Glycogen synthase kinase-3beta inhibition attenuates the development of bleomycin-induced lung injury.

Abstract

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.

• Authors: S Cuzzocrea, T Genovese, E Mazzon, E Esposito, C Muià, M Abdelrahman, R Di Paola, P Bramanti, C Thiemermann
• Journal: International journal of immunopathology and pharmacology (Int J Immunopathol Pharmacol) 2007 Jul-Sep Vol. 20 Issue 3 Pg. 619-30 ISSN: 0394-6320 [Print] England
• PMID: 17880775 (Publication Type: Journal Article)

Chemical References

• 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
• Antibiotics, Antineoplastic
• Cytokines
• Enzyme Inhibitors
• Thiadiazoles
• Bleomycin
• Peroxidase
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Animals
• Antibiotics, Antineoplastic (adverse effects)
• Bleomycin (adverse effects)
• Cytokines (immunology)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta
• Lung (drug effects, enzymology, immunology, pathology)
• Lung Diseases (chemically induced, prevention & control)
• Male
• Mice
• Mice, Inbred Strains
• Peroxidase (metabolism)
• Thiadiazoles (pharmacology, therapeutic use)