Contribution of type I NOS to expired gas  NO and bronchial responsiveness in mice

Sanctis, George T. De; Mehta, Sanjay; Kobzik, Lester; Yandava, Chandri; Jiao, Aiping; Huang, Paul L.; Drazen, Jeffrey M.

doi:10.1152/ajplung.1997.273.4.l883

Cited by 50 publications

(60 citation statements)

References 26 publications

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“…In that earlier study (56), iNOS-deficient mice suffered a worsened colitis and a prolonged infection, indicating that epithelial-derived iNOS does play a role in protecting the host against colonic bacteria. The actions of nNOS have been studied in many systems, including in the airways in which its actions are crucial to the development of some asthma models (8). Less is known about the role of nNOS in experimental colitis.…”

Section: Discussionmentioning

confidence: 99%

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Vallance¹,

Dijkstra²,

Qiu³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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The role of nitric oxide (NO) in inflammatory bowel diseases has traditionally focused on the inducible form of NO synthase (iNOS). However, the constitutive endothelial (eNOS) and neuronal (nNOS) isoforms may also impact on colitis, either by contributing to the inflammation or by regulating mucosal integrity in response to noxious stimuli. To date, studies examining the roles of the NOS isoforms in experimental colitis have been conflicting, and the mechanisms by which these enzymes exert their effects remain unclear. To investigate and clarify the roles of the NOS isoforms in gut inflammation, we induced trinitrobenzenesulfonic acid colitis in eNOS, nNOS, and iNOS knockout (KO) mice, assessing the course of colitis at early and late times. Both eNOS and iNOS KO mice developed a more severe colitis compared with wild-type mice. During colitis, iNOS expression dramatically increased on epithelial and lamina propria mononuclear cells, whereas eNOS expression remained localized to endothelial cells. Electron and fluorescence microscopy identified bacteria in the ulcerated colonic mucosa of eNOS KO mice, but not in wild-type, iNOS, or nNOS KO mice. Furthermore, eNOS KO mice had fewer colonic goblet cells, impaired mucin production, and exhibited increased susceptibility to an inflammatory stimulus that was subthreshold to other mice. This susceptibility was reversible, because the NO donor isosorbide dinitrate normalized goblet cell numbers and ameliorated subsequent colitis in eNOS KO mice. These results identify a protective role for both iNOS and eNOS during colitis, with eNOS deficiency resulting in impaired intestinal defense against lumenal bacteria and increased susceptibility to colitis. mucus; bacteria; inflammatory bowel diseases; goblet cells SEVERAL FACTORS HAVE BEEN implicated in the pathogenesis of human inflammatory bowel diseases (IBD) including an immunological intolerance to enteric microflora (10 -12, 43), as well as defects in mucosal barrier function (47). Recently, attention has been focused on the overproduction of nitric oxide (NO) in IBD (7,31,46,58). Several studies have identified increased levels of NO in the rectal dialysates (46), in the inflamed mucosa of patients with ulcerative colitis (UC) (3), and in animal models of colitis (26,37,60). The increased NO synthase (NOS) activity was identified predominantly as the inducible form of NOS (iNOS) (23). Whereas the two constitutive isoforms, neuronal (nNOS) and endothelial-derived (eNOS), modulate several aspects of intestinal physiology (6, 53), their contribution to the inflammatory response has received less attention.Despite considerable evidence that iNOS-derived NO contributes to tissue destruction in colitis and other inflammatory states (27), conflicting results have been obtained by using pharmacological inhibitors of NOS in animal models of IBD. Several studies have found that the nonspecific NOS inhibitor N G -nitro-L-arginine methyl ester reduced intestinal inflammation (17, 37, 45); other studies found little benefit (20) o...

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Section: Discussionmentioning

confidence: 99%

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Vallance¹,

Dijkstra²,

Qiu³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The present data indicate that iNOS accounts for y60% of the NO measured in exhaled air stemming from the lower respiratory tract. The remaining portion appears to be synthesised by nNOS, which has been shown to make up y40% of the NO measured in the lower respiratory tract [19].…”

Section: Discussionmentioning

confidence: 99%

Increased eNO and pulmonary iNOS expression in eNOS null mice

Cook¹,

Vollenweider²,

Ménard³

et al. 2003

Eur Respir J

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Increased eNO and pulmonary iNOS expression in eNOS null mice. S. Cook, P. Vollenweider, B. Ménard, M. Egli, P. Nicod, U. Scherrer. #ERS Journals Ltd 2003. ABSTRACT: Nitric oxide (NO) is a major regulatory molecule of the cardiovascular system; however, measurement of vascular NO synthesis in vivo represents a major challenge. NO stemming from the lower respiratory tract has been used as a marker of vascular endothelial function. Experimental evidence for this concept is lacking. Therefore, the aim of the present study was to investigate this relationship.Lower respiratory tract exhaled NO concentration, together with systemic and pulmonary artery pressure, was measured in endothelial nitric oxide synthase (NOS) (eNOS) null mice (eNOS-/-). Similar studies were performed in inducible NOS (iNOS) null mice (iNOS-/-).Defective endothelial NO synthesis in eNOS-/-mice (evidenced by systemic and pulmonary hypertension) was associated with augmented exhaled NO levels (12.5¡1.9 versus 9.8¡1.2 parts per billion (ppb), eNOS-/-versus wild type), whereas normal endothelial NO synthesis in iNOS-/-mice was associated with decreased exhaled NO levels (4.3 ¡ 1.5 ppb). Augmented exhaled NO levels in eNOS-/-mice were associated with upregulation of iNOS expression in the lung.These results indicate that inducible nitric oxide synthase is a major determinant of gaseous nitric oxide production in the lung, and lower respiratory tract exhaled nitric oxide does not always represent a marker of vascular endothelial nitric oxide synthesis. Since the late 1980s, nitric oxide (NO) has emerged as a major regulator of the cardiovascular system [1]. Measurement of vascular endothelial nitric oxide synthase (NOS) (eNOS) activity and its final product NO in vivo still represents a major challenge, because the small amount of NO produced by the endothelium is rapidly scavenged by haemoglobin and then inactivated. To date, the contribution of NO to the regulation of vascular tone has been assessed by indirect methods, examining specific modifications of physiological responses induced by NOS inhibitors and NO donors, and/or measuring levels of NO metabolites or cyclic guanosine monophosphate [2].NO is present in the exhaled air of many animal species and humans [3], but its origin and physiological function are incompletely understood. In the respiratory tract, all three NOS isoforms are expressed in tissues close to the airways. Although there is consensus that under normal conditions, a large proportion of the exhaled NO is synthesised by inducible NOS (iNOS) located in the epithelial cells of the upper respiratory tract [4,5], the origin and function of lower respiratory tract exhaled NO is incompletely understood. It has been claimed that exhaled NO stemming from the lower respiratory tract represents a marker of vascular endothelial NO synthesis [6][7][8][9][10][11][12]. Experimental evidence for this concept is lacking, however, and studies in humans, using pharmacological NOS inhibitors, suggest that eNOS barely albeit significantly, cont...

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“…In a recent study airway hyperresponsiveness to methacholine was completely abolished in eNOS-overexpressing, ovalbumin-challenged mice compared with control mice in conjunction with a decrease in the number of lymphocytes and eosinophils in the bronchoalveolar lavage fluid (416). In contrast to eNOS it has also been postulated that in mice nNOS could have a role in promoting airway hyperresponsiveness (74,75). Different groups of investigators have shown that acute bronchoconstriction induced by allergen inhalation is potentiated by NOS inhibitors in sensitized guinea pigs in vivo, suggesting a modulation by endogenous protective NO on early asthmatic reaction in animal model (286,342,343).…”

Section: In Vivo Studiesmentioning

confidence: 99%

“…Exhaled NO production by the airways and lung parenchyma, in turn, appears to be determined by 1) the activity of all three NO synthase (NOS) isoforms, but particularly isoforms I and II (75,443); 2) the activity of arginase 2 and metabolic enzymes that regulate the endogenous NOS inhibitor asymmetric dimethyl arginine (313); 3) prokaryotic, denitrifying species colonizing the upper and lower airways (131); 4) SNO catabolic enzymes (88, 133, 403); and 5) processes/enzymes that regulate airway pH and nitrite reduction, such as glutaminase (184).…”

Section: Exhaled Nitric Oxidementioning

confidence: 99%

Nitric Oxide in Health and Disease of the Respiratory System

Ricciardolo¹,

Sterk²,

Gaston³

et al. 2004

Physiological Reviews

773

649

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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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Contribution of type I NOS to expired gas NO and bronchial responsiveness in mice

Cited by 50 publications

References 26 publications

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Increased eNO and pulmonary iNOS expression in eNOS null mice

Nitric Oxide in Health and Disease of the Respiratory System

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