Vascular Endothelial Growth Factor Drives Autocrine Epithelial Cell Proliferation and Survival in Chronic Rhinosinusitis with Nasal Polyposis

Lee, Hyun Sil; Myers, Allen C.; Kim, Jean

doi:10.1164/rccm.200905-0740oc

Cited by 60 publications

(61 citation statements)

References 72 publications

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“…The present study provides evidence supporting an important role for VEGF in the pathogenesis of nasal polyposis, as we measured significantly high levels of mRNA expression both for VEGF and its receptor FLT-1 in nasal polyps compared to control turbinate mucosa. These findings are in accordance with recent literature (20)(21)(22)(23)(24), although, to the best of our know ledge, this is the first study to report mRNA expression levels of both VEGF and its receptor FLT-1 in human nasal polyp tissue. Mounting evidence suggests that, besides its influence on blood vessel formation, VEGF may even be directly involved in the pathogenesis of bronchial asthma (30,31).…”

Section: Discussionsupporting

confidence: 93%

“…Our main finding was the increased expression of mRNA levels of VEGF, FLT-1, Ang-1, Ang-2, Tie-2A, Tie-2B, SDF-1α and SDF-1β in NP tissue samples compared to normal turbinate tissue samples. There is conflicting evidence regarding the exact role of angiogenic growth factors in the pathophysio logy of nasal polyposis (20)(21)(22)(23)(24). It has been suggested that proangiogenic factors are involved in the disease process through the formation of edema, the activation of inflammatory cell migration and activation of the nitric oxide synthase pathway (13,(20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

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Investigation of angiogenetic pathways in nasal polyposis

et al. 2012

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Abstract. Tissue angiogenesis is a complex phenomenon that results in the growth of new blood vessels from the microcirculation. This process has been known to play a crucial role in tumor growth as well as several benign diseases. The aim of this study was to assess mRNA expression of various angiogenic factors and chemokines in nasal polyps and compare the results to normal nasal mucosa. mRNA expression was measured using real-time RT-PCR for the following angiogenic factors and chemokines: VEGF, VEGFR-1, Ang-1, Ang-2, Tie-2A, Tie-2B, SDF-1α, SDF-1β, CXCR4 and YY1. Biopsy specimens from nasal polyps in the polyposis group and middle turbinates in the control group were studied. A total of 18 nasal polyposis patients were studied and compared to 10 control subjects. Results showed VEGF, VEGFR-1, Ang-1, Ang-2, Tie-2A, Tie-2B, SDF-1α and SDF-1β mRNA expression to be significantly higher in nasal polyposis patients compared to the control group (p<0.05). The findings of this study support the role of angiogenic growth factors in the pathogenenesis of nasal polyposis. Further studies are required to confirm these results and evaluate potential clinical implications. IntroductionNasal polyposis (NP) constitutes a chronic inflammatory disease of the nose and sinuses characterized by the appearance of protruding tissue swellings of the nasal mucosa. These swellings most commonly originate from the middle meatus and anterior ethmoids. On histologic examination, they are typically characterized by proliferation of the epithelial layer, glandular hyperplasia, thickening of the basal membrane, focal fibrosis, edema and cellular infiltration of the stromal layer. Nasal polyps are relatively common in the general population and significantly affect patient quality of life. Despite these facts, etiology of the disease remains largely unknown (1-4).Tissue angiogenesis is a complex phenomenon that results in the growth of new blood vessels from the microcirculation (5-7). This process has been known to play a crucial role in tumor growth, where it is regarded as a prerequisite allowing for the expansion of tumor populations beyond the size restricted by oxygen and nutrient diffusion (6). It also facilitates tumor progression and metastasis by causing degradation of the epithelial basement membrane and providing cancer cells with new capillaries for entering the circulation (7,8).Increasing evidence shows that angiogenesis may also play a critical role in benign disorders (9,10). The phenomenon, appearing in the form of growth of new blood vessels or the enlargement of existing ones, has been strongly associated with airway remode ling in chronic asthma and chronic obstructive pulmonary disease (11,12). In addition, using immunohistochemistry it has been shown that vascular endothelial growth factor (VEGF), possibly the most important driver of angiogenesis, along with its receptors, are strongly expressed in nasal polyp tissues, thus supporting a role in the development of chronic inflammation and edema in this disease (13).Re...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Investigation of angiogenetic pathways in nasal polyposis

et al. 2012

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“…Vascular endothelial growth factor is up-regulated in CRSwNP and drives epithelial cell proliferation. 22 In particular, VEGF-A has neurotrophic effects and has been proposed as a potential therapy for neurodegenerative disorders.23 It is possible that the positive correlation we found is due to increased vascularization and improved olfactory neuron function, but this is purely speculative.…”

Section: Discussionmentioning

confidence: 88%

Mucous Cytokine Levels in Chronic Rhinosinusitis–Associated Olfactory Loss

Schlosser

Mulligan

Hyer

et al. 2016

JAMA Otolaryngol Head Neck Surg

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IMPORTANCE Olfactory loss is a frequent symptom of patients with chronic rhinosinusitis (CRS), but our understanding of how inflammatory cytokines affect olfaction is limited. OBJECTIVES To examine whether inflammatory cytokines are present in the olfactory cleft and whether they correlate with objective olfaction. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional study, patients with CRS underwent quantitative olfactory testing using the Sniffin Sticks test to calculate a composite threshold discrimination identification (TDI) score from October 21, 2013, to November 12, 2015. Nasal mucus was collected using a sponge placed in the olfactory cleft for 5 minutes, and Cytometric Bead Array was used to measure secreted immunomodulatory products. Correlations between TDI score and secreted mediators were then calculated. Data analysis was performed from October 15, 2015, to December 17, 2015. MAIN OUTCOMES AND MEASURES Composite TDI scores and mean secreted mediator levels in mucus from the olfactory cleft. RESULTS Thirty-four patients were enrolled (mean [SD] age, 57.3 [15.7] years; female, 21 [61.8%]; white, 26 [76.5]). The TDI scores were lower in patients with CRS with nasal polyps (CRSwNP) than in patients with CRS without nasal polyps (CRSsNP) (difference, 8.7; 95% CI, 2.5–15.0; P = .007). Interleukin (IL) 5 levels were inversely correlated with TDI scores in patients with CRSwNP and those with CRSsNP (mean [SE] β estimate, −46.56 [15.11]; P = .005), whereas IL-6, IL-7, and vascular endothelial growth factor A were positively correlated with TDI scores only in the CRSwNP cohort. Subscale olfactory TDI scores followed similar correlations to composite TDI scores. CONCLUSIONS AND RELEVANCE In this study, inflammatory cytokines were found in mucus collected from the olfactory cleft. Levels of IL-5, in addition to other cytokines, were associated with objective olfactory function. Further inquiry is needed to establish the source of mucous cytokines and establish whether they play a causal role in olfactory loss.

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“…Alternatively, epithelial VEGF-A may not be associated with peribronchial angiogenesis in CF