Inflammatory stimulation and hypoxia cooperatively activate HIF-1α in bronchial epithelial cells: involvement of PI3K and NF-κB

Jiang, Hong; Zhu, Ye; Xu, Hui; Sun, Yinghao; Li, Qi Fang

doi:10.1152/ajplung.00394.2009

Cited by 58 publications

(47 citation statements)

References 54 publications

(63 reference statements)

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“…Whereas tissue hypoxia is associated with protein stabilization and increased half-life, normoxic activation occurs via increased HIF-1α protein synthesis or its modification [11,23,24]. For example, it has been demonstrated that stimulation of primary HBECs by pro-inflammatory cytokines TNFα/IL-4 induces expression and transcriptional activity of HIF-1α under normoxic condition and amplifies HIF-1α activation in hypoxia [22]. Since the inflammatory microenvironment in COPD is enriched with cytokines and pro-inflammatory mediators [29], this could be another mechanism of HIF-1α stabilization/activation in COPD.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor‐1 signalling promotes goblet cell hyperplasia in airway epithelium

Polosukhin

Cates

Lawson

et al. 2011

The Journal of Pathology

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Goblet cell hyperplasia is a common feature of chronic obstructive pulmonary disease (COPD) airways, but the mechanisms that underlie this epithelial remodelling in COPD are not understood. Based on our previous finding of hypoxia-inducible factor-1α (HIF-1α) nuclear localization in large airways from patients with COPD, we investigated whether hypoxia-inducible signalling could influence the development of goblet cell hyperplasia. We evaluated large airway samples obtained from 18 lifelong non-smokers and 13 former smokers without COPD, and 45 former smokers with COPD. In these specimens, HIF-1α nuclear staining occurred almost exclusively in COPD patients in areas of airway remodelling. In COPD patients, 93.2 ± 3.9% (range 65 – 100%) of goblet cells were HIF-1α positive in areas of goblet cell hyperplasia, whereas nuclear HIF-1α was not detected in individuals without COPD or in normal-appearing pseudostratified epithelium from COPD patients. To determine the direct effects of hypoxia-inducible signalling on epithelial cell differentiation in vitro, human bronchial epithelial cells (HBECs) were grown in air-liquid interface cultures under hypoxia (1% O2) or following treatment with a selective HIF-1α stabilizer, (2R)-[(4-biphenylylsulphonyl)amino]-N-hydroxy-3-phenyl-propionamide (BiPS). HBECs grown in hypoxia or with BiPS treatment were characterized by HIF-1α activation, carbonic anhydrase IX expression, mucus-producing cell hyperplasia and increased expression of MUC5AC. Analysis of signal transduction pathways in cells with HIF-1α activation showed increased ERK1/2 phosphorylation without activation of epidermal growth factor receptor, Ras, PI3K-Akt or STAT6. These data indicate an important effect of hypoxia-inducible signalling on airway epithelial cell differentiation and identify a new potential target to limit mucus production in COPD.

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Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor‐1 signalling promotes goblet cell hyperplasia in airway epithelium

Polosukhin

Cates

Lawson

et al. 2011

The Journal of Pathology

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“…Real-time quantitative PCR estimation of the mRNA levels was performed as previously described [21] . Briefly, total RNA was prepared from the lung tissue using RNeasy (Qiagen, Shanghai, China), and cDNA was synthesized using the highcapacity cDNA reverse transcription kit (Applied Biosystems, Carlsbad, CA, USA) according to the manufacturer's protocols.…”

Section: Real-time Quantitative Polymerase Chain Reaction (Pcr)mentioning

confidence: 99%

“…Western blotting assays were performed as we have described previously [21] . The intensity of each band was quantified using Quantity One-4.2.3 software (Bio-Rad, Hercules, CA, USA) and normalized relative to the total level of p42/p44 by density analysis.…”

Section: Western Blotting Assaymentioning

confidence: 99%

Inhibition of hypoxia inducible factor-1α ameliorates lung injury induced by trauma and hemorrhagic shock in rats

Hong

Huang

et al. 2012

Acta Pharmacol Sin

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Aim: Ischemia/reperfusion is an initial triggering event that leads to gut-induced acute lung injury (ALI). In this study, we investigated whether hypoxia inducible factor-1α (HIF-1α) played a role in the pathogenesis of lung injury induced by trauma and hemorrhagic shock (T/HS). Methods: Male Wistar rats underwent laparotomy and hemorrhagic shock for 60 min. Sham-shock animals underwent laparotomy but without hemorrhagic shock. After resuscitation for 3 h, the rats were sacrificed. Morphologic changes of the lungs and intestines were examined. Bronchoalveolar lavage fluid (BALF) was collected. Lung water content, pulmonary myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), nitrite/nitrate, TNF-α, IL-1β, and IL-6 in the lungs were measured. The gene expression of pulmonary HIF-1α and iNOS, and HIF-1α transcriptional activity in the lungs were also assessed. The apoptosis in the lungs was determined using TUNEL assay and cleaved caspase-3 expression. Results: Lung and intestinal injuries induced by T/HS were characterized by histological damages and a significant increase in lung water content. Compared to the sham-shock group, the BALF cell counts, the pulmonary MPO activity and the MDA, nitrite/nitrate, TNF-α, IL-1β, and IL-6 levels in the T/HS group were significantly increased. Acute lung injury was associated with a higher degree of pulmonary HIF-1α and iNOS expression as well as apoptosis in the lungs. Intratracheal delivery of HIF-1α inhibitor YC-1 (1 mg/kg) significantly attenuated lung injury, and reduced pulmonary HIF-1α and iNOS expression and HIF-1α transcriptional activity in the T/HS group. Conclusion: Local inhibition of HIF-1α by YC-1 alleviates the lung injury induced by T/HS. Our results provide novel insight into the pathogenesis of T/HS-induced ALI and a potential therapeutic application.

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“…Elevated inflammatory cytokines [e.g., interleukin-1␤ (IL-1␤) and tumor necrosis factor (TNF-␣)], prostaglandin E 2 (PGE 2 ), placental growth factor (PIGF), nuclear factor-B (NF-B) activation, and oxidants are implicated not only in inflammatory pathophysiology of human SCD and transgenic sickle mice, but also in HIF-1␣ activation (11,31,33,38,44,47,55,60). Among the sources of oxidative stress in SCD and transgenic sickle mice are reperfusion injury, plasma membrane NADPH oxidase (59), increased plasma xanthine oxidase (2), endothelial NO synthase (eNOS) decoupling (28), hemoglobin autoxidation (23), and decreased bioavailability of NO (48).…”

mentioning

confidence: 99%

Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1α expression in normoxic sickle mice: microvascular implications

Kaul

Fabry

Suzuka

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Kaul DK, Fabry ME, Suzuka SM, Zhang X. Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1␣ expression in normoxic sickle mice: microvascular implications. Am J Physiol Heart Circ Physiol 304: H42-H50, 2013. First published November 2, 2012; doi:10.1152/ajpheart.00296.2012.-Chronic inflammation is a salient feature of sickle cell disease (SCD) and transgenic-knockout sickle (BERK) mice. Inflammation is implicated in the activation of hypoxia-inducible factor-1␣ (HIF-1␣) under normoxic conditions. We hypothesize that, in SCD, inflammation coupled with nitric oxide (NO) depletion will induce expression of HIF-1␣, a transcription factor with wide-ranging effects including activation of genes for vasoactive molecules. To this end, we have examined the expression of HIF-1␣ in normoxic BERK mice expressing exclusively human ␣-and ␤ S -globins, and evaluated the effect of fetal hemoglobin (HbF) in BERK mice (i.e., Ͻ1.0%, 20%, and 40% HbF). HbF exerts antisickling and anti-inflammatory effects. Here, we show that HIF-1␣ is expressed in BERK mice under normoxic conditions, accompanied by increased expression of its vasoactive biomarkers such as VEGF, heme oxygenase-1 (HO-1), and serum ET-1 levels. In BERK mice expressing HbF, HIF-1␣ expression decreases concomitantly with increasing HbF, commensurately with increased NO bioavailability, and shows a strong inverse correlation with plasma NO metabolites (NOx) levels. Reduced HIF-1␣ expression is associated with decreased HO-1, VEGF, and ET-1. Notably, arteriolar dilation, enhanced volumetric blood flow, and low blood pressure in normoxic BERK mice all show a trend toward normalization with the introduction of HbF. Also, arginine treatment reduced HIF-1␣, as well as VEGF expression in normoxic BERK mice, supporting a role of NO bioavailability in HIF-1␣ activation. Thus HIF-1␣ expression in normoxic sickle mice is likely a consequence of chronic inflammation, and HbF exerts an ameliorating effect by decreasing sickling, increasing NO bioavailability, and reducing inflammation. sickle cell disease; hypoxia-inducible factor-1␣; fetal hemoglobin; nitric oxide; oxidative stress; inflammation HEMOGLOBIN S (HBS) polymerization under deoxygenated conditions and abnormal red blood cell rheology are central to the pathophysiology of sickle cell disease (SCD), the consequences of which can lead to vaso-occlusion, reperfusion injury, oxidative stress, hemolysis, reduced nitric oxide (NO) bioavailability, and inflammation (15,19,25,41). In SCD, vaso-occlusive events may result in episodes of tissue ischemia. Tissue ischemia is normally associated with the activation of hypoxia-inducible factor-1␣ (HIF-1␣). Under normoxic conditions, HIF-1␣ expression can be triggered by inflammation (26, 55), a prominent feature of human SCD and transgenic sickle mice (24). Activation of HIF is implicated in cellular adaptive responses to hypoxia and inflammation. HIF can trigger transcription of genes for vasoactive molecules such as vascular endothelial growth factor (VEGF), heme oxygena...

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Inflammatory stimulation and hypoxia cooperatively activate HIF-1α in bronchial epithelial cells: involvement of PI3K and NF-κB

Cited by 58 publications

References 54 publications

Hypoxia‐inducible factor‐1 signalling promotes goblet cell hyperplasia in airway epithelium

Hypoxia‐inducible factor‐1 signalling promotes goblet cell hyperplasia in airway epithelium

Inhibition of hypoxia inducible factor-1α ameliorates lung injury induced by trauma and hemorrhagic shock in rats

Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1α expression in normoxic sickle mice: microvascular implications

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