge and in vitro after mast cell stimulation with several secretagogues. It has also been shown to potentiate antigen-stimulated rat serosal mast cell mediator release by its action on cell surface adenosine receptors. Corticosteroids are effective anti-inflammatory hormones produced by the adrenal cortex that inhibit mast cell mediator release after chronic in vivo administration. To explore the importance and the mechanisms of action of adenosine and steroids in the mast cell secretory process and to compare and contrast a potentiator and an inhibitor of mast cell mediator release, functional and pharmacologic studies of rat serosal and mouse bone marrow mast cells will be conducted in the presence of these agents. Adenosine release and fluctuations in cellular ATP content will be assessed by HPLC of supernatants and pellets from mast cells grown in the presence of theophylline, dexamethasone, and sodium cromolyn. Mast cell adenosine receptors will be directly characterized by radioligand binding utilizing (3H) adenosine or a more specific labeled adenosine agonist that is resistant to adenosine deaminase. Potential biochemical alterations induced by adenosine and its analogs such as changes in phospholipid, cyclic AMP, and arachidonic acid metabolism, as well as phospholipase A2 and C and protein kinase activities, will be studied. The dissociation between degranulation and generation of leukotrienes and prostaglandins will be explored by a careful comparison of these two avenues of mediator release and a precise quantitation of arachidonic acid metabolites. Corticosteroids induce the production of lipomodulin, a phospholipase inhibitory protein. The activities of mast cell phospholipases A2 and C after chronic steroid administration and changes in phospholipid turnover and diacylglycerol levels will be assessed. Identifying the specific step where corticosteroids exert their effect on mast cell secretion will be attempted by adding exogenous arachidonic acid metabolites and fusogenic phospholipase products to reverse the inhibition of mediator release. A further understanding of the biochemistry of adenosine and steroids as they relate to mast cell mediator release may aid in the development of agents useful in the treatment of asthma and allergy.