An inhaled inducible nitric oxide synthase inhibitor reduces damage of Candida-induced acute lung injury

Ohsugi, Shuji; Iwasaki, Yoshinobu; Takemura, Yoshizumi; Nagata, Kazuhiro; Harada, Hidehiko; Yokomura, Ichiro; Hosogi, Shigekuni; Yuba, Tatsuya; Niisato, Naomi; Mitsuya, Hiroaki; Matsubara, Hiroaki; Fushiki, Shinji; Marunaka, Yoshinori

doi:10.2220/biomedres.28.91

Cited by 10 publications

(9 citation statements)

References 50 publications

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“…The temporal association between AhR-mediated elevation in pulmonary neutrophil number and iNOS levels in the infected lung, combined with the reported causal relationship between iNOS and neutrophil recruitment in other model systems (30, 31, 55), suggests a causal relationship may exist. To determine if the AhR-mediated increase in iNOS is necessary for or drives the enhanced neutrophil recruitment to the infected lung, we used the NOS inhibitor N5-[imino(methylamino)methyl]-L-ornithine (L-NMMA).…”

Section: Resultsmentioning

confidence: 89%

Novel Cellular Targets of AhR Underlie Alterations in Neutrophilic Inflammation and Inducible Nitric Oxide Synthase Expression during Influenza Virus Infection

Wheeler

Martin²,

Lawrence³

2013

The Journal of Immunology

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The underlying reasons for variable clinical outcomes from respiratory viral infections remain uncertain. Several studies suggest that environmental factors contribute to this variation, but limited knowledge of cellular and molecular targets of these agents hampers our ability to quantify or modify their contribution to disease and improve public health. The aryl hydrocarbon receptor (AhR) is an environment sensing transcription factor that binds many anthropogenic and natural chemicals. The immunomodulatory properties of AhR ligands are best characterized with extensive studies of changes in CD4+ T cell responses. Yet, AhR modulates other aspects of immune function. We previously showed that during influenza virus infection, AhR activation modulates neutrophil accumulation in the lung, and this contributes to increased mortality in mice. Enhanced levels of inducible nitric oxide synthase (iNOS) in infected lungs are observed during the same timeframe as AhR-mediated increased pulmonary neutrophilia. In this study, we evaluated whether these two consequences of AhR activation are causally linked. Reciprocal inhibition of AhR-mediated elevations in iNOS and pulmonary neutrophilia reveal that, although they are contemporaneous, they are not causally related. We show using Cre/loxP technology that elevated iNOS levels and neutrophil number in the infected lung result from separate, AhR-dependent signaling in endothelial and respiratory epithelial cells, respectively. Studies using mutant mice further reveal that AhR-mediated alterations in these innate responses to infection require a functional nuclear localization signal and DNA binding domain. Thus, gene targets of AhR in non-hematopoietic cells are important new considerations for understanding AhR-mediated changes in innate anti-viral immunity.

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Section: Resultsmentioning

confidence: 89%

Novel Cellular Targets of AhR Underlie Alterations in Neutrophilic Inflammation and Inducible Nitric Oxide Synthase Expression during Influenza Virus Infection

Wheeler

Martin²,

Lawrence³

2013

The Journal of Immunology

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“…Ohsugi et al [43] demonstrated that inhaled ONO-1714, a very potent but moderately selective iNOS inhibitor, diminished pulmonary inflammation, NO x and peroxynitrite production and prolonged survival in a Candida albicansinduced ALI model in mice.…”

Section: Ali and Ards (Acute Respiratory Distress Syndrome)mentioning

confidence: 99%

Inhibition of inducible nitric oxide synthase in respiratory diseases

Heßlinger¹,

Strub²,

Boer³

et al. 2009

Biochemical Society Transactions

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Nitric oxide (NO) is a key physiological mediator and disturbed regulation of NO release is associated with the pathophysiology of almost all inflammatory diseases. A multitude of inhibitors of NOSs (nitric oxide synthases) have been developed, initially with low or even no selectivity against the constitutively expressed NOS isoforms, eNOS (endothelial NOS) and nNOS (neuronal NOS). In the meanwhile these efforts yielded potent and highly selective iNOS (inducible NOS) inhibitors. Moreover, iNOS inhibitors have been shown to exert beneficial anti-inflammatory effects in a wide variety of acute and chronic animal models of inflammation. In the present mini-review, we summarize some of our current knowledge of inhibitors of the iNOS isoenzyme, their biochemical properties and efficacy in animal models of pulmonary diseases and in human disease itself. Moreover, the potential benefit of iNOS inhibition in animal models of COPD (chronic obstructive pulmonary disease), such as cigarette smoke-induced pulmonary inflammation, has not been explicitly studied so far. In this context, we demonstrated recently that both a semi-selective iNOS inhibitor {l-NIL [N6-(1-iminoethyl)-l-lysine hydrochloride]} and highly selective iNOS inhibitors (GW274150 and BYK402750) potently diminished inflammation in a cigarette smoke mouse model mimicking certain aspects of human COPD. Therefore, despite the disappointing results from recent asthma trials, iNOS inhibition could still be of therapeutic utility in COPD, a concept which needs to be challenged and validated in human disease.

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“…We also reported that nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) played a crucial role in Candida-induced ALI and demonstrated that the iNOS inhibitor L-NAME had a beneficial effect on Candida-induced ALI (17). Furthermore, we showed that a novel iNOS inhibitor, ONO-1714, a novel selective iNOS inhibitor (1S,5S,6R,7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane hydrochloride), reduced Candida-induced ALI (20). Numerous clinical and case studies have indicated that inhaled NO decreases pulmonary hypertension and improves hypoxemia in ARDS (24).…”

Section: Bronchoalveolar Lavage (Bal)mentioning

confidence: 72%

Effect of inducible nitric oxide synthase on apoptosis in Candida-induced acute lung injury

et al. 2008

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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-α, 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.

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An inhaled inducible nitric oxide synthase inhibitor reduces damage of Candida-induced acute lung injury

Cited by 10 publications

References 50 publications

Novel Cellular Targets of AhR Underlie Alterations in Neutrophilic Inflammation and Inducible Nitric Oxide Synthase Expression during Influenza Virus Infection

Novel Cellular Targets of AhR Underlie Alterations in Neutrophilic Inflammation and Inducible Nitric Oxide Synthase Expression during Influenza Virus Infection

Inhibition of inducible nitric oxide synthase in respiratory diseases

Effect of inducible nitric oxide synthase on apoptosis in Candida-induced acute lung injury

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