The Toxicology of Inhaled Nitric Oxide

Weinberger, Barry; Laskin, Debra L.; Heck, Diane E.; Laskin, Jeffrey D.

doi:10.1093/toxsci/59.1.5

Cited by 278 publications

(163 citation statements)

References 114 publications

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“…There are probably several mechanisms underlying the alteration of the NO-induced surfactant secretion (45). The partial effects of cGMP and of SIN-1, a peroxynitrite donor, which is the result of the reaction of NO with superoxide anion, suggest the existence of at least two mechanisms, including an oxidative pathway.…”

Section: Discussionmentioning

confidence: 99%

Diesel particles increase phosphatidylcholine release through a NO pathway in alveolar type II cells

Juvin

Fournier

Grandsaigne

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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(DEPs) have been shown in vivo as well as in vitro to affect the respiratory function and in particular the immune response to infection and allergens. In the current study, we investigated the effect of DEPs on the production of phosphatidylcholine (PC), a major constituent of surfactant, by rat alveolar type II (ATII) primary cells in vitro. Our results demonstrate that incubation of ATII cells with DEPs lead to a time-and dose-dependent increase in labeled PC release. This effect was mimicked by nitric oxide (NO) donors and cGMP and was abolished by inhibitors of NO synthase (NOS). In addition, a NOS inhibitor inhibits by itself the basal secretion of PC. We next examined the effects of DEPs on NOS gene expression and showed that DEPs increase NO production and upregulate both protein content and mRNA levels of the inducible NOS (NOS II). Together our data demonstrate that DEPs alter the production of surfactant by ATII cells through a NO-dependent signaling pathway. surfactant; nitric oxide MAJOR AIR POLLUTANTS include nitrogen dioxide, ozone sulfur dioxide, and breathable particulate matter of diameter inferior to 10 m (PM10) (12,27). Several studies have particularly implicated diesel exhaust particles (DEPs), a major component of PM10, as contributing to the incidence and severity of respiratory diseases during air pollution episodes. Epidemiological studies have reported that high levels of DEPs are associated with worsening peak flow, inhaler usage, respiratory symptoms, and emergency room visits in asthmatic children and adults (34,38). In a cohort of over half a million adults residing in 151 metropolitan areas in the United States between 1982 and 1989, fine particulate pollution was associated with cardiopulmonary and lung cancer mortality (33). Similarly, a recent work has demonstrated an increased mortality and morbidity rate after DEPs exposure (26).Airway epithelial cells are primary targets for air pollutants. Several studies have investigated the effect of DEPs on nasal, bronchial, and alveolar epithelial cells. In nasal cells, DEPs enhance cytokine expression synergistically with allergens and increase local eosinophil adhesion (15,16,44). In bronchial epithelial cells, DEPs are internalized, inducing airway inflammation (4,8,41) and hyperresponsiveness (43).DEPs also interact with alveolar type II (ATII) cells since their small size (0.1-1 m) allows them to reach the alveolar space (32,46,48). ATII cells regulate the intra-alveolar homeostasis through four main functions. They secrete a large panel of cytokines (5, 13, 31, 39), serve as progenitors to the alveolar type I cells (18), actively transport ions (23), and synthesize and secrete surfactant. We previously demonstrated that one of these functions (i.e., cytokine secretion) was altered by DEPs (24). Synthesis and secretion of surfactant are other very important functions of ATII cells. Surfactant prevents alveolar collapse at end expiration by lowering surface tension at the air/extracellular lining interface in the alveoli and dist...

