Cuzzocrea S, Genovese T, Mazzon E, Esposito E, Muià C, Abdelrahman M, Di Paola R, Bramanti P, Thiemermann C
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
Int J Immunopathol Pharmacol. 2007 Jul-Sep;20(3):619-30. doi: 10.1177/039463200702000320.
Glycogen synthase kinase-3 (GSK-3) is an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and has recently been implicated in the pathophysiology of a number of diseases. The aim of this study is to investigate the effects of TDZD-8, a potent and selective GSK-3beta inhibitor, on the development of lung injury caused by administration of bleomycin (BLM). Mice subjected to intra-tracheal administration of BLM developed significant lung injury characterized by marked neutrophil infiltration and tissue edema. An increase in immunoreactivity to nitrotyrosine, iNOS, TNF-alpha and IL-1beta was also observed in the lungs of BLM-treated mice. In contrast, administration of BLM-treated mice with TDZD-8 (1 mg/kg daily) significantly reduced (I) the degree of lung injury, (II) the increase in staining (immunohistochemistry) for myeloperoxidase (MPO), nitrotyrosine, iNOS, TNF-alpha and IL-1beta and (III) the degree of apoptosis, as evaluated by Bax and Bcl-2 immunoreactivity and TUNEL staining. Taken together, these results clearly demonstrate treatment with the GSK-3beta inhibitor TDZD-8 reduces the development of lung injury and inflammation induced by BLM in mice.
糖原合酶激酶-3（GSK-3）是一种普遍存在的丝氨酸-苏氨酸蛋白激酶，参与多种细胞过程，最近被认为与多种疾病的病理生理学有关。本研究的目的是探讨强效选择性GSK-3β抑制剂TDZD-8对博来霉素（BLM）所致肺损伤发展的影响。经气管内给予BLM的小鼠出现了明显的肺损伤，其特征为显著的中性粒细胞浸润和组织水肿。在接受BLM治疗的小鼠肺中还观察到硝基酪氨酸、诱导型一氧化氮合酶（iNOS）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的免疫反应性增加。相比之下用TDZD-8（每日1mg/kg）处理BLM治疗的小鼠显著降低了：（I）肺损伤程度；（II）髓过氧化物酶（MPO）、硝基酪氨酸、iNOS、TNF-α和IL-1β染色（免疫组织化学）的增加；以及（III）通过Bax和Bcl-2免疫反应性及TUNEL染色评估的细胞凋亡程度。综上所述，这些结果清楚地表明用GSK-3β抑制剂TDZD-8治疗可减少BLM诱导的小鼠肺损伤和炎症的发展。
