Effects of GW274150, a novel and selective inhibitor of iNOS activity, in acute lung inflammation.
1. The aim of this study was to investigate the effect of GW274150, a novel, potent and selective inhibitor of inducible nitric oxide synthase (iNOS) activity in a model of lung injury induced by carrageenan administration in the rats. 2. Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by: fluid accumulation in the pleural cavity which contained a large number of polymorphonuclear cells (PMNs) as well as an infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NO(x)), tumour necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta). 3. All parameters of inflammation were attenuated in a dose-dependent manner by GW274150 (2.5, 5 and 10 mg x kg(-1) injected i.p. 5 min before carrageenan). 4. Carrageenan induced an upregulation of the intracellular adhesion molecules-1 (ICAM-1), as well as nitrotyrosine and poly (ADP-ribose) (PAR) as determined by immunohistochemical analysis of lung tissues. 5. The degree of staining for the ICAM-1, nitrotyrosine and PAR was reduced by GW274150. These results clearly confirm that NO from iNOS plays a role in the development of the inflammatory response by altering key components of the inflammatory cascade. 6. GW274150 may offer a novel therapeutic approach for the management of various inflammatory diseases where NO and related radicals have been postulated to play a role.
Dugo
Laura
L
Department Clinical and Experimental Medicine and Pharmacology, University of Messina, Italy.
Marzocco
Stefania
S
Mazzon
Emanuela
E
Di Paola
Rosanna
R
Genovese
Tiziana
T
Caputi
Achille P
AP
Cuzzocrea
Salvatore
S
D000818:Animals; D002351:Carrageenan; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D053583:Interleukin-1beta; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis; D009195:Peroxidase / Q000378:metabolism; D011001:Pleuropneumonia / Q000139:chemically induced / Q000188:drug therapy; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy*; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D053583:Interleukin-1beta; D009566:Nitrates; D009573:Nitrites; D010446:Peptide Fragments; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; C409004:GW 274150; C052994:interleukin-1beta (163-171); D018799:Intercellular Adhesion Molecule-1; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D002351:Carrageenan; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011065:Poly(ADP-ribose) Polymerases