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Section: Discussionmentioning

confidence: 99%

Diesel particles increase phosphatidylcholine release through a NO pathway in alveolar type II cells

Juvin

Fournier

Grandsaigne

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…On the other hand, increased methemoglobin levels are a known toxic effect of inhaled NO therapy, commonly used for hypoxic neonates. NO can combine with hemoglobin to produce nitrosylhemoglobin and thus form methemoglobin by oxidation (Weinberger et al, 2001;Hamon et al, 2010). Based on our observations, we can hypothesize that lower doses of ARG were beneficial to decrease methemoglobin levels because of the antioxidant properties of NO.…”

Section: Discussionmentioning

confidence: 58%

L-arginine, a nitric oxide precursor, reduces dapsone-induced methemoglobinemia in rats

Moraes

Bergamaschi

Bianchi

et al. 2012

Braz. J. Pharm. Sci.

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Dapsone use is frequently associated to hematological side effects such as methemoglobinemia and hemolytic anemia, which are related to N-hydroxylation mediated by the P450 enzyme system. The aim of the present study was to evaluate the influence of L-arginine supplementation, a precursor for the synthesis of nitric oxide, as single or multiple dose regimens on dapsone-induced methemoglobinemia. Male Wistar rats were treated with L-arginine at 5, 15, 30, 60 and 180 mg/kg doses (p.o., gavage) in single or multiple dose regimens 2 hours prior to dapsone administration (40 mg/kg, i.p.). The effect of the nitric oxide synthase inhibitor L-NAME was investigated by treatment with multiple doses of 30 mg/kg (p.o., gavage) 2 hours before dapsone administration. Blood samples were collected 2 hours after dapsone administration. Erythrocytic methemoglobin levels were assayed by spectrophotometry. The results showed that multiple dose supplementations with 5 and 15 mg/kg L-arginine reduced dapsoneinduced methemoglobin levels. This effect is mediated by nitric oxide formation, since the reduction in methemoglobin levels by L-arginine is blocked by simultaneous administration with L-NAME, a nitric oxide synthase inhibitor. Uniterms:Dapsone. Methemoglobinemia. L-arginine. Nitric oxide. L-NAME.O uso da dapsona é frequentemente associado a efeitos adversos hematológicos, como a metemoglobinemia e anemia hemolítica, ambos relacionados com a N-hidroxilação mediada pelo sistema P450. O objetivo do estudo foi avaliar a influência da suplementação de L-arginina, um precursor da síntese de óxido nítrico, administrado em regime de dose única ou múltipla na metemoglobinemia induzida pela dapsona. Ratos machos Wistar foram tratados com L-arginina (po, gavagem) em dose única ou múltipla de 5, 15, 30, 60 e 180 mg/kg 2 horas antes da administração de dapsona (40 mg/kg, ip). O efeito do L-NAME, um inibidor de óxido nítrico sintase (NOS), foi avaliado através do tratamento com doses múltiplas de 30 mg/kg. Amostras de sangue foram coletadas duas horas após a administração de dapsona. A concentração de metemoglobina eritrocitária foi analisada por espectrofotometria. Os resultados mostraram que a suplementação em dose múltipla de 5 e 15 mg/kg de L-arginina reduziu os níveis de metemoglobina induzida pela dapsona. Este efeito é mediado pela formação de óxido nítrico, uma vez que a redução nos níveis de metemoglobina pela L-arginina é bloqueada pela administração simultânea de L-NAME, um inibidor da óxido nítrico sintase. Unitermos:Dapsona. Metemoglobinemia. L-arginina. Óxido nítrico. L-NAME. INTRODUCTIONDapsone (4,4'-diaminodiphenylsulfone, DDS) is a potent antibacterial and anti-inflammatory compound and has been clinically used in the treatment of leprosy as a component of a multidrug therapy that includes a combination of DDS, clofazimine and rifampicin (Katoch 2002;Walker, Lockwood 2007). The drug is also used for the treatment of malaria and Pneumocystic carinii pneumonia in patients with acquired immunodeficiencysyndrome (Powell et al., 1...

