STEROID ACTION IN BACTERIAL ENDOTOXIC SHOCK

我们的假设是细菌内毒素引起 来自网状内皮系统的介质， 肝脏中激素调节代谢的改变。 在我们实验室的前21/2年中获得的证据表明， 该项目建议释放免疫调节单核因子， 内毒素给药后与糖皮质激素相互作用 作用于基因表达。 在这项研究的继续中，我们 提出了单核因子，如IL 1，TNF， 和干扰素，在改变糖皮质激素的作用，在内毒素血症。 这将通过滴定介质的抑制活性来完成- 富含血浆（从感染BCG的CF-1小鼠获得， 用2微克细菌内毒素激发） 小鼠和H35大鼠肝癌细胞（RHC）培养物。 改变 糖皮质激素诱导色氨酸加氧酶（TO）、酪氨酸 磷酸烯醇丙酮酸羧激酶 （PEPCK）和糖原合成酶（GS）将在 单核因子治疗。 这些肝酶的诱导受损 将与肝细胞溶质结合减少相关， 地塞米松。 此外，我们将滴定抑制活性 从内毒素处理的枯否细胞释放的因子。 交叉- 富含介质的血浆和枯否细胞液的吸附， 已知单核因子的单特异性抗体将评估 单核因子可能的协同或拮抗作用， 改变糖皮质激素的作用。 在拟议的研究中，我们还将 评估糖皮质激素对单核因子介质的影响 在内毒素作用期间影响糖皮质激素的作用 冲击. 我们将测量T0、TAT， 肾上腺切除（adenoma）小鼠和adenoma小鼠的PEPCK和GS 用外源性类固醇重组 重组IL 1、TNF和 将在小鼠和RHC中使用IFN，以测试 类固醇对单核细胞因子的作用 提出的长期目标 研究的目的是了解 糖皮质激素-单核因子相互作用， 内毒素休克时糖皮质激素的作用可能是 通过治疗干预逆转。 这反过来又会导致 提高了非常严重和危及生命的临床 综合征

Our hypothesis is that bacterial endotoxin evokes the release of mediators from the reticuloendothelial system that mediate alterations in hormone regulated metabolism in the liver. Evidence obtained in our laboratory during the first 21/2 years of this project suggest immunomodulatory monokines, released following endotoxin administration interact with glucocorticoid actionon gene expression. In the continuation of this study we propose to characterize the role of monokines, such as IL 1, TNF, and IFN, in altered glucocorticoid action during endotoxemia. This will be done by titrating the inhibitory activity of mediator- rich plasma (obtained from CF-1 mice infected with BCG and challenged with 2 micrograms of bacterial endotoxin) in C3H/HeJ mice and Reuber H35 rat hepatoma cell (RHC) cultures. Altered glucocorticoid induction of tryptophan oxygenase (TO), tyrosine aminotransferase (TAT), phosphoenolpyruvate carboxykinase (PEPCK), and glyogen synthase (GS) will be monitored after monokine treatment. Impaired induction of these liver enzymes will be correlated with decreased hepatic cytosolic binding of dexamethasone. In addition we will titrate the inhibitory activity of factors released from endotoxin treated Kupffer cells. Cross- adsorption of mediator-rich plasma and Kupffer cell fluids with monospecific antibodies to known monokines will assess the possible synergistic or antagonistic effects of monokines on altered glucocorticoid action. In the proposed study we will also assess the influence of glucocorticoids on the monokine mediators that are found to affect glucocorticoid action during endotoxic shock. We will measure the inhibition of induction of TO, TAT, PEPCK and GS in adrenal-ectomized (adrx) mice and adrx mice reconstituted with exogenous steroid. Recombinant IL 1, TNF and IFN will be used in both mice and RHC to test the influence of steroids on monokine action. The long term goal of this proposed research is to understand the molecular events underlying glucocorticoid-monokine interactions so that the perturbation in glucocorticoid action during endotoxic shock may possibly be reversed with therapeutic intervention. This, in turn, will lead to improved survival from a very serious and life-threatening clinical syndrome.