Nitric Oxide Synthase Enzymes in the Airways of Mice Exposed to Ovalbumin: NOS2 Expression Is NOS3 Dependent (original) (raw)
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Role of Nitric Oxide in Chronic Allergen-Induced Airway Cell Proliferation and Inflammation
Journal of Pharmacology and Experimental Therapeutics, 2003
Chronic cellular inflammation and airway wall remodeling with subepithelial fibrosis and airway smooth muscle thickening are features of chronic asthma. We determined the role of nitric oxide in the pathogenesis of allergen-induced airway cell proliferation and inflammation by studying the effects of a relatively selective prodrug inhibitor of nitric-oxide synthase type 2 (NOS2), L-N 6-(1-iminoethyl)-lysine-5-tetrazole amide (SC-51). Brown-Norway rats were sensitized to ovalbumin and were exposed to ovalbumin aerosol every 3rd day on six occasions and were treated orally with either vehicle or SC-51 (10 mg ⅐ kg Ϫ1 ; 12 doses). We measured inflammatory cell accumulation in the airways and proliferation of cells by incorporation of bromodeoxyuridine. There Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
Ambient level of NO2 augments the inflammatory response to inhaled allergen in asthmatics
Respiratory Medicine, 2002
Air pollution constitutes an important factor for asthma aggravation, and there is increased concern about respiratory health effects of common air pollutants.The purpose of this study was to examine how exposure to a high ambient concentration nitrogen dioxide (NO 2 ) prior to a bronchial allergen challenge modulated the inflammatory response in the bronchi. Thirteen subjects with mild asthma and allergy were exposed at rest to either purified air or 500 mg  m À3 NO 2 for 30 min, followed 4 h later by an allergen inhalation challenge.The exposures (NO 2 or air) were performed in random order and at least 4 weeks apart. Lung function during NO 2 /air exposure and allergen challenge was measured by plethysmography, and then hourly by portable spirometry after exposures. Subjective symptoms were recorded during and after exposure. Bronchoscopy with bronchial wash (BW) and bronchoalveolar lavage (BAL) was performed 19 h after allergen challenge. NO 2 +allergen enhanced the percentage of neutrophils in both BW and BAL compared to air+allergen (BW19 vs.11, P¼0.05;BAL 3 vs.1, P¼0.02 medianvalues).The levels of eosinophil cationicprotein (ECP) in BW was higher after NO 2 +allergen compared to air+allergen (9.0 vs.3.6 mg/l; P¼0.02, medianvalues).There was no NO 2-associated effect on symptoms or pulmonary function.These data suggestthat ambient NO 2 can enhance allergic inflammatory reaction in the airways without causing symptoms or pulmonary dysfunction. r
American Journal of Respiratory and Critical Care Medicine, 2001
Pharmacological evidence supports a role of a transient decreased endogenous nitric oxide (NO) synthesis in ovalbumin (OVA)-induced early airway hyperresponsiveness in guinea pigs. However, no data are available regarding the expression and activity of the constitutive NO synthases (cNOS; NOS1 and NOS3, nNOS and eNOS, respectively) in this model. Therefore, we evaluated cNOS activity (conversion of L -[ 3 H]arginine to L -[ 3 H]citrulline in the presence of Ca 2 ϩ and calmodulin), nitrate and nitrite (NOx) concentration (modified Griess method), and NOS1 and NOS3 protein expression (Western blot) in lung homogenates and in the tracheal smooth muscle from OVA-immunized and multiple aerosol-challenged guinea pigs (six challenges, once daily). The expression and activity of the inducible NOS isoform (NOS2), the levels of exhaled NO, and the in vivo airway reactivity were also determined. Constitutive NOS activity and NO x concentration were significantly lower 6 h after the last OVA challenge as compared with saline exposure, being similar at 24 h. Expression of NOS1 paralleled cNOS activity, which was reduced 6, but not 24 h after OVA challenge. The decrease in NOS1 expression was accompanied by a significant decrease in the amounts of exhaled NO and by a maximal airway hyperresponsiveness to histamine. The levels of NOS3 were not modified at the two time points evaluated, and no NOS2 expression and activity were found at any time point. Similar modifications were observed in the tracheal smooth muscle. We conclude that OVA stimulation in immunized guinea pigs induced a transient reduction in NOS1 protein expression and activity in the respiratory system, which probably participates in airway hyperresponsiveness.
Elevated levels of NO are localized to distal airways in asthma
Free Radical Biology and Medicine, 2011
The contribution of nitric oxide (NO) to the pathophysiology of asthma remains incompletely defined despite its established pro-and anti-inflammatory effects. Induction of the inducible nitric oxide synthase (iNOS), arginase and superoxide pathways is correlated with increased airway hyperresponsiveness (AHR) in asthmatic subjects. To determine the contributions of these pathways in proximal and distal airways, we compared bronchial wash (BW) to traditional bronchoalveolar lavage (BAL) for measurements of reactive nitrogen/oxygen species, arginase activation, and cytokine/chemokine levels in asthmatic and normal subjects. Levels of NO were preferentially elevated in the BAL, demonstrating higher-level NOS activation in the distal airway compartment of asthmatic subjects. In contrast, DHE + cells which have the potential to generate
Mediators of Inflammation, 2002
NITROGEN dioxide (NO 2 ) is a common indoor and outdoor air pollutant whose role in the induction of asthma is unclear. We investigated the effects of NO 2 on the development of asthma-like responses to allergenic challenge in BALB/c mice. Ovalbumin (OVA)-immunized mice were intranasally challenged with OVA or saline solution just before starting a 3 h exposure to 5 or 20 ppm NO 2 or air. Twenty parts per million of NO 2 induced a significant increase of bronchopulmonary hyperreactivity in OVA-challenged mice and of permeability according to the fibronectin content of the bronchoalveolar lavage fluid (BALF) 24 h after exposure, as compared with air or 5 ppm NO 2 . Eosinophilia (cell counts in the BALF and eosinophil peroxidase of lung tissue) was detected at 24 and 72 h with similar levels for air and 20 ppm NO 2 , whereas a marked reduction was unexpectedly observed for 5 ppm NO 2 . At 24 h, interleukin-5 in the BALF was markedly reduced at 5 ppm compared with 20 ppm NO 2 and was also more intense for 20 ppm NO 2 than for the air group. In contrast to specific IgG1 titers, anti-OVA IgE titers and interleukin-4 in the BALF were not affected by NO 2 exposure. Irrespective of the concentration of NO 2 , OVA-challenged mice did not develop late mucosal metaplasia compared with those exposed to OVA-air. These results indicate that a short exposure to NO 2 can exacerbate or inhibit some features of the development of allergic disease in mice and may depend on the concentration of pollutant.
Experimental and Toxicologic Pathology, 2005
The major features of chronic obstructive pulmonary disease (COPD) comprise a not fully reversible airflow limitation associated with an abnormal inflammatory response, increased mucus production and development of emphysema-like lesions. Animal models that closely mimic these alterations represent an important issue for the investigation of pathophysiological mechanisms. Since most animal models in this area have focused on specific aspects of the disease, we aimed to investigate whether exposure of C57BL/6 mice to nitrogen dioxide (NO 2 ) may cause a more complex phenotype covering several of the characteristics of the human disease. Therefore, mice were exposed to NO 2 for 14 h each day for up to 25 days. Initial dose response experiments revealed the induction of a significant inflammatory response at a dose of 20 ppm NO 2 . Mice developed progressive airway inflammation together with a focal inflammation of the lung parenchyma characterized by a predominant influx of neutrophils and macrophages. In addition, goblet cell hyperplasia was detected in the central airways and increased collagen deposition was found in the lung parenchyma. NO 2 -exposed mice developed emphysema-like lesions as indicated by a significantly increased mean linear intercept as compared to control mice. Finally, the assessment of lung functional parameters revealed the development of progressive airway obstruction over time. In conclusion, our data provide evidence that the inflammatory response to NO 2 exposure is associated with increased mucus production, development of airspace enlargement and progressive airway obstruction. Thus, NO 2 -exposed mice may serve as a model to investigate pathophysiological mechanisms that contribute to the development of human COPD.
Endogenous nitric oxide in allergic airway disease
Journal of Allergy and Clinical Immunology, 2000
There has been intense research into the role nitric oxide (NO) plays in physiologic and pathologic mechanisms. The presence of NO in exhaled breath and the high concentrations in nasal airways stimulated many studies examining exhaled and nasal NO as potential markers of airway inflammation, enabling repeated monitoring of airway inflammation not possible with invasive tests (eg, bronchoscopy). In airway inflammation, NO is not merely a marker but may have anti-inflammatory and proinflammatory effects. Nasal NO measurement may be used in the noninvasive diagnosis and monitoring of nasal disease. This review was compiled by speakers who gave presentations on NO at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in 1999 on exhaled and nasal NO, in vitro studies of NO, the chemistry of airway NO formation, and standardized measurement of exhaled mediators. (J Allergy Clin Immunol 2000;105:438-48.)
Journal of Experimental Medicine, 1999
Asthma is a chronic disease characterized by increased airway responsiveness and airway inflammation. The functional role of nitric oxide (NO) and the various nitric oxide synthase (NOS) isoforms in human asthma is controversial. To investigate the role of NO in an established model of allergic asthma, mice with targeted deletions of the three known isoforms of NOS (NOS1, 2, and 3) were studied. Although the inducible (NOS2) isoform was significantly upregulated in the lungs of ovalbumin (OVA)-sensitized and -challenged (OVA/OVA) wild-type (WT) mice and was undetectable in similarly treated NOS2-deficient mice, airway responsiveness was not significantly different between these groups. OVA/OVA endothelial (NOS3)-deficient mice were significantly more responsive to methacholine challenge compared with similarly treated NOS1 and NOS1&3-deficient mice. Airway responsiveness in OVA/OVA neuronal (NOS1)-deficient and neuronal/endothelial (NOS1&3) double-deficient mice was significantly le...
Nitrogen dioxide enhances allergic airway inflammation and hyperresponsiveness in the mouse
AJP: Lung Cellular and Molecular Physiology, 2005
In addition to being an air pollutant, nitrogen dioxide (NO 2 ) is a potent inflammatory oxidant generated endogenously by myeloperoxidase and eosinophil peroxidase. In these studies, we sought to determine the effects of NO 2 exposure on mice with ongoing allergic airway disease pathology. Mice were sensitized and challenged with the antigen, ovalbumin (OVA) to generate airway inflammation and subsequently exposed to 5 or 25 parts per million (ppm) NO 2 for 3 days, or 5 days followed by a 20 day recovery period. While 5 ppm NO 2 elicited no pathologic changes, inhalation of 25 ppm NO 2 alone induced acute lung injury, which peaked after 3 days and was characterized by increases in protein, lactate dehydrogenase (LDH), and neutrophils recovered by bronchoalveolar lavage (BAL), as well as lesions within the terminal bronchioles. Importantly, 25 ppm NO 2 was also sufficient to cause airways hyperresponsiveness (AHR) in mice, a cardinal feature of asthma. The inflammatory changes were ameliorated after 5 days of inhalation and completely resolved after 20 days of recovery following the 5 day inhalation. In contrast, in mice immunized and challenged with OVA, inhalation of 25 ppm NO 2 caused a marked augmentation of eosinophilic inflammation and terminal bronchiolar lesions, which extended significantly into the alveoli. Moreover, 20 days post cessation of the 5 day 25 ppm NO 2 inhalation regimen, eosinophilic and neutrophilic inflammation, pulmonary lesions, and AHR were still present in mice immunized and challenged with OVA. Collectively, these observations suggest an important role for NO 2 in the airway pathologies associated with asthma, both in the modulation of the degree and the duration of the inflammatory response, as well as in the induction of AHR.