Glycogen synthase kinase-3beta inhibition attenuates the development of bleomycin-induced lung injury.
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.
Cuzzocrea
S
S
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy. salvator@unime.it
Genovese
T
T
Mazzon
E
E
Esposito
E
E
Muià
C
C
Abdelrahman
M
M
Di Paola
R
R
Bramanti
P
P
Thiemermann
C
C
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001761:Bleomycin / Q000009:adverse effects*; D016207:Cytokines / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009195:Peroxidase / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology / Q000627:therapeutic use*
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D004791:Enzyme Inhibitors; D013830:Thiadiazoles; D001761:Bleomycin; D009195:Peroxidase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3