Inhibition of glycogen synthase kinase‐3β attenuates the development of carrageenan‐induced lung injury in mice

Background and purpose: Glycogen synthase kinase‐3 (GSK‐3) is a 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 was to investigate the effects of GSK‐3β inhibition in a model of acute inflammation. Here, we have investigated the effects of TDZD‐8, a potent and selective GSK‐3β inhibitor, in a mouse model of carrageenan‐induced pleurisy. Experimental approach: Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E 2 (PGE 2 ), tumour necrosis factor‐α, (TNF‐α) and interleukin‐1β (IL‐1β). Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM‐1 and P‐selectin, iNOS, COX‐2 as well as nitrotyrosine as determined by immunohistochemical analysis of lung tissues. Key results: Administration of TDZD‐8 (1, 3 or 10 mg kg −1 , i.p.), 30 min prior to injection of carrageenan, caused a dose‐dependent reduction in all the parameters of inflammation measured. Conclusions and Implications: Thus, based on these findings we propose that inhibitors of the activity of GSK‐3β, such as TDZD‐8, may be useful in the treatment of various inflammatory diseases. British Journal of Pharmacology (2006) 149 , 687–702. doi: 10.1038/sj.bjp.0706902