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“…A review of the toxicology of inhaled NO has recently been published. 67 Nitrogen Dioxide and Methemoglobinemia Formation of NO 2 during NO breathing is dependent on the NO concentration, inspiratory oxygen concentration (FiO 2 ), and residence time of these gases. 68 Increased airway reactivity has been reported in humans after exposures to as low as 1.5 ppm NO 2 .…”

Section: Toxicity and Side Effects Of Inhaled Nomentioning

confidence: 99%

“…Tissue hypoxia can be produced at excessive circulating metHb concentrations. 67 The enzyme metHb reductase rapidly converts metHb to Hb in the red blood cell.…”

Section: Toxicity and Side Effects Of Inhaled Nomentioning

confidence: 99%

Inhaled Nitric Oxide

2004

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Since the recognition of nitric oxide (NO) as a key endothelial-derived vasodilator molecule in 1987, the field of NO research has expanded to encompass many areas of biomedical research. It is now well established that NO is an important signaling molecule throughout the body. The therapeutic potential of inhaled NO as a selective pulmonary vasodilator was suggested in a lamb model of pulmonary hypertension and in patients with pulmonary hypertension in 1991. 1,2 Because NO is scavenged by hemoglobin (Hb) on diffusing into the blood and is thereby rapidly inactivated, the vasodilatory effect of inhaled NO is limited largely to the lung. This is in contrast to intravenously infused vasodilators that can cause systemic vasodilation and severe systemic arterial hypotension.Recent data indicate that inhaled NO can be applied in various diseases. For example, studies suggest that inhaled NO is a safe and effective agent to determine the vasodilatory capacity of the pulmonary vascular bed. This article summarizes the pharmacology and physiology of inhaled NO and reviews the current uses of inhaled NO for the treatment, evaluation, and prevention of cardiovascular and respiratory diseases. Pharmacology and Physiology of Inhaled NO Chemistry of NO GasNO is a colorless, odorless gas that is only slightly soluble in water. 3 NO and its oxidative byproducts (eg, NO 2 and N 2 O 4 ) are produced by the partial oxidation of atmospheric nitrogen in internal combustion engines, in the burning cinder cones of cigarettes, and in lightning storms. Medical-grade NO gas is produced under carefully controlled conditions, diluted with pure nitrogen, and stored in the absence of oxygen. The recent article by Williams 4 provides a review of the chemistry of NO. Therapeutic Versus Endogenous NO Concentrations in the AirwayAlthough early studies of inhaled NO in the treatment of pulmonary hypertension used concentrations of 5 to 80 ppm, it has since been realized that concentrations Ͼ20 ppm provide little additional hemodynamic benefit in most patients. In some adults with acute respiratory failure, the effective concentrations of inhaled NO required to improve oxygenation can be as low as 10 ppb. 5,6 Of note, NO has been detected in exhaled human breath. The majority of exhaled NO in normal humans appears to be derived from nasal bacterial flora (25 to 64 ppb), with lower concentrations measured in the mouth, trachea, and distal airway (1 to 6 ppb). 5,7 Mechanism of ActionAfter inhalation, NO diffuses rapidly across the alveolarcapillary membrane into the subjacent smooth muscle of pulmonary vessels to activate soluble guanylate cyclase (Figure 1). This enzyme mediates many of the biological effects of NO and is responsible for the conversion of GTP to cGMP. Increased intracellular concentrations of cGMP relax smooth muscle via several mechanisms. The physiological actions of cGMP are limited to its area of synthesis by its hydrolysis to GMP by cyclic nucleotide phosphodiesterases (PDE) or by its export from the cell. Of the 11 reported...

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The Toxicology of Inhaled Nitric Oxide

Cited by 278 publications

References 114 publications

Diesel particles increase phosphatidylcholine release through a NO pathway in alveolar type II cells

Diesel particles increase phosphatidylcholine release through a NO pathway in alveolar type II cells

L-arginine, a nitric oxide precursor, reduces dapsone-induced methemoglobinemia in rats

Inhaled Nitric Oxide

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