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

Abstract

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-3b inhibition in a model of acute inflammation. Here, we have investigated the effects of TDZD-8, a potent and selective GSK-3b 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-a, (TNF-a) and interleukin-1b (IL-1b). 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 À1 , i.p.), 30 min prior to injection of carrageenan, caused a dosedependent 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-3b, such as TDZD-8, may be useful in the treatment of various inflammatory diseases.

Oleuropein an Olive Oil Compound in Acute and Chronic Inflammation Models: Facts and Perspectives

“…Recent studies have observed that the acute consumption of olive oil decreased the activation of NF-B system on mononuclear cells from healthy men (Perez-Martinez et al, 2007) and that 3,4-DHPEA-EA, trans-resveratrol, and hydroxytyrosol incubated with human umbilical vein endothelial cells inhibit LPS-triggered NF-B and AP-1 activation (Carluccio et al, 2003). Moreover, various experimental evidence have clearly suggested that NF-B plays a central role in the regulation of many genes responsible for the generation of mediators or proteins in acute lung inflammation associated with carrageenan administration (Cuzzocrea et al, 2006) such us TNF-, IL-1 , nitric oxide synthase inducible (iNOS) and COX-2. By inhibiting the activation of NF-B, the production of joint destructive inflammatory mediators may be reduced as well.…”

“…Measurement of cytokines -Tumor Necrosis Factor-(TNF-) levels were evaluated in the plasma from CIA and sham mice as previously described (Cuzzocrea et al, 2006). The assay was carried out using a colorimetric commercial ELISA kit (Calbiochem-Novabiochem Co., Milan, Italy) with a lower detection limit of 10 pg/ml.…”

Effect of PD98059, a Selective MAPK3/MAPK1 Inhibitor, on Acute Lung Injury in Mice

“…Recent evidence suggests that the activation of NF-KB may also be under the control of oxidant/antioxidant balance. Moreover, various experimental evidence has clearly suggested that NF-KB plays a central role in the regulation of many genes responsible for the generation of mediators or proteins in acute lung inflammation associated with carrageenan administration (23). NF-KB is normally sequestered in the cytoplasm, bound to regulatory protein IKBs.…”

GSK-3beta Inhibitor Induces Expression of Nrf2/TrxR2 Signaling Pathway to Protect against Renal Ischemia/Reperfusion Injury in Diabetic Rats

“…GSK-3β is a serine/threonine protein kinase that participates in the regulation of cellular functions [26][27][28]. Upon external stimulation, GSK-3β is activation and phosphorylated, which may reduce enzyme activities and change the activity or function of its downstream components.…”