Increased expression of vascular endothelial growth factor and hypoxia inducible factor-1α in lung tissue of patients with chronic bronchitis

Lee, Seung Hyeun; Lee, Sang Hoon; Kim, Chul‐Hwan; Yang, Kyung-Sook; Min, Kyung Hoon; Hur, Gyu Young; Lee, Seung Heon; Lee, Sung Yong; Kim, Je Hyeong; Shin, Chol; Shim, Jae Jeong; In, Kwang Ho; Kang, Kyung Ho; Lee, Sang Yeub

doi:10.1016/j.clinbiochem.2014.01.012

Cited by 39 publications

(27 citation statements)

References 34 publications

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“…Adherent mucus is also the site of most bacterial airways infections, including those causing exacerbations in CF and COPD, and, even when “sterile”, it appears to be a pro-inflammatory DAMP 27 . Moreover, mucus plugging induces local, epithelia hypoxia 24 , which is an increasingly recognized feature of the CB syndrome 41 , important for both inflammatory responses and anaerobic infection. Notably, therapies designed to clear mucus from airway surfaces are predicted to be therapeutic for these conditions.…”

Section: Discussionmentioning

confidence: 99%

Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease

et al. 2017

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Airway diseases, including cigarette smoke-induced chronic bronchitis, cystic fibrosis, and primary ciliary dyskinesia are associated with decreased mucociliary clearance (MCC). However, it is not known whether a simple reduction in MCC or concentration-dependent mucus adhesion to airway surfaces dominates disease pathogenesis or whether decreasing the concentration of secreted mucins may be therapeutic. To address these questions, Scnn1b-Tg mice, which exhibit airway mucus dehydration/adhesion, were compared to and crossed with Muc5b- and Muc5ac-deficient mice. Absence of Muc5b caused a 90% reduction in MCC, whereas Scnn1b-Tg mice exhibited an ~50% reduction. However, the degree of MCC reduction did not correlate with bronchitic airways pathology, which was observed only in Scnn1b-Tg mice. Ablation of Muc5b significantly reduced the extent of mucus plugging in Scnn1b-Tg mice. However, complete absence of Muc5b in Scnn1b-Tg mice was associated with increased airway inflammation, suggesting that Muc5b is required to maintain immune homeostasis. Loss of Muc5ac had few phenotypic consequences in Scnn1b-Tg mice. These data suggest that: (1) mucus hyperconcentration dominates over MCC reduction alone to produce bronchitic airways pathology; (2) Muc5b is the dominant contributor to the Scnn1b-Tg phenotype; and (3) therapies that limit mucin secretion may reduce plugging, but complete Muc5b removal from airway surfaces may be detrimental.

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Section: Discussionmentioning

confidence: 99%

Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease

et al. 2017

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“…Interestingly, similar studies looking at the expression of HIF-1α and VEGF in patients with chronic bronchitis (rather than emphysema) have shown HIF-1α and VEGF are increased in this patient group [49]. This suggests that the endothelium might be involved in different ways depending on the clinical presentation of COPD.…”

Section: Introductionmentioning

confidence: 80%

The role of the endothelium in asthma and chronic obstructive pulmonary disease (COPD)

Green

Turner

2017

Respir Res

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COPD and asthma are important chronic inflammatory disorders with a high associated morbidity. Much research has concentrated on the role of inflammatory cells, such as the neutrophil, in these diseases, but relatively little focus has been given to the endothelial tissue, through which inflammatory cells must transmigrate to reach the lung parenchyma and cause damage. There is evidence that there is an abnormal amount of endothelial tissue in COPD and asthma and that this tissue and its’ progenitor cells behave in a dysfunctional manner. This article reviews the evidence of the involvement of pulmonary endothelium in COPD and asthma and potential treatment options for this.

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“…9 Like the skin, the airway is 'bathed' in ambient oxygen, yet increased expression of hypoxia-inducible factor (HIF)-1α has been detected in the bronchial epithelium in COPD. 10 More compellingly (since inflammatory mediators also upregulate the expression of HIF), 11 the airway epithelium of mice overexpressing the β-epithelial Na + channel (a model of cystic fibrosis (CF)) stained strongly with the specific hypoxia probe pimonidazole hydrochloride (Hypoxyprobe, 12 which binds at a threshold of ≤1.3 kPa O 2 13 ), confirming that the inflamed airway is a profoundly hypoxic environment. Neutrophils infiltrate the hypoxic bronchial tissues in patients with COPD, 14 and airway neutrophilia correlates with decline in lung function 15 and with HRCT indicators of peripheral airway dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia upregulates neutrophil degranulation and potential for tissue injury

Hoenderdos

Lodge

Hirst

et al. 2016

Thorax

105

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BackgroundThe inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown.Methods and resultsFollowing exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release.ConclusionHypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion.

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Increased expression of vascular endothelial growth factor and hypoxia inducible factor-1α in lung tissue of patients with chronic bronchitis

Cited by 39 publications

References 34 publications

Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease

Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease

The role of the endothelium in asthma and chronic obstructive pulmonary disease (COPD)

Hypoxia upregulates neutrophil degranulation and potential for tissue injury

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