RSV Causes HIF-1α Stabilization via NO Release in Primary Bronchial Epithelial Cells

Kilani, Muna; Mohammed, Kamal A.; Nasreen, Najmunnisa; Tepper, Robert S.; Antony, Veena B.

doi:10.1007/s10753-004-6047-y

Cited by 45 publications

(36 citation statements)

References 34 publications

(46 reference statements)

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“…Although recent studies suggest the involvement of HIF-1 in airway epithelial responses to viral infection (38) and in inflammatory signaling or subepithelial remodeling during allergic airway inflammation (32), chronic obstructive pulmonary disease (33), or idiopathic pulmonary fibrosis (68), the importance of HIF-1␣ activation and the involvement of NO in these conditions is not clear at present. Analogous to previous studies showing biphasic regulation of cell migration by TNF-␣, with initial activation of filopodia and increased cell migration followed by inhibition of cell migration and up-regulation of p53 at later stages (54), our results may suggest that the induction of NO production during inflammation may similarly be involved in such biphasic regulation of epithelial cell migration to assure coordinated wound repair.…”

Section: Discussionmentioning

confidence: 99%

“…HIF-1 not only mediates adaptive responses to hypoxia but is also recognized to play important roles in inflammatory processes (31), and recent studies have demonstrated HIF-1␣ activation during chronic airway inflammation (32,33), conditions typically associated with increased NOS2 expression. Although it is well appreciated that HIF-1 can be activated under normoxic conditions by inflammatory cytokines (34 -36) or bacterial or viral stimuli (37,38), which was in some cases attributed to intermediate NO production (38), the significance of HIF-1 in mediating airway inflammation and/or injury is only beginning to be appreciated.…”

mentioning

confidence: 99%

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Inflammatory Levels of Nitric Oxide Inhibit Airway Epithelial Cell Migration by Inhibition of the Kinase ERK1/2 and Activation of Hypoxia-inducible Factor-1α

Bove

Hristova

Wesley

et al. 2008

Journal of Biological Chemistry

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Increased synthesis of NO during airway inflammation, caused by induction of nitric-oxide synthase 2 in several lung cell types, may contribute to epithelial injury and permeability. To investigate the consequence of elevated NO production on epithelial function, we exposed cultured monolayers of human bronchial epithelial cells to the NO donor diethylenetriaamine NONOate. At concentrations generating high nanomolar levels of NO, representative of inflammatory conditions, diethylenetriaamine NONOate markedly reduced wound closure in an in vitro scratch injury model, primarily by inhibiting epithelial cell migration. Analysis of signaling pathways and gene expression profiles indicated a rapid induction of the mitogen-activated protein kinase phosphatase (MPK)-1 and decrease in extracellular signal-regulated kinase (ERK)1/2 activation, as well as marked stabilization of hypoxia-inducible factor (HIF)-1␣ and activation of hypoxia-responsive genes, under these conditions. Inhibition of ERK1/2 signaling using U0126 enhanced HIF-1␣ stabilization, implicating ERK1/2 dephosphorylation as a contributing mechanism in NO-mediated HIF-1␣ activation. Activation of HIF-1␣ by the hypoxia mimic cobalt chloride, or cell transfection with a degradation-resistant HIF-1␣ mutant construct inhibited epithelial wound repair, implicating HIF-1␣ in NO-mediated inhibition of cell migration. Conversely, NO-mediated inhibition of epithelial wound closure was largely prevented after small interfering RNA suppression of HIF-1␣. Finally, NO-mediated inhibition of cell migration was associated with HIF-1␣-dependent induction of PAI-1 and activation of p53, both negative regulators of epithelial cell migration. Collectively, our results demonstrate that inflammatory levels of NO inhibit epithelial cell migration, because of suppression of ERK1/2 signaling, and activation of HIF-1␣ and p53, with potential consequences for epithelial repair and remodeling during airway inflammation.Inflammatory diseases of the respiratory tract are commonly associated with increased production of NO, because of induction and activation of the inducible isoform of nitric-oxide synthase (NOS2), 2 within inflammatory immune cells as well as within the respiratory epithelium (1, 2). Indeed, elevated concentrations of exhaled NO and increased epithelial expression of NOS2 are characteristic features of chronic inflammatory airway diseases such as asthma (1, 2). The biological roles of NOS2 within the airway epithelium include contribution to innate host defense (3, 4), regulation of epithelial ion transport (5), and maintenance of epithelial barrier integrity (1, 6, 7). In addition, our recent studies showed that physiological concentrations of NO can promote airway epithelial cell migration and repair in response to in vitro injury, which was associated with increased expression and activation of gelatinase B (matrix metalloproteinase-9; MMP-9) (8). In contrast to these salutary properties of constitutive airway NO production, increased epithelial NOS2 expression ha...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inflammatory Levels of Nitric Oxide Inhibit Airway Epithelial Cell Migration by Inhibition of the Kinase ERK1/2 and Activation of Hypoxia-inducible Factor-1α

Bove

Hristova

Wesley

et al. 2008

Journal of Biological Chemistry

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“…Viral infection is generally appreciated to induce stabilization of HIF-1α in target cells, which consequently contributes to local inflammation. For example, the common upper respiratory tract pathogen respiratory syncytial virus (RSV) induces HIF-1α in primary human bronchial epithelial cells via a NO-dependent pathway [29]. Increased HIF-1α levels stimulates VEGF production, enhancing monolayer permeability, which may play a role in the airway edema of acute RSV infection.…”

Section: Hif-1α Dynamics In Viral Infectionmentioning

confidence: 99%

Hypoxia inducible factor (HIF) function in innate immunity and infection

2007

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The hypoxia-inducible transcription factor (HIF-1α) is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. Recently, HIF-1α has been discovered to function as a global regulator of macrophage and neutrophil inflammatory and innate immune functions, as befits these specialized phagocytic cells who must operate effectively in the hypoxic microenvironments of infected tissues. This review summarizes current knowledge of the role of HIF-1α in mammalian innate immunity, emphasizing insight gained from conditional gene targeting of the transcription factor in the myeloid cell lineage. Dynamic changes in HIF-1α expression in the course of bacterial, viral, or parasitic infections are outlined and inferences drawn regarding the consequences for pathogen and host. A better understanding of HIF-1α function may provide novel and rational approaches for boosting innate immune function in the therapy of certain complicated infectious disease conditions.

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“…VSV can induce HIF-1α stabilisation in bronchial cells, potentially contributing to the clinical airway oedema of acute VSV infection (Kilani et al, 2004). Other viruses also induce HIF-1α stabilisation (see 1.2.3.3.2).…”

Section: Discussionmentioning

confidence: 99%

“…The nuclear antigens of Epstein-Barr virus bind to PHD, inhibiting HIF-1α degredation (Darekar et al, 2012). The respiratory tract pathogen respiratory syncytial virus (RSV) induces HIF-1α in human bronchial cells via a NO-dependent pathway, and the resultant increased VEGF also enhances monolayer permeability, a pathway which may contribute to airway oedema of acute RSV infection (Kilani et al, 2004). Hypoxia-independent stabilization of HIF-1α in vitro and in vivo has also been observed in another study of RSV (Haeberle et al, 2008), further supporting HIF-1α stabilisation occurring as a result of a viral infection.…”

Section: Hif-1α and The Immune Response To Viral Pathogensmentioning

confidence: 99%

Methodology for the measurement of HIF-1α in bovine leukocytes and assessment of the molecule as a biomarker for bovine respiratory disease outcome

Gestier¹

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Bovine respiratory disease (BRD) is a multi-factorial inflammatory respiratory disease complex and is a significant problem for the beef industry. While the infectious agents involved are known and vaccines exist for some, the host factors determining outcome of infections are still only partially understood. The aim of this project was to explore the usefulness of an inflammation regulatory molecule as a biomarker for susceptibility/resistance to the development of BRD in beef cattle.The transcription factor HIF-1α is recognised for its importance in the development and coordination of an immune response to hypoxia and inflammation caused by infectious agents. For this reason, HIF-1α was identified as an attractive biomarker candidate for BRD susceptibility.The initial objective of this study was to develop methods by which the level of HIF-1α stabilisation in response to hypoxia could be measured in key immune cells. Once developed, the second objective of the study was to use these methodologies to determine whether there was significant positive or negative correlation between the regulation of HIF-1α and the development of clinical BRD. The experimental hypothesis was that there is a significant difference in HIF-1α regulation between animals with clinical BRD compared with other clinically healthy animals, and thus in response to hypoxia there would be a difference in the lymphocyte and monocyte HIF-1α expression between these two groups of cattle. This project developed a methodology for hypoxic culture of bovine lymphocytes and monocytes to induce HIF-1α stabilisation. Tube cultures for lymphocyte analysis were cultured with 1.25 x10 6 cells in 250 µl serum-free medium suspension treated with 200 µM cobalt chloride and 5 µg/ml LPS; with a non-stimulated control tube containing only the cells suspended in serum-free medium.Chamber slides for monocyte analysis were cultured containing 2.5 x 10 6 cells in 500µl serum-free medium with or without stimulants. Tubes and chamber slides were cultured for 18 hours in 5% CO 2 at 37°C. Tube cultured cells underwent post-culture fluorescent staining using a fluorochromeconjugated HIF-1α antibody for measurement of HIF-1α fluorescence in B lymphocytes and T lymphocytes using flow cytometry. T lymphocytes were labelled using a fluorochrome-conjugated anti-CD3 antibody and B lymphocytes labelled using a fluorochrome-conjugated anti-CD20antibody. An additional protocol was developed to measure monocyte HIF-1α expression using immunocytochemical staining of chamber slide cultures. This alternative approach was necessitated by the finding of poor monocyte survival during hypoxic culture and the the pre-flow cytometry staining procedures. These methodologies for the stabilisation and measurement of HIF-1α in bovine lymphocytes and monocytes were then applied to a sample population of 88 feedlot cattle, 34 of which had been treated in the feedlot for clinical BRD (cases), while the remainder was untreated, clinically healthy controls. The groups were compared using t...

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RSV Causes HIF-1α Stabilization via NO Release in Primary Bronchial Epithelial Cells

Cited by 45 publications

References 34 publications

Inflammatory Levels of Nitric Oxide Inhibit Airway Epithelial Cell Migration by Inhibition of the Kinase ERK1/2 and Activation of Hypoxia-inducible Factor-1α

Inflammatory Levels of Nitric Oxide Inhibit Airway Epithelial Cell Migration by Inhibition of the Kinase ERK1/2 and Activation of Hypoxia-inducible Factor-1α

Hypoxia inducible factor (HIF) function in innate immunity and infection

Methodology for the measurement of HIF-1α in bovine leukocytes and assessment of the molecule as a biomarker for bovine respiratory disease outcome

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