Effect of epithelial denudation, inflammatory mediators and mast cell activation on the sensitivity of isolated human airways to methacholine

Jongejan, R. C.; Jongste, Johan de; Raatgeep, R. C.; Stijnen, Theo; Bonta, I. L.; Kerrebijn, K. F.

doi:10.1016/0014-2999(91)90714-2

Cited by 9 publications

(5 citation statements)

References 23 publications

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“…This observation is relevant in view of the damage and loss of epithelium that is observed by bronchoscopy in asthmatics, and their enhanced sensitivity to cold [20, 21]. It is also consistent with the observation that epithelial denudation in human airways is associated to an increased sensitivity to methacholine [22]. The fact that LT enhances the contractile response of intact tracheas suggests that the inhibition of epithelium-dependent pathways could be involved in this response.…”

Section: Discussionsupporting

confidence: 71%

Effect of the Airway Epithelium on the Contraction of Rat Isolated Trachea under Conditions of Low Temperature

Gonzalez

Santacana²

2000

Respiration

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Background: The exposure of the airways to low temperature (LT) is a well-known trigger of bronchoconstriction and asthma. However, the mechanisms involved in this response are not well understood. In particular, the specific role of the airway epithelium in the response to LT has not been well established. Objective: The purpose of this work is to study the regulatory role of the airway epithelium in the contractile response of the rat trachea under conditions of LT. Methods: Isolated rat tracheas were stimulated with acetylcholine (ACH) at 37 and 18°C, and dose-response curves were generated in epithelium-intact or epithelium-denuded conditions. EC₅₀ and E_max were determined under these conditions. Results: Epithelium denudation at 37°C, increases the tracheal sensitivity to ACH, (EC₅₀ from 5.9 to 2.6 µM, p = 0.003). The effects of denudation were even more pronounced at 18°C. E_max was significantly decreased under these conditions. Exposure of intact tracheas to 18°C also produced a significant increase in tracheal sensitivity (EC₅₀ from 5.9 to 1.5 µM, p = 0.0004), although no changes in E_max were noted. Conclusions: These results strongly suggest that the airway epithelium diminishes the sensitivity of the airway smooth muscle to ACH at 37 and 18°C, and that it is also needed to observe the maximal contractile response under LT conditions. Therefore, the spasmogenic effect of low temperature is significantly potentiated by the absence of airway epithelium.

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Section: Discussionsupporting

confidence: 71%

Effect of the Airway Epithelium on the Contraction of Rat Isolated Trachea under Conditions of Low Temperature

Gonzalez

Santacana²

2000

Respiration

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“…It seems likely that epithelial damage is a major contributor to the altered responsiveness to inhaled MCh. The epithelium could serve as a barrier that could reduce access of MCh to the smooth muscle or might attenuate the responsiveness to MCh through the release of relaxant substances such as NO or prostaglandins [18-20]. The mechanism of AHR following Cl 2 may be similar to that of ozone in that both forms of injury are associated with oxidant damage to the tissues.…”

Section: Discussionmentioning

confidence: 99%

Dimethylthiourea protects against chlorine induced changes in airway function in a murine model of irritant induced asthma

et al. 2010

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BackgroundExposure to chlorine (Cl2) causes airway injury, characterized by oxidative damage, an influx of inflammatory cells and airway hyperresponsiveness. We hypothesized that Cl2-induced airway injury may be attenuated by antioxidant treatment, even after the initial injury.MethodsBalb/C mice were exposed to Cl2 gas (100 ppm) for 5 mins, an exposure that was established to alter airway function with minimal histological disruption of the epithelium. Twenty-four hours after exposure to Cl2, airway responsiveness to aerosolized methacholine (MCh) was measured. Bronchoalveolar lavage (BAL) was performed to determine inflammatory cell profiles, total protein, and glutathione levels. Dimethylthiourea (DMTU;100 mg/kg) was administered one hour before or one hour following Cl2 exposure.ResultsMice exposed to Cl2 had airway hyperresponsiveness to MCh compared to control animals pre-treated and post-treated with DMTU. Total cell counts in BAL fluid were elevated by Cl2 exposure and were not affected by DMTU treatment. However, DMTU-treated mice had lower protein levels in the BAL than the Cl2-only treated animals. 4-Hydroxynonenal analysis showed that DMTU given pre- or post-Cl2 prevented lipid peroxidation in the lung. Following Cl2 exposure glutathione (GSH) was elevated immediately following exposure both in BAL cells and in fluid and this change was prevented by DMTU. GSSG was depleted in Cl2 exposed mice at later time points. However, the GSH/GSSG ratio remained high in chlorine exposed mice, an effect attenuated by DMTU.ConclusionOur data show that the anti-oxidant DMTU is effective in attenuating Cl2 induced increase in airway responsiveness, inflammation and biomarkers of oxidative stress.

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“…1). The sensitivity (ϪlogEC10 value) was defined by the negative logarithm of the concentration of ACh that induced a contraction equal to 10% of the maximal effect induced by ACh (10 Ϫ3 M) (18). In functional studies, slope (and resulting location parameter EC50) should not be described because it is the result of different transducer functions (each of these having their own DRC).…”

Section: Methodsmentioning

confidence: 99%

Role of nitric oxide synthase/arginase balance in bronchial reactivity in patients with chronic obstructive pulmonary disease

Tadié¹,

Henno²,

Leroy³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Competition between nitric oxide synthases (NOSs) and arginases for their common substrate l-arginine could be involved in the regulation of cholinergic airway reactivity and subsequent airway remodeling. The aims of this study were to evaluate the relationships between the expression of this enzymatic balance and the effects of NOS and arginase inhibition on bronchoconstrictive response to acetylcholine of patients without and with early chronic obstructive pulmonary disease (COPD). Twenty-two human bronchi [15 COPD (9 GOLD-0, 6 GOLD-1, -2-A), 7 nonsmokers] were investigated for immunohistochemistry and modulation of acetylcholine-induced airway constriction. Significantly increased expression of NOS2 in immunoblots of bronchial tissue and staining in smooth muscle cells was evidenced in patients with COPD compared with control subjects, whereas no modification of arginase expression was evidenced. Forced expiratory volume in 1 s (FEV1) and NOS2 expression were negatively correlated (rho=-0.54, P=0.027). Pharmacological experiments demonstrated that resting tension was elevated in COPD compared with control subjects (2,243+/-154 vs. 1,574+/-218 mg, P=0.03) and was positively correlated with the expression of NOS2 (rho=0.61, P=0.044), whereas constrictor response to acetylcholine was similar [active tension, sensitivity (-logEC10), and reactivity (slope)]. The sole effect of the specific arginase inhibitor Nomega-hydroxy-nor-L-arginine (1 microM) was to decrease sensitivity in COPD patients, whereas 1 mM NG-nitro-L-arginine methyl ester unexpectedly decreased resting tension because of a non-cGMP-dependent effect. In conclusion, an upregulation of NOS2 expression in COPD patients is involved in airway tone regulation and functional airflow limitation, whereas increased arginase activity is involved in airway sensitivity.

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Effect of epithelial denudation, inflammatory mediators and mast cell activation on the sensitivity of isolated human airways to methacholine

Cited by 9 publications

References 23 publications

Effect of the Airway Epithelium on the Contraction of Rat Isolated Trachea under Conditions of Low Temperature

Effect of the Airway Epithelium on the Contraction of Rat Isolated Trachea under Conditions of Low Temperature

Dimethylthiourea protects against chlorine induced changes in airway function in a murine model of irritant induced asthma

Role of nitric oxide synthase/arginase balance in bronchial reactivity in patients with chronic obstructive pulmonary disease

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