Inhibition or knock out of inducible nitric oxide synthase result in resistance to bleomycin-induced lung injury.
BACKGROUND
In the present study, by comparing the responses in wild-type mice (WT) and mice lacking (KO) the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the role played by iNOS in the development of on the lung injury caused by bleomycin administration. When compared to bleomycin-treated iNOSWT mice, iNOSKO mice, which had received bleomycin, exhibited a reduced degree of the (i) lost of body weight, (ii) mortality rate, (iii) infiltration of the lung with polymorphonuclear neutrophils (MPO activity), (iv) edema formation, (v) histological evidence of lung injury, (vi) lung collagen deposition and (vii) lung Transforming Growth Factor beta1 (TGF-beta1) expression.


METHODS
Mice subjected to intratracheal administration of bleomycin developed a significant lung injury. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in lungs from bleomycin-treated iNOSWT mice.


RESULTS
The intensity and degree of nitrotyrosine staining was markedly reduced in tissue section from bleomycin-iNOSKO mice. Treatment of iNOSWT mice with of GW274150, a novel, potent and selective inhibitor of iNOS activity (5 mg/kg i.p.) also significantly attenuated all of the above indicators of lung damage and inflammation.


CONCLUSIONS
Taken together, our results clearly demonstrate that iNOS plays an important role in the lung injury induced by bleomycin in the mice.
Genovese
Tiziana
T
Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy. tgenovese@unime.it
Cuzzocrea
Salvatore
S
Di Paola
Rosanna
R
Failla
Marco
M
Mazzon
Emanuela
E
Sortino
Maria Angela
MA
Frasca
Giuseppina
G
Gili
Elisa
E
Crimi
Nunzio
N
Caputi
Achille P
AP
Vancheri
Carlo
C
D000818:Animals; D001761:Bleomycin; D004351:Drug Resistance; D007113:Immunity, Innate / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D013440:Sulfides / Q000008:administration & dosage
D013440:Sulfides; C409004:GW 274150; D001761:Bleomycin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse