Airway Nitric Oxide Diffusion in Asthma

Silkoff, Philip E.; Sylvester, J. T.; Zamel, Noé; Permutt, Solbert

doi:10.1164/ajrccm.161.4.9903111

Cited by 221 publications

(87 citation statements)

References 28 publications

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“…However, active mechanisms have been postulated to explain the efficacy and duration of the deep breaths on bronchial tone in healthy humans. Admittedly, nitric oxide could be one of the putative molecules capable of actively reducing airway smooth muscle tone (3,34), but whether the amount of this compound is differently released in the small compared with the large airways during inflation maneuvers of various depth or whether the airways have different sensitiveness to it is unknown. If this was the case in the present study, then it could be speculated that multiple mechanisms likely concurred to dilate the airways and keep them open after a series of breaths with different sizes.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of induced bronchoconstriction in healthy subjects: effects of breathing depth

Salerno¹,

Pellegrino²,

Trocchio³

et al. 2005

Journal of Applied Physiology

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The effects of breathing depth in attenuating induced bronchoconstriction were studied in 12 healthy subjects. On four separate, randomized occasions, the depth of a series of five breaths taken soon (ϳ1 min) after methacholine (MCh) inhalation was varied from spontaneous tidal volume to lung volumes terminating at ϳ80, ϳ90, and 100% of total lung capacity (TLC). Partial forced expiratory flow at 40% of control forced vital capacity (V part) and residual volume (RV) were measured at control and again at 2, 7, and 11 min after MCh. The decrease in V part and the increase in RV were significantly less when the depth of the five-breath series was progressively increased (P Ͻ 0.001), with a linear relationship. The attenuating effects of deep breaths of any amplitude were significantly greater on RV than V part (P Ͻ 0.01) and lasted as long as 11 min, despite a slight decrease with time when the end-inspiratory lung volume was 100% of TLC. In conclusion, in healthy subjects exposed to MCh, a series of breaths of different depth up to TLC caused a progressive and sustained attenuation of bronchoconstriction. The effects of the depth of the five-breath series were more evident on the RV than on V part, likely due to the different mechanisms that regulate airway closure and expiratory flow limitation. deep breath; airflow obstruction; partial forced expiratory flow; residual volume SEVERAL STUDIES HAVE DOCUMENTED the ability of reversing induced airway narrowing by deep breaths in healthy humans (4, 5, 7, 14, 18, 23-25, 31, 35, 38). This effect has been inferred from the increase in forced expiratory flows or the decrease in airway resistance or residual volume (RV) when a full lung inflation was taken after exposing the airways to a constrictor agent. This phenomenon is basically absent or modest in asthma and chronic obstructive pulmonary disease and may contribute to explain the degree of airway hyperresponsiveness (2,4,5,14,(23)(24)(25). The understanding of the mechanisms regulating airway tone in healthy conditions becomes central to the knowledge of the pathophysiology of obstructive lung diseases. All studies have so far focused on the effects of deep breaths taken to total lung capacity (TLC), but little is known about the effects of submaximal inspirations. The only few studies that addressed this issue were conducted in animals after exposing the airways or isolated airway smooth muscle to a constrictor agent and documented a progressive decrease in airway resistance or decrease in airway smooth muscle force with gradual increments of the depth of lung inflations (11, 32).The present study was conducted in healthy humans to examine the effects on airway function of a series of five breaths of variable depth taken soon after inducing airway narrowing by methacholine (MCh). It was intended to address three main questions. First, is induced airway narrowing progressively attenuated by increasing the amplitude of the breaths, or is there a threshold for the effects of lung inflation to become apparent? Second, f...

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Section: Discussionmentioning

confidence: 99%

Attenuation of induced bronchoconstriction in healthy subjects: effects of breathing depth

Salerno¹,

Pellegrino²,

Trocchio³

et al. 2005

Journal of Applied Physiology

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“…reactive oxygen species ͉ reactive nitrogen species ͉ asthma ͉ allergy T he exhaled air of asthmatic individuals contains higher levels of NO ⅐ than found in exhalate of healthy nonsmoking individuals (1)(2)(3)(4)(5)(6)(7). The role of NO ⅐ in asthma is unclear, but studies suggest that NO ⅐ relaxes bronchial smooth muscle, leading to bronchodilatation, inhibits proinflammatory signaling events (8,9), or conversely contributes to airway inflammation and injury through formation of toxic reactive nitrogen species (RNS) (10).…”

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confidence: 99%

NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response

Dweik

Comhair

Gaston

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

241

210

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A wealth of evidence supports increased NO (NO ⅐ ) in asthma, but its roles are unknown. To investigate how NO participates in inflammatory airway events in asthma, we measured NO ⅐ and NO ⅐ chemical reaction products [nitrite, nitrate, S-nitrosothiols (SNO), and nitrotyrosine] before, immediately and 48 h after bronchoscopic antigen (Ag) challenge of the peripheral airways in atopic asthmatic individuals and nonatopic healthy controls. Strikingly, NO 3 ؊ was the only NO ⅐ derivative to increase during the immediate reactive oxygen species ͉ reactive nitrogen species ͉ asthma ͉ allergy T he exhaled air of asthmatic individuals contains higher levels of NO ⅐ than found in exhalate of healthy nonsmoking individuals (1-7). The role of NO ⅐ in asthma is unclear, but studies suggest that NO ⅐ relaxes bronchial smooth muscle, leading to bronchodilatation, inhibits proinflammatory signaling events (8, 9), or conversely contributes to airway inflammation and injury through formation of toxic reactive nitrogen species (RNS) (10). Ultimately, the functional role of NO ⅐ , as any molecule, will depend on both its concentration and association with other biomolecules and proteins (11). In this context, NO ⅐ is a highly reactive molecule, and exhaled NO ⅐ likely represents only a fraction of the total NO ⅐ in the lung. NO ⅐ reacts with oxygen or reactive oxygen species (ROS) to form oxidation products, such as NO 2 Ϫ , NO 3 Ϫ , and RNS (8,(10)(11)(12)(13). NO ⅐ or RNS may lead to nitration of tyrosine residues in proteins or nitrosylation of biologic constituents to form S-nitrosothiols (SNO); 100% of NO ⅐ reaction products are partitioned in the liquid phase of the lung (8,10,11,13). Notably, the temporal sequence of change in NO ⅐ and its downstream reaction products within airways during an asthmatic attack is unknown.Airway antigen (Ag) challenge has been used in atopic individuals as an experimental model to study mechanisms͞medi-ators that lead to asthmatic responses and airway inflammation (14-19). Exposure of asthmatic individuals to appropriate Ag results in both an immediate asthmatic response occurring within minutes and a similar but prolonged late response after many hours. The immediate response has been associated with release of bronchoconstrictor mediators and ROS, and the late response with thickening of the airway mucosa by edema and inflammatory cell influx (14-19). To investigate the functional role of NO ⅐ in the asthmatic response, we measured NO ⅐ generation and downstream product formation (nitrite, nitrate, SNO, and nitrotyrosine) before, immediately and 48 h after bronchoscopic Ag challenge of the peripheral airways in atopic asthmatic individuals and nonatopic healthy controls. The results reveal clear differences in NO ⅐ chemical reactions in the early and late responses to Ag challenge in asthmatic airways, which support distinct functions for NO ⅐ in asthmatic inflammatory events during the immediate and late phase of an asthma attack. MethodsStudy Population. All individuals were screened by h...

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“…The H 2 O 2 concentration and NO levels in exhaled air condensate are increased in stable asthmatics and they may contribute to airway edema and inflammation [39,40,41]. The inflammatory and immune cells in the airways (such as macrophages, neutrophils and eosinophils) release increased amounts of ROS in asthmatic patients [15, 42], and their ability to produce O 2 – correlates with the degree of bronchial responsiveness to inhaled methacholine [43].…”

Section: Discussionmentioning

confidence: 99%

Effects of Alpha Tocopherol and Probucol Supplements on Allergen-Induced Airway Inflammation and Hyperresponsiveness in a Mouse Model of Allergic Asthma

Okamoto

Murata

Tamai

et al. 2006

Int Arch Allergy Immunol

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Objective: We investigated the role of antioxidants in airway hyperresponsiveness to acetylcholine using young asthma model mice, which were sensitized and stimulated with ovalbumin. Methods: The mice had been fed either a normal diet, an α-tocopherol-supplemented diet or a probucol-supplemented diet 14 days before the first sensitization. They were immunized with antigen at intervals of 12 days and, starting from 10 days after the second immunization, they were exposed to antigen 3 times every 4th day using an ultrasonic nebulizer. Twenty-four hours after the last antigen inhalation, airway responsiveness to acetylcholine was measured and bronchoalveolar lavage fluid (BALF) was collected. A blood and lung tissue study was also carried out. Results: Twenty-four hours after the last antigen challenge, both IL-4 and IL-5 in the BALF of α-tocopherol-supplemented mice were significantly decreased. The IL-5 level in probucol-supplemented mice was also decreased, but there was no difference in IL-4 levels. The serum IgE level was decreased in probucol-supplemented mice. Differential cell rates of the fluid revealed a significant decrease in eosinophils due to antioxidant supplementation. Airway hyperresponsiveness to acetylcholine was also repressed in antioxidant-supplemented mice. In histological sections of lung tissue, inflammatory cells and mucus secretion were markedly reduced in antioxidant-supplemented mice. We investigated the antioxidant effect on our model mice by examining 8-isoprostane in BALF and lung tissue, and acrolein in BALF; however, our experiment gave us no evidence of the antioxidant properties of either α-tocopherol or probucol contributing to the reduction of airway inflammation. Conclusion: These findings indicate that α-tocopherol and probucol suppress allergic responses in asthma model mice, although these two drugs cause suppression in different ways that are unrelated to antioxidation.

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Airway Nitric Oxide Diffusion in Asthma

Cited by 221 publications

References 28 publications

Attenuation of induced bronchoconstriction in healthy subjects: effects of breathing depth

Attenuation of induced bronchoconstriction in healthy subjects: effects of breathing depth

NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response

Effects of Alpha Tocopherol and Probucol Supplements on Allergen-Induced Airway Inflammation and Hyperresponsiveness in a Mouse Model of Allergic Asthma

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