糖皮质激素通过抑制p38MAPK信号通路缓解大鼠内毒素性急性肺损伤

目的： 研究糖皮质激素对内毒素导致的急性肺损伤的影响及作用机制。方法: 成年雄性SD大鼠被随机分为6组：对照组（control 组，n=6）；LPS组（n=24）；地塞米松＋LPS组（Dex＋LPS组，n=24）；糖皮质激素受体拮抗剂RU486组（RU486组，n=6）；RU486+LPS组（n=24）以及RU486＋Dex＋LPS组（n=24）。除对照组和RU486组外，其余4组在注射LPS后1、3、6、12 h又被分为4个亚组。分别检测各组大鼠支气管肺泡灌洗液（BALF）中TNF-α和IL-6的浓度，肺组织的病理变化，以及肺组织中p38MAPK的活化状态和MKP-1的表达情况。另外又分别比较了LPS组与RU486＋LPS组、Dex＋LPS组与RU486＋Dex＋LPS组大鼠48 h的死亡率。结果: 注射LPS后，BALF中TNF-α 和IL-6的浓度明显升高（P<0.05），HE染色显示肺组织内广泛炎症反应。而这些现象在应用RU486后变得更加严重，并且RU486＋LPS组的死亡率也明显高于LPS组(P<0.05)。地塞米松能明显缓解LPS导致的肺损伤，糖皮质激素受体(GR)参与此作用。另外，在注射LPS后，肺组织中磷酸化的p38MAPK的表达明显升高，而MKP-1的表达则明显受到抑制。地塞米松能显著降低p38MAPK的磷酸化，这一作用也是GR依赖的。结论: 糖皮质激素活化GR诱导肺组织中MKP-1的表达，进而抑制p38MAPK的活化，从而发挥其抗炎作用，缓解LPS诱导的肺损伤。

Glucocorticoid attenuates LPS-induced acute lung injury by inhibiting p38MAP kinase in rats

AIM: To examine the role of glucocorticoid receptor (GR) in regulation of lipopolysaccharide (LPS)-induced lung injury. METHODS:Male Sprague-Dawley rats were divided into six groups randomly: control group (n=6), LPS group (n=6 each), Dex+LPS group (n=6 each), RU486 group (n=6), RU486+LPS group (n=6 each) and RU486+Dex+LPS group (n=6 each). All groups were subjected into 1 h, 3 h, 6 h and 12 h time point subgroups after LPS administration, except of control group and RU486 group. The concentrations of TNF-α and IL-6 in bronchoalveolar lavage fluids (BALF) were detected by ELISA. The histopathologic changes of lung tissues, the activation of p38MAPK and the expression of MKP-1 in lung tissue were also observed. Further, to confirm the role of GR in this model, the mortality of rats in LPS group vs RU486+LPS group and in Dex+LPS group vs RU486+Des+LPS group was compared. RESULTS: LPS induced lung injury and the secretions of TNF-α and IL-6 in BALF, which were significantly enhanced by pretreatment of RU486 (P<0.05). RU486 pretreatment also significantly increased the LPS-induced lethality (P<0.05). Dexamethasone attenuated LPS-induced lung damage, cytokine release and mortality rates, and the protective effects might be mediated by GR. Western blotting analysis showed dexamethasone inhibited the phosphorylation of p38MAPK in lung tissues by induction of MKP-1, and these actions were also GR dependent. CONCLUSION: GR plays an essential role in regulation of LPS-induced acute lung injury. Anti-inflammatory effects of hormone-activated GR may be mediated by inhibition of p38MAPK phosphorylation/activation, which is associated with the induction of MKP-1.