Differential Expression of iNOS and cNOS mRNA in Human Vascular Smooth Muscle Cells and Endothelial Cells under Normal and Inflammatory Conditions

MacNaul, Karen L.; Hutchinson, Nancy I.

doi:10.1006/bbrc.1993.2398

Cited by 225 publications

(117 citation statements)

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“…bNOS expression thus seems to be regulated in an entirely independent fashion, not comparable to that of eNOS and iNOS. Moreover, it does not seem to be affected by an increase in endogenous NO production, as expected because of the marked iNOS upregulation, which is in line with previous in vitro studies (Buga et al, 1993;MacNaul and Hutchinson, 1993;Schwartz et al, 1997).…”

Section: Ermert Et Alsupporting

confidence: 76%

“…This was a striking finding of the present investigation, with underlying mechanisms for this type of regulatory response to endotoxin being currently unknown. In previous studies in cultured cells, a down-regulation of eNOS, triggered by increased NO production via LPS-induced iNOS expression, has been reported (Buga et al, 1993;MacNaul and Hutchinson, 1993;Schwartz et al, 1997). To our knowledge, such negative feedback regulation of eNOS expression by enhanced iNOS-derived NO formation has so far not been demonstrated in whole lung tissue but may well be operative to explain the disparate regulations of iNOS and eNOS in the present study.…”

Section: Ermert Et Almentioning

confidence: 37%

“…Moreover, too little information exists about the regulation of the different NOS isoenzymes, and thus the background of endogenous NO formation in ARDS and septic lung failure is still unclear (Payen, 1998). Such regulation may apparently include iNOS and enhanced expression of iNOS in several cell types such as epithelial cells (Kobzik et al, 1993;Warner et al, 1995;Watkins et al, 1997), alveolar macrophages (Kobzik et al, 1993;Tracey et al, 1994), or endothelial cells (Kobzik et al, 1993;MacNaul and Hutchinson, 1993), which has been reported in several studies in response to mitogen stimulation. In addition, regulation of eNOS and bNOS may be affected, however, only minimal information about the regulation of these constitutive isoforms in response to LPS or cytokines currently exists.…”

mentioning

confidence: 99%

“…In addition, regulation of eNOS and bNOS may be affected, however, only minimal information about the regulation of these constitutive isoforms in response to LPS or cytokines currently exists. Some recent evidence suggests that the activity of the constitutive eNOS may be downregulated during inflammation (MacNaul and Hutchinson, 1993;Schwartz et al, 1997).…”

mentioning

confidence: 99%

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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: Ermert Et Alsupporting

confidence: 76%

Section: Ermert Et Almentioning

confidence: 37%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…First, although TNFα has been shown to enhance NOS-2-derived NO production induced by LPS or LPS plus IFNγ (Feinstein et al 1994;MacNaul and Hutchinson 1993;Pahan et al 1998), results from the present study are the first to demonstrate that TNFα mediates this enhancement, like TGFβ1, by expanding the pool of astrocytes that express NOS-2. Moreover, these results indicate that this mode of regulating gene expression (i.e., population-based) may be a more general mechanism by which certain cytokines increase NO production from astrocytes.…”

Section: Discussionmentioning

confidence: 77%

TGFβ1 and TNFα potentiate nitric oxide production in astrocyte cultures by recruiting distinct subpopulations of cells to express NOS-2

Hamby¹,

Gragnolati²,

Hewett³

et al. 2008

Neurochemistry International

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Nitric oxide (NO) synthase-2 (NOS-2), a key source of NO at sites of neuroinflammation, is induced in astrocyte cultures treated with lipopolysaccharide (LPS) plus interferon-γ (IFNγ). A recent study examining the regulation of astrocytic NOS-2 expression demonstrated that transforming growth factor-β1 (TGFβ1) potentiated LPS plus IFNγ-induced NOS-2 expression via expansion of the pool of astrocytes that express NOS-2. Results in the current report indicate that this population-based mechanism of increasing NOS-2 expression is not restricted to TGFβ1, since it also accounts for the potentiation of NO production in astrocyte cultures by tumor necrosis factor-α (TNFα). In contrast to TGFβ1, which required 24 hr preincubation for optimal potentiation of NO production, TNFα was maximally effective when added concurrently with LPS plus IFNγ. Nevertheless, under conditions that optimally potentiated NO production, both cytokines recruited similar numbers of astrocytes to express NOS-2 (% NOS-2-positive cells after LPS plus IFNγ alone or with TNFα or TGFβ1 was 9.5 ± 1.2, 25.3 ± 2.9, and 32.4 ± 3.0, respectively). Interestingly, stimulation of astrocytes in the presence of both TGFβ1 and TNFα additively increased the number of astrocytes that expressed NOS-2 protein (% NOS-2-positive cells was 61.0 ± 4.2) relative to each cytokine alone. Potentiation of NO production by either TNFα or TGFβ1 was not ablated by neutralizing antibodies to TGFβ1 or TNFα, respectively. Thus, the two cytokines act independently to recruit separate pools of astrocytes to express NOS-2. These results are consistent with the notion that astrocytes possess an innate heterogeneity with respect to responsiveness to these cytokines. KeywordsLPS; cytokines; heterogeneity; NO; iNOS; nitric oxide synthase Nitric oxide (NO) is an endogenously derived free radical gas that affects a spectrum of homeostatic and physiologic processes, including blood flow and coagulation, normal brain and heart function, and innate immunity (Belge et al. 2005;Ignarro et al. 1999;MacMicking et al. 1997;Yun et al. 1996). However, it can be harmful under certain pathophysiological conditions. Within the CNS, aberrant NO production has been linked to cerebrovascular dysfunction ( Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NO is derived from L-arginine by the catalytic action of three different NOS isoforms (Stuehr 1999). NOS-1 and -3 are constitutively expressed in neurons and endothelial cells, respectively, and thus were initially termed nNOS and eNOS. In contrast, NOS-2 is not constitutively expressed but can be induced ...

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Nitric Oxide and Septic Shock

Cobb¹

1996

JAMA

123

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Differential Expression of iNOS and cNOS mRNA in Human Vascular Smooth Muscle Cells and Endothelial Cells under Normal and Inflammatory Conditions

Cited by 225 publications

References 0 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

TGFβ1 and TNFα potentiate nitric oxide production in astrocyte cultures by recruiting distinct subpopulations of cells to express NOS-2

Nitric Oxide and Septic Shock

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