Decreased Pulmonary and Tracheal Smooth Muscle  Expression and Activity of Type 1 Nitric Oxide Synthase  (nNOS) after Ovalbumin Immunization and Multiple  Aerosol Challenge in Guinea Pigs

A, Samb; Pretolani, Marina; Dinh-Xuan, Anh Tuan; Ouksel, H.; Crinon, Jacques; Lisdero, Constanza; Aubier, Michel; Boczkowski, Jorge

doi:10.1164/ajrccm.164.1.2004030

Cited by 44 publications

(33 citation statements)

References 28 publications

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“…Tracheal preparations from antigen-challenged guinea pigs did not display substantially different response patterns with respect to animals subjected only to OVA sensitization, indicating that, in our experimental model, sensitization alone is able to determine alterations in tracheal responsiveness to COX and NOS inhibitors that persist in the asthma model of antigen-challenged guinea pig. The absence of an NO-mediated influence on the control of smooth muscle responsiveness in asthmatic airways has been already reported in guinea pigs as a result of arginase activity up-regulation (Meurs et al, 2002) or neuronal nitric-oxide synthase protein down-regulation (Samb et al, 2001). Therefore, our data extend the available evidence indicating a lack of influence by NO on the control of airway smooth muscle responsiveness in multiple antigen-challenged animals in the presence of COX isoform inhibition.…”

Section: Discussionsupporting

confidence: 86%

“…Animals were sacrificed for tracheal removal 6 h after the last challenge. The multiple antigen-challenged guinea pig is a model that reproduces several of the characteristic features of asthma, including bronchial hyper-reactivity and inflammation (Samb et al, 2001). The presence of airway hyper-reactivity to histamine was confirmed 6 h after last antigen challenge by preliminary experiments in anesthetized guinea pigs, recording pulmonary inflation pressure as an index of airway resistance (data not shown).…”

Section: Methodsmentioning

confidence: 83%

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Role of Cyclooxygenase Isoforms and Nitric-Oxide Synthase in the Modulation of Tracheal Motor Responsiveness in Normal and Antigen-Sensitized Guinea Pigs

Nieri¹,

Martinelli²,

Blandizzi³

et al. 2006

J Pharmacol Exp Ther

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The effects of selective cyclooxygenase (COX) isoform (COX-1, COX-2) inhibition, alone or in combination with nitric-oxide synthase (NOS) blockade, on in vitro tracheal muscle responsiveness to histamine were investigated in healthy and ovalbumin (OVA)-sensitized guinea pigs. Immunohistochemistry showed that COX-1 and COX-2 are constitutively present in normal guinea pig trachea, particularly in the epithelial layer, and that COX-2 expression is enhanced in OVA-sensitized animals both in epithelial and subepithelial tissues. In normal guinea pigs, SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] (COX-1 inhibitor) or DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone] (COX-2 inhibitor) significantly increased the contractile response to histamine, these effects being not additive. NOS inhibition by L-N G -nitro-arginine methyl ester (L-NAME) did not affect histamine-induced contraction but reversed the increase caused by COX-1 blockade while not modifying the enhancement associated with COX-2 inhibition. In guinea pigs subjected to OVA sensitization and challenge, COX-2, but not COX-1, inhibition enhanced the motor responses to histamine without any influence by L-NAME. In normal, but not in sensitized animals, the removal of epithelial layer from tracheal preparations abolished the enhancing action of DFU on histaminemediated contraction. A COX-2-dependent release of prostacyclin (PGI 2 ), but not prostaglandin E 2 , was observed in tracheal tissues from normal and OVA-sensitized guinea pigs. In conclusion, both COX-1 and COX-2 are constitutive in guinea pig trachea, and COX-2 expression is enhanced by OVA sensitization; in normal animals, epithelial COX-2 exerts a PGI 2 -dependent inhibitory control on tracheal contractility, and this isoform is subjected to upstream regulation by epithelial COX-1 and NOS through a complex interplay; and following antigen sensitization, the inhibitory control on tracheal contractility is maintained by COX-2 induced at subepithelial cell sites.Both nitric oxide (NO) and prostaglandins (PGs) are relevant mediators in airway physiology and pathology, and their production is regulated by different enzyme isoforms. NO is formed from L-arginine by NO synthase (NOS), of which three isoforms have been identified: neuronal NOS, inducible NOS, and endothelial NOS (Ogden and Moore, 1995). PG synthesis depends on cyclooxygenase (COX), two main isozymes of which are currently recognized: COX-1, constitutively expressed in different tissues, and COX-2, regarded as an inducible isoform, since an increase in its expression has been associated with inflammatory processes (Simmons et al., 2004).It is generally believed that the production of NO and PGs by constitutive enzyme isoforms is important for physiological functions, whereas their formation via inducible isoforms is involved mainly in inflammatory and other pathological responses (Di Rosa et al., 1996). Increasing evidence suggests a link between NOS and COX pathways (Di Rosa ...

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Section: Discussionsupporting

confidence: 86%

Section: Methodsmentioning

confidence: 83%

Role of Cyclooxygenase Isoforms and Nitric-Oxide Synthase in the Modulation of Tracheal Motor Responsiveness in Normal and Antigen-Sensitized Guinea Pigs

Nieri¹,

Martinelli²,

Blandizzi³

et al. 2006

J Pharmacol Exp Ther

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“…More recently, it has been noted that expression of NOS I is reduced at 6 h, but not at 24 h, after allergen challenge in association with a decrease in constitutive NOS activity and in the amounts of exhaled NO. Together with maximal airway hyperresponsiveness to histamine, this suggests that the transient downregulated NOS I may have a role in airway hyperresponsiveness (387). In agreement with the previous studies, Toward and Broadley (423) found that exposure to inhaled LPS initially inhibited NO synthesis and the reduced NO levels coincided with the period of increased airway reactivity to histamine (1 h after exposure) in guinea pig.…”

Section: In Vivo Studiessupporting

confidence: 86%

Nitric Oxide in Health and Disease of the Respiratory System

Ricciardolo¹,

Sterk²,

Gaston³

et al. 2004

Physiological Reviews

770

642

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During the past decade a plethora of studies have unravelled the multiple roles of nitric oxide (NO) in airway physiology and pathophysiology. In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone. On the other hand, NO derived from iNOS seems to be a proinflammatory mediator with immunomodulatory effects. The concentration of this molecule in exhaled air is abnormal in activated states of different inflammatory airway diseases, and its monitoring is potentially a major advance in the management of, e.g., asthma. Finally, the production of NO under oxidative stress conditions secondarily generates strong oxidizing agents (reactive nitrogen species) that may modulate the development of chronic inflammatory airway diseases and/or amplify the inflammatory response. The fundamental mechanisms driving the altered NO bioactivity under pathological conditions still need to be fully clarified, because their regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways.

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“…Reduced expression of eNOS or nNOS has been observed after repeated allergen challenge in guinea pigs and mild asthmatic patients, respectively [101,106]. In addition, it has been demonstrated that reduced bioavailability of Larginine, the substrate for NOS, may underlie the deficiency in NO and subsequent AHR [96,107].…”

Section: Acute Modulation Of Ahrmentioning

confidence: 99%

Airway hyperresponsiveness in asthma: lessons from in vitro model systems and animal models

Gosens¹,

Zaagsma²

2008

European Respiratory Journal

105

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Airway hyperresponsiveness (AHR) is a hallmark clinical symptom of asthma. At least two components of AHR have been identified: 1) baseline AHR, which is persistent and presumably caused by airway remodelling due to chronic recurrent airway inflammation; and 2) acute and variable AHR, which is associated with an episodic increase in airway inflammation due to environmental factors such as allergen exposure.Despite intensive research, the mechanisms underlying acute and chronic AHR are poorly understood. Owing to the complex variety of interactive processes that may be involved, in vitro model systems and animal models are indispensable to the unravelling of these mechanisms at the cellular and molecular level.The present paper focuses on a number of translational studies addressing the emerging central role of the airway smooth muscle cell, as a multicompetent cell involved in acute airway constriction as well as structural changes in the airways, in the pathophysiology of airway hyperresponsiveness.

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Decreased Pulmonary and Tracheal Smooth Muscle Expression and Activity of Type 1 Nitric Oxide Synthase (nNOS) after Ovalbumin Immunization and Multiple Aerosol Challenge in Guinea Pigs

Cited by 44 publications

References 28 publications

Role of Cyclooxygenase Isoforms and Nitric-Oxide Synthase in the Modulation of Tracheal Motor Responsiveness in Normal and Antigen-Sensitized Guinea Pigs

Role of Cyclooxygenase Isoforms and Nitric-Oxide Synthase in the Modulation of Tracheal Motor Responsiveness in Normal and Antigen-Sensitized Guinea Pigs

Nitric Oxide in Health and Disease of the Respiratory System

Airway hyperresponsiveness in asthma: lessons from in vitro model systems and animal models

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