Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome - Evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids
Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome - Evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids
复制标题
DOI：
10.1164/ajrccm.165.7.2106014
复制
发表时间：
2002-04-01
影响因子：
24.7
通讯作者：
Stentz, F
中科院分区：
文献类型：
--
作者：
Meduri, GU;Tolley, EA;Stentz, F
核因子-κ B（NF-κ B）和糖皮质激素受体-α（GR-α）在调节炎症中具有截然相反的功能。我们研究了未缓解的急性呼吸窘迫综合征（ARDS）是否与全身炎症诱导的糖皮质激素抵抗有关，以及长期给予甲基强的松龙是否加速了全身炎症指标的抑制并使免疫系统对糖皮质激素的敏感性正常化。一项随机试验评估了长期使用甲基强的松龙治疗未缓解的ARDS患者，在随机化前后采集了一系列血浆样本。在血浆中，我们测量了肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）、IL-1 β和IL-6、促肾上腺皮质激素（ACTH）和皮质醇的浓度。检查患者血浆影响正常外周血白细胞（PBL）的NF-κ B和GR-信号转导系统的能力。接受甲基强的松龙治疗的患者随着时间的推移，TNF-α、IL-1 β、IL-6、ACTH和皮质醇浓度逐渐持续降低。暴露于甲基强的松龙治疗期间采集的血浆样本的正常PBL在GR介导的活性的所有方面均表现出显著的进行性增加，NF-κ B DNA结合和TNF-α和IL-1 β转录显著降低。这些发现为内源性糖皮质激素在炎症控制中的不足和全身炎症诱导的ARDS外周糖皮质激素抵抗的存在提供了支持。延长甲基强的松龙给药可加速ARDS患者全身炎症和外周获得性糖皮质激素抵抗的消退。
Nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor-alpha (GR-alpha) have diametrically opposed functions in regulating inflammation. We investigated whether unresolving acute respiratory distress syndrome (ARDS) is associated with systemic inflammation-induced glucocorticoid resistance and whether prolonged methylprednisolone administration accelerates the suppression of systemic inflammatory indices and normalizes the sensitivity of the immune system to glucocorticoids. Patients enrolled into a randomized trial evaluating prolonged methylprednisolone administration in unresolving ARDS had serial plasma samples collected before and after randomization. In the plasma, we measured the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) IL-1beta and IL-6, adrenocorticotropic hormone (ACTH), and cortisol. The ability of patient plasma to influence the NF-kappaB and GR-signal transduction systems of normal peripheral blood leukocytes (PBL) was examined. Patients treated with methylprednisolone had progressive and sustained reductions of TNF-alpha, IL-1beta, IL-6, ACTH, and cortisol concentrations over time. Normal PBL exposed to plasma samples collected during methylprednisolone exhibited significant progressive increases in all aspects of GR-mediated activity and significant reductions in NF-kappaB DNA-binding and transcription of TNF-alpha and IL-1beta. These findings provide support for the presence of endogenous glucocorticoid inadequacy in the control of inflammation and systemic inflammation-induced peripheral glucocorticoid resistance in ARDS. Prolonged methylprednisolone administration accelerated the resolution of both systemic inflammation and peripheral acquired glucocorticoid resistance in ARDS.