Effect of inhaled NG-nitro-L-arginine methyl ester on Candida-induced acute lung injury.
OBJECTIVE
Nitric oxide (NO) and peroxynitrite play a crucial role in acute lung injury (ALI). Whether NO synthase (NOS) inhibition is beneficial in the treatment of lung injury remains controversial. The objective of this study was to test the hypothesis that local inhibition of NOS in the lung reduces lung injury.


METHODS
We developed a model of Candida-induced ALI in the mouse by IV injection of Candida albicans. To evaluate the effect of NOS inhibitor, mice were pretreated by inhalation of saline solution or N(G)-nitro-L-arginine methyl ester (L-NAME) before induction of Candida-induced ALI.


RESULTS
After inhalation of 1 mM aerosolized L-NAME, nitrite-nitrate concentrations in BAL fluid (BALF) were significantly lower at 24 h and 48 h than those in mice treated with C albicans alone. Tumor necrosis factor-alpha, interleukin-1beta, and macrophage inflammatory protein-2 concentrations in lung homogenates, measured by enzyme-linked immunosorbent assay, and neutrophil counts in BALF were decreased by inhalation of L-NAME (n = 6 per group). Immunohistochemical analysis of inducible NOS (iNOS) and nitrotyrosine, a major product of protein nitration by peroxynitrite, revealed that alveolar macrophages and alveolar epithelial cells were positive for both substances in Candida-induced ALI. Inhalation of L-NAME markedly suppressed iNOS protein expression and nitrotyrosine production. Histologic evidence of lung injury decreased and survival improved after inhalation of L-NAME.


CONCLUSIONS
We conclude that NO might play a crucial role in the pathogenesis of Candida-induced ALI, and such injury might be reduced by local inhibition of NOS. Our findings suggest that inhalation of L-NAME is beneficial in the treatment of Candida-induced ALI.
Nagata
Kazuhiro
K
Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602, Japan. nagata@koto.kpu-m.ac.jp
Iwasaki
Yoshinobu
Y
Takemura
Yoshizumi
Y
Harada
Hidehiko
H
Yokomura
Ichiro
I
Fushiki
Shinji
S
Nakagawa
Masao
M
D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002177:Candidiasis / Q000150:complications*; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000633:toxicity*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control
D016207:Cytokines; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester