Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica, Italy.
Naunyn Schmiedebergs Arch Pharmacol. 2011 Jul;384(1):21-37. doi: 10.1007/s00210-011-0637-7. Epub 2011 May 2.
The extracellular signal-regulated kinase (ERK) cascade has long been known to be central to the activation of cellular processes such as proliferation, differentiation, and oncogenic transformation. The mitogen-activated protein (MAP) serine/threonine family of protein kinases, of which ERK is a member, is activated by a mechanism that includes protein kinase cascades. Mitogen-activated protein kinases (MAPKs) are well-conserved enzymes connecting cell surface receptors to intracellular regulatory targets; they are activated in response to a wide variety of stimuli. The aim of this study was to investigate the effects of PD98059, a highly selective inhibitor of MAP/ERK kinase1 (MEK1) activation, on the development of lung inflammation and fibrosis. Lung injury was induced by intratracheal instillation of bleomycin (1 mg/kg), and PD98059 (10 mg/kg, 10% dimethyl sulfoxide, i.p.) was administrated 1 h after bleomycin instillation and daily for 7 days. PD98059 treatment shows therapeutic effects on pulmonary damage, decreasing many inflammatory and apoptotic parameters, such as (1) cytokine production; (2) IkBα degradation and NF-kB nuclear translocation; (3) iNOS expression; (4) nitrotyrosine and PAR localization; and (5) the degree of apoptosis, as evaluated by Bax and Bcl-2 balance, FAS ligand expression, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. In particular, to assess whether PD98059 treatment influences MAPKs pathway, we have also investigated the expression of activated ERK and JNK after bleomycin-induced pulmonary fibrosis, showing that the inhibition of the cascade reduces the inflammatory processes that lead to the appearance of the fibrosis. Taken together, all our results clearly show that PD98059 reduces the lung injury and inflammation due to the intratracheal bleomycin administration in mice.
细胞外信号调节激酶（ERK）级联反应长期以来一直被认为是激活细胞过程（如增殖、分化和致癌转化）的核心。丝氨酸/苏氨酸蛋白激酶的丝裂原激活蛋白（MAP）家族，ERK 是其成员之一，其激活机制包括蛋白激酶级联反应。丝裂原激活蛋白激酶（MAPK）是将细胞表面受体与细胞内调节靶标连接起来的高度保守的酶；它们在响应各种刺激时被激活。本研究旨在探讨高选择性 MAP/ERK 激酶 1（MEK1）激活抑制剂 PD98059 对肺炎症和纤维化发展的影响。通过气管内滴注博莱霉素（1mg/kg）诱导肺损伤，PD98059（10mg/kg，10%二甲亚砜，腹腔内注射）在博莱霉素滴注后 1 小时给予，并每天给予 7 天。PD98059 治疗对肺损伤具有治疗作用，可降低许多炎症和凋亡参数，如（1）细胞因子产生；（2）IkBα降解和 NF-kB 核易位；（3）iNOS 表达；（4）硝基酪氨酸和 PAR 定位；（5）通过 Bax 和 Bcl-2 平衡、FAS 配体表达和末端脱氧核苷酸转移酶 dUTP 缺口末端标记染色评估的凋亡程度。特别是，为了评估 PD98059 治疗是否影响 MAPKs 途径，我们还研究了博莱霉素诱导肺纤维化后激活的 ERK 和 JNK 的表达，表明级联反应的抑制减少了导致纤维化出现的炎症过程。总之，我们所有的结果都清楚地表明，PD98059 减少了小鼠气管内博莱霉素给药引起的肺损伤和炎症。
