Dual Action of iNOS-derived Nitric Oxide in Allergen-induced Airway Hyperreactivity in Conscious, Unrestrained Guinea Pigs

Schuiling, Martin; Meurs, Herman; Zuidhof, Annet B.; Venema, Nicolette; Zaagsma, Johan

doi:10.1164/ajrccm.158.5.9803027

Cited by 71 publications

(79 citation statements)

References 44 publications

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“…For example, it has been reported that pretreatment of mice with specific iNOS inhibitors decreases airway eosinophilia in response to allergen stimulation, either by blocking chemokine expression (71) or by delaying the efflux of eosinophils from the bone marrow (72). In contrast, other investigators have been unable to demonstrate a protective effect of iNOS inhibition on pulmonary leukocytosis (73)(74)(75), and iNOSdeficient mice paradoxically exhibit enhanced lung injury in response to OVA challenge (76). Our demonstration that bilirubin treatment does not alter chemokine levels and is associated with an increase (as opposed to a decrease) in the number of circulating eosinophils makes it unlikely that the effects of this bile pigment on airway inflammation are related to alterations in iNOS expression.…”

Section: Discussioncontrasting

confidence: 55%

Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration

Keshavan

Deem²,

Schwemberger

et al. 2005

The Journal of Immunology

145

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During lymphocyte migration, engagement of VCAM-1 stimulates the generation of endothelial cell-derived reactive oxygen species (ROS) and activation of matrix metalloproteinases, facilitating endothelial retraction. Because bilirubin is a potent antioxidant, we examined the hypothesis that this bile pigment inhibits VCAM-1-dependent cellular events. The migration of isolated murine splenic lymphocytes across monolayers of murine endothelial cell lines (which constitutively express VCAM-1) is significantly inhibited by physiological concentrations of bilirubin, in the absence of an effect on lymphocyte adhesion. Bilirubin administration also suppresses VCAM-1-stimulated ROS generation and reduces endothelial cell matrix metalloproteinase activity. In a murine asthma model characterized by VCAM-1-dependent airway inflammation, treatment of C57BL6/J mice with i.p. bilirubin decreases the total leukocyte count in the lung parenchyma and lavage fluid, through specific inhibition of eosinophil and lymphocyte infiltration. Blood eosinophil counts were increased in bilirubin-treated animals, while VCAM-1 expression in the capillary endothelium and cytokine levels in both lung lavage and supernatants from cultured lymph node lymphocytes were unchanged, suggesting that bilirubin inhibits leukocyte migration. Conclusion: bilirubin blocks VCAM-1-dependent lymphocyte migration in vitro and ameliorates VCAM-1-mediated airway inflammation in vivo, apparently through the suppression of cellular ROS production. These findings support a potential role for bilirubin as an endogenous immunomodulatory agent.

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Section: Discussioncontrasting

confidence: 55%

Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration

Keshavan

Deem²,

Schwemberger

et al. 2005

The Journal of Immunology

145

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“…Interestingly, iNOS-derived NO per se had no proinflammatory effects in the airways and even decreased airway responsiveness to methacholine [42]. Using in vivo studies in our guinea pig model of allergic asthma, we have previously demonstrated that iNOS-derived NO, aside from promoting airway inflammation and epithelial damage, also had some beneficial effect on allergen-induced AHR after the LAR, by partially attenuating the hyperresponsiveness due to its bronchodilating effect [10]. Remarkably, treatment with a selective iNOS inhibitor did not affect allergen-induced AHR in asthmatic patients, although levels of exhaled NO were markedly reduced [43].…”

Section: +mentioning

confidence: 88%

“…Using a guinea pig model of acute allergic asthma, we have previously demonstrated that both NO, derived from iNOS which is induced during the LAR [4,10], and superoxide are involved the development of AHR after the LAR, presumably by the formation of peroxynitrite [11]. Thus, incubation of perfused tracheal preparations with L-NAME, as well as superoxide dismutase, fully reverted the AHR after the LAR in these preparations [11].…”

Section: Cell and Animal Studies H Maarsingh Et Almentioning

confidence: 94%

“…In an in vivo guinea pig model for allergic asthma, we have previously demonstrated that iNOS may have both beneficial and detrimental effects on allergen-induced AHR to histamine after the LAR, by functional antagonism of the histamineinduced bronchoconstriction and promoting airway inflammation and epithelial damage, respectively [10]. Additionally, in perfused guinea pig airways ex vivo, the AHR after the LAR was reversed by the nonselective nitric oxide synthase (NOS) inhibitor N v -nitro-L-arginine methyl ester (L-NAME) as well as by the superoxide anion scavenger superoxide dismutase, indicating that peroxynitrite is strongly involved in the development of AHR after the LAR [11].…”

mentioning

confidence: 99%

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l-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

Maarsingh¹,

Bossenga²,

Bos³

et al. 2009

Eur Respir J

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ABSTRACT:Peroxynitrite has been shown to be crucially involved in airway hyperresponsiveness (AHR) after the late asthmatic reaction (LAR). Peroxynitrite production may result from simultaneous synthesis of nitric oxide (NO) and superoxide by inducible NOsynthase (iNOS) at low L-arginine concentrations. L-Arginine availability to iNOS is regulated by its cellular uptake, which can be inhibited by eosinophil-derived polycations and by arginase, which competes with iNOS for the common substrate.Using a guinea pig model of allergic asthma, we investigated whether aberrant L-arginine homeostasis could underlie peroxynitrite-mediated AHR after the LAR.After the LAR, arginase activity in the airways and eosinophil peroxidase release from bronchoalveolar lavage cells were increased. These changes were associated with a 2.0-fold AHR to methacholine as measured in isolated perfused tracheal preparations. AHR was reduced by exogenous L-arginine administration. Moreover, both the arginase inhibitor N v -hydroxy-nor-Larginine (nor-NOHA) and the polycation antagonist heparin normalised airway responsiveness. These effects were reversed by the nitric oxide synthase inhibitor N v -nitro-L-arginine methyl ester (L-NAME), indicating that both agents reduced AHR by restoring bronchodilating NO production.In conclusion, in allergen-challenged guinea pigs, the AHR after the LAR is caused by arginaseand polycation-induced attenuation of L-arginine availability to iNOS, which may switch the enzyme to simultaneous production of superoxide and NO, and, consequently, peroxynitrite.

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“…Indeed, both in vivo and ex vivo studies using the same species indicate that a deficiency of both epithelial and neuronal cNOS-derived NO underlies the development of AHR following the allergen-induced early asthmatic reaction ( fig. 1) [77,96,97]. A deficiency of cNOS activity and endogenous bronchodilating NO contributing to AHR was also demonstrated after repeated allergen challenge of sensitised guinea pigs [98,99].…”

Section: Acute Modulation Of Ahrmentioning

confidence: 91%

Airway hyperresponsiveness in asthma: lessons fromin vitromodel systems and animal models: Fig. 1—

Gosens¹,

Zaagsma²

2008

Eur Respir J

107

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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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Dual Action of iNOS-derived Nitric Oxide in Allergen-induced Airway Hyperreactivity in Conscious, Unrestrained Guinea Pigs

Cited by 71 publications

References 44 publications

Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration

Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration

l-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

Airway hyperresponsiveness in asthma: lessons fromin vitromodel systems and animal models: Fig. 1—

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