Effect of inducible nitric oxide synthase on apoptosis in Candida-induced acute lung injury.
Excessive nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) aggravates acute lung injury (ALI) by producing peroxinitrite. We previously showed that the expression of iNOS and lung injury were suppressed by inhalation of a novel iNOS inhibitor, ONO-1714, in mice with Candida-induced ALI, and that nitric oxide produced by iNOS and apoptosis of epithelial cells were found to have a crucial role in Candida-induced ALI. In the present study, we investigated the effect of NO on the apoptosis of alveolar epithelial cells in Candida-induced ALI. Mice were pretreated by inhalation of ONO-1714 or saline (vehicle control of ONO-1714), and were given an intravenous injection of Candida albicans to induce ALI. After 24 h from injection of Candida albicans, we performed bronchoalveolar lavage and removed lung tissues. We assessed apoptosis on the basis of TUNEL staining and caspase 3 activity. Our results showed that apoptosis was suppressed by inhibition of iNOS-derived NO production by ONO-1714 inhalation. The augmented production of NO increased FasL, TNF-alpha, and mRNA production of Bax of lung that induced apoptosis of alveolar epithelial cells. Inhibition of iNOS-derived NO production by ONO-1714 inhalation ameliorated Candida-induced ALI and improved survival by suppressing apoptosis of alveolar epithelial cells.
Hosogi
Shigekuni
S
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. hosogi@koto.kpu-m.ac.jp
Iwasaki
Yoshinobu
Y
Yamada
Takahiro
T
Komatani-Tamiya
Nobuyo
N
Hiramatsu
Atsushi
A
Kohno
Yoshihito
Y
Ueda
Mikio
M
Arimoto
Taichiro
T
Marunaka
Yoshinori
Y
D055371:Acute Lung Injury / Q000473:pathology* / Q000503:physiopathology; D000578:Amidines / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002175:Candida / Q000378:metabolism; D002177:Candidiasis / Q000473:pathology / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D053222:Fas Ligand Protein; D006574:Heterocyclic Compounds, 2-Ring; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3