Expression of nitric oxide synthase isoforms (NOS II and NOS III) in adult rat lung in hyperoxic pulmonary hypertension

Steudel, Wolfgang; Watanabe, Masahiro; Dikranian, Krikor; Jacobson, Margaretha; Jones, Rosemary

doi:10.1007/s004410051238

Cited by 33 publications

(30 citation statements)

References 55 publications

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“…In accordance with previous observations (Asano et al, 1994;Steudel et al, 1999;Tracey et al, 1994;Watkins et al, 1997), iNOS expression was noted in bronchial epithelial cells of large and small airways. Such prominent constitutive iNOS expression in the bronchial epithelium may reflect the fact that this epithelium represents a barrier with a large external surface, being naturally exposed to airborne noxious and microbial agents even in the absence of lung infection.…”

Section: Discussionsupporting

confidence: 93%

“…Such prominent constitutive iNOS expression in the bronchial epithelium may reflect the fact that this epithelium represents a barrier with a large external surface, being naturally exposed to airborne noxious and microbial agents even in the absence of lung infection. In addition, iNOS was expressed in bronchial smooth muscle cells, myocytes of pulmonary hilar veins (this study ;Steudel et al, 1999), alveolar macrophages, cells within the BALT, and VSMC of partially and fully muscular vessels (this study). Microdensitometry of immunohistochemical staining intensity showed the most intensive iNOS expression in control lungs to be present in bronchial epithelial cells of large bronchi and in myocytes of large hilar veins.…”

Section: Discussionmentioning

confidence: 68%

“…This was anticipated for the constitutive isoforms bNOS and eNOS (Asano et al, 1994;Kobzik et al, 1993;Shaul et al, 1994;Steudel et al, 1999), although an entire profile of cellular localization of both isoforms in lung tissue has so far not been shown. A recent study reported eNOS expression in epithelial cells, endothelial cells, and VSMC in normal rat lung tissue, which corresponds well with the data presented in this study.…”

Section: Discussionmentioning

confidence: 94%

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Cell-Specific Nitric Oxide Synthase-Isoenzyme Expression and Regulation in Response to Endotoxin in Intact Rat Lungs

Ermert

Ruppert

Günther

et al. 2002

Laboratory Investigation

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SUMMARY:Nitric oxide (NO) produced by NO synthase (NOS) serves as a ubiquitous mediator molecule involved in many physiologic lung functions, including regulation of vascular and bronchial tone, immunocompetence, and neuronal signaling. On the other hand, excessive and inappropriate NO synthesis in inflammation and sepsis has been implicated in vascular abnormalities and cell injury. At least three different NOS isoforms (neuronal/brain [bNOS], inducible [iNOS], and endothelial [eNOS]) have been described, which are all expressed in normal lung tissue. We investigated the cell-specific expression of bNOS, iNOS, and eNOS in perfused control rat lungs and lungs undergoing stimulation with endotoxin in the presence and absence of plasma constituents. Lung immunohistochemistry and quantitative evaluation of staining intensity showed endotoxininduced increase in iNOS expression in particular in bronchial epithelial cells, cells of the bronchus-associated lymphoid tissue (BALT), alveolar macrophages, and vascular smooth muscle cells in a time-and dose-dependent fashion. In endothelial cells, which did not express iNOS at baseline, newly induced iNOS was found in response to endotoxin. In contrast, expression of eNOS was markedly suppressed under endotoxin challenge, particularly in bronchial epithelium, BALT, and alveolar macrophages but also in vascular smooth muscle cells and endothelial cells. eNOS expression in bronchial smooth muscle cells was not altered. In contrast to iNOS and eNOS, cellular expression of bNOS in epithelial cells, nerve fibers, BALT, and endothelial cells did not change in response to endotoxin. All changes in NOS regulation were found to be independent of plasma constituents. We conclude that endotoxin exerts a profound impact on the cell-specific NOS regulation in a large number of lung cell types. Prominent features include de novo synthesis or up-regulation of iNOS, in contrast to down-regulation of eNOS, which may well contribute to vascular abnormalities, inflammatory sequelae, and loss of physiologic functions in septic lung failure. (Lab Invest 2002, 82:425-441).

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 94%

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Cell-Specific Nitric Oxide Synthase-Isoenzyme Expression and Regulation in Response to Endotoxin in Intact Rat Lungs

Ermert

Ruppert

Günther

et al. 2002

Laboratory Investigation

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“…Recent reports have shown that hyperoxic conditions can result in up-regulation of NOS (37)(38)(39)(40). This notion raises the possibility that hyperoxia provided protection from L-NAMEinduced teratogenesis by modulating NO synthesis, although evidence for oxygen-mediated NOS up-regulation in embryonic or fetal tissues is (to our knowledge) lacking.…”

Section: Tiboni Et Almentioning

confidence: 99%

The Nitric Oxide Synthesis Inhibitor Nω-Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia

2003

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In the present study the relationship between exposure to the nitric oxide synthesis inhibitor N -nitro-L-arginine methyl ester (L-NAME) and the induction of limb defects, with respect to stage specificity and dose dependency, was investigated in the mouse. ICR (CD-1) mice were dosed s.c with L-NAME at 50 or 90 mg/kg on gestation d 12, 13, 14, 15, or 16. A group of animals treated with vehicle on gestation d 14 served as control. Uterine contents were evaluated for teratogenesis on gestation d 18. A treatment-related disruption of limb development was noted. The effect was dose dependent and phase specific. L-NAME became teratogenically operational on gestation d 13 and elicited its maximum effect on gestation d 14, whereas no significant teratogenicity was observed when exposure occurred after gestation d 15. In utero exposure to L-NAME also reduced embryo viability relative to controls. When the higher dose was injected on gestation d 16, a significant number of dams delivered preterm. In a parallel study, the ability of hyperoxia to prevent limb teratogenesis was investigated. To this aim, a group of L-NAMEtreated animals (90 mg/kg s.c. on gestation d 14) were exposed to 98 to 100% O 2 for 12 h. L-NAME-treated mice breathing room air served as positive controls. In response to hyperoxia, a significant decrement of L-NAME-induced limb defects was found. This study characterizes for the first time the teratogenic capacity of L-NAME in the mouse. Results obtained with hyperoxia fit the hypothesis that hypoxic tissue damage may play a contributory role in L-NAME-induced limb defects. NO is a colorless gaseous molecule involved in the regulation of diverse important physiologic processes, including vascular tone, platelet reactivity, smooth muscle contractility, neurotransmission, and the cytotoxic action of immune cells (1). NO is generated endogenously during the conversion of L-arginine to citrulline by a family of enzymes known as NOS. At least three isoforms of NOS have been isolated, including the constitutive eNOS and neuronal NOS isoforms, and the inducible isoform, iNOS (1). Pharmacologic manipulation of NOS activity can be achieved by several classes of NOS inhibitors including L-arginine analogs, which act by denying NOS its substrate in a competitive manner (2).The L-arginine analog L-NAME, a nonselective inhibitor of NOS, has been shown to be teratogenic when administered to rats (3-8). Limb reduction defects with associated characteristic areas of macroscopic hemorrhage were the most common phenotypic alterations noted (3-8). L-NAME is not the only L-arginine analog known to cause dysmelia, as N -nitro-Larginine also induced limb defects (9). Notably, disruptions similar to those induced by L-arginine analogs have been noted in knockout mice lacking eNOS (10, 11). The current state of knowledge on L-NAME teratogenicity also includes the following facts: 1) the period of fetal vulnerability has an onset relatively late in gestation (3-5); 2) both oral (3-6) and parenteral (5) treatments are effective;...

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“…Although iNOS (113) and reactive nitrogen oxide intermediates (114) are elevated in hyperoxia and may participate in hyperoxiainduced lung injury, it is apparent that under appropriate conditions NO (including iNOS-derived NO) may limit hyperoxic lung injury (115). In this regard: (1 ) inhalation of NO has been shown to reduce hyperoxia-induced apoptosis in lungs of intact animals (116), (2 ) pharmacologic inhibition of NO synthesis exacerbates hyperoxic injury (117), and (3 ) iNOS null mutant mice have enhanced inflammation (accumulation of neutrophils) early in the course of hyperoxia (118).…”

Section: No and Acute Lung Injurymentioning

confidence: 99%

Nitric Oxide and Zinc Homeostasis in Acute Lung Injury

Croix

Leelavaninchkul²,

Watkins³

et al. 2005

Proceedings of the American Thoracic Society

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Among putative small molecules that affect sensitivity to acute lung injury, zinc and nitric oxide are potentially unique by virtue of their interdependence and dual capacities to be cytoprotective or injurious. Nitric oxide and zinc appear to be linked via an intracellular signaling pathway involving S-nitrosation of metallothoineinitself a small protein known to be an important inducible gene product that may modify lung injury. In the present article, we summarize recent efforts using genetic and fluorescence optical imaging techniques to: (1 ) demonstrate that S-nitrosation of metallothionein affects intracellular zinc homeostasis in intact pulmonary endothelial cells; and (2 ) reveal a protective role for this pathway in hyperoxic and LPS-induced injury.

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Expression of nitric oxide synthase isoforms (NOS II and NOS III) in adult rat lung in hyperoxic pulmonary hypertension

Cited by 33 publications

References 55 publications

Cell-Specific Nitric Oxide Synthase-Isoenzyme Expression and Regulation in Response to Endotoxin in Intact Rat Lungs

Cell-Specific Nitric Oxide Synthase-Isoenzyme Expression and Regulation in Response to Endotoxin in Intact Rat Lungs

The Nitric Oxide Synthesis Inhibitor Nω-Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia

Nitric Oxide and Zinc Homeostasis in Acute Lung Injury

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