Inhibition of Nitric-Oxide Synthase Enhances Antigen-Induced Contractions and Increases Release of Cysteinyl-Leukotrienes in Guinea Pig Lung Parenchyma: Nitric Oxide as a Protective Factor

Larsson, Anna‐Karin; Bäck, Magnus; Hjoberg, Josephine; Dahlén, Sven-Erik

doi:10.1124/jpet.105.086694

Cited by 21 publications

(20 citation statements)

References 33 publications

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“…A direct relaxant effect by NO on airway smooth muscle has been excluded also by Larsson et al (2005) in lung parenchymal strips from sensitized guinea pigs, where the authors revealed an indirect protective effect of NO on antigen-induced contraction via inhibition of leukotrienes release from mast cells.…”

Section: Discussionmentioning

confidence: 96%

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: Discussionmentioning

confidence: 96%

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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“…Regarding the lower airways, orally exhaled NO is considered a biomarker of inflammation, particularly in allergic asthma [20]. Interestingly, two recent in vitro studies of the effect of NO donors and NO synthase inhibitors on antigen induced contractile responses and pro-inflammatory mediator release in peripheral lung tissue, support the belief that NO has a protective anti-inflammatory effect also in lung parenchyma [24,25]. In a review of in vivo and in vitro studies of NO and the regulation of mast cell activation, the conclusion was that the protective anti-inflammatory role of NO was predominant over pro-inflammatory effects, due to the inhibitory actions of NO on mast cell degranulation with decreased mediator release and expression of cytokines [26].…”

Section: Discussionmentioning

confidence: 99%

Clara cell protein in nasal lavage fluid and nasal nitric oxide - biomarkers with anti-inflammatory properties in allergic rhinitis

et al. 2012

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BackgroundClara cell protein (CC16) is ascribed a protective and anti-inflammatory role in airway inflammation. Lower levels have been observed in asthmatic subjects as well as in subjects with intermittent allergic rhinitis than in healthy controls. Nasal nitric oxide (nNO) is present in high concentrations in the upper airways, and considered a biomarker with beneficial effects, due to inhibition of bacteria and viruses along with stimulation of ciliary motility. The aim of this study was to evaluate the presumed anti-inflammatory effects of nasal CC16 and nNO in subjects with allergic rhinitis.MethodsThe levels of CC16 in nasal lavage fluids, achieved from subjects with persistent allergic rhinitis (n = 13), intermittent allergic rhinitis in an allergen free interval (n = 5) and healthy controls (n = 7), were analyzed by Western blot. The levels of nNO were measured by the subtraction method using NIOX®. The occurrences of effector cells in allergic inflammation, i.e. metachromatic cells (MC, mast cells and basophiles) and eosinophils (Eos) were analyzed by light microscopy in samples achieved by nasal brushing.ResultsThe levels of CC16 correlated with nNO levels (r2 = 0.37; p = 0.02) in allergic subjects.The levels of both biomarkers showed inverse relationships with MC occurrence, as higher levels of CC16 (p = 0.03) and nNO (p = 0.05) were found in allergic subjects with no demonstrable MC compared to the levels in subjects with demonstrable MC. Similar relationships, but not reaching significance, were observed between the CC16 and nNO levels and Eos occurrence. The levels of CC16 and nNO did not differ between the allergic and the control groups.ConclusionsThe correlation between nasal CC16 and nNO levels in patients with allergic rhinitis, along with an inverse relationship between their levels and the occurrences of MC in allergic inflammation, may indicate that both biomarkers have anti-inflammatory effects by suppression of cell recruitment. The mechanisms behind these observations warrant further analyses.

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“…In fact there may be a mechanistic explanation of the unchanged levels of urinary LTE 4 in the current study. Thus, it was recently observed in a model of the peripheral lung that NO specifically inhibits allergen-induced release of leukotrienes [29]. It might be that the increased levels of NO during early airway inflammation represent an important protective mechanism intended to limit the development of the inflammation.…”

Section: Discussionmentioning

confidence: 99%

Early rise in exhaled nitric oxide and mast cell activation in repeated low-dose allergen challenge

Ihre

Gyllfors²,

Gustafsson³

et al. 2006

European Respiratory Journal

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Repeated low-dose allergen inhalation challenge mimics natural allergen exposure, providing a model for early mechanisms in the triggering of asthma. The current authors performed a controlled study to evaluate the time course of changes in exhaled nitric oxide fraction (Fe,NO) and urinary biomarkers of airway inflammation.Eight subjects with mild allergic asthma completed two 7-day repeated low-dose challenge periods, with diluent and allergen, respectively. Subjects were symptom free at inclusion and were investigated when not exposed to specific allergen. Pulmonary function and symptoms were followed, and Fe,NO and urinary mediators were correlated to changes in airway responsiveness to histamine and adenosine.Despite no change in pulmonary function (forced expiratory volume in one second mean¡SEM fall 0.3¡0.7 versus 0.6¡1.0%, for diluent and allergen, respectively) and no asthma symptoms, repeated allergen exposure, in contrast to diluent, caused significant increases in histamine responsiveness (2.3 doubling doses), an early and gradual increase in Fe,NO (up to a doubling from baseline) and a small increase in the mast cell marker 9a11b-prostaglandin F 2 after adenosine challenge.In conclusion, serial measurements of exhaled nitric oxide fraction have the potential to provide a very sensitive strategy for early detection of emerging airway inflammation and subsequent changes in airway hyperresponsiveness to histamine.

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Inhibition of Nitric-Oxide Synthase Enhances Antigen-Induced Contractions and Increases Release of Cysteinyl-Leukotrienes in Guinea Pig Lung Parenchyma: Nitric Oxide as a Protective Factor

Cited by 21 publications

References 33 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

Clara cell protein in nasal lavage fluid and nasal nitric oxide - biomarkers with anti-inflammatory properties in allergic rhinitis

Early rise in exhaled nitric oxide and mast cell activation in repeated low-dose allergen challenge

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