Effect of inhaled NG-nitro-L-arginine methyl ester on Candida-induced acute lung injury
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Published on: July 6, 2019
Kazuhiro Nagata1, Yoshinobu Iwasaki, Yoshizumi Takemura
1Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602, Japan. nagata@koto.kpu-m.ac.jp
Study Objectives:
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.
Design:
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.
Measurements And 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.
Insights
Inhaled nitric oxide synthase (NOS) inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) reduced lung injury and improved survival in a mouse model of Candida-induced acute lung injury (ALI). This suggests local NOS inhibition is a potential treatment for ALI.
Area of Science:
- Pulmonary Medicine
- Immunology
- Pharmacology
Background:
- Nitric oxide (NO) and peroxynitrite are implicated in acute lung injury (ALI).
- The role of nitric oxide synthase (NOS) inhibition in treating lung injury is debated.
- Candida albicans infection serves as a model for ALI.
Purpose of the Study:
- To investigate the hypothesis that local NOS inhibition in the lung mitigates lung injury.
- To evaluate the therapeutic potential of inhaled N(G)-nitro-L-arginine methyl ester (L-NAME) in a Candida-induced ALI model.
Main Methods:
- A mouse model of Candida-induced ALI was established via intravenous Candida albicans injection.
- Mice were pretreated with inhaled saline or L-NAME before ALI induction.
- Nitrite-nitrate levels, inflammatory markers (TNF-α, IL-1β, MIP-2), neutrophil counts, iNOS, and nitrotyrosine expression were measured.
Main Results:
- Inhaled L-NAME significantly reduced nitrite-nitrate levels in bronchoalveolar lavage fluid (BALF).
- L-NAME decreased inflammatory markers, neutrophil infiltration, inducible NOS (iNOS) expression, and nitrotyrosine production in the lungs.
- Histological lung injury was reduced, and survival was improved in L-NAME treated mice.
Conclusions:
- Nitric oxide plays a significant role in the pathogenesis of Candida-induced ALI.
- Local inhibition of NOS, specifically through inhaled L-NAME, demonstrates therapeutic benefits in reducing ALI.
- Inhaled L-NAME is a promising treatment strategy for Candida-induced ALI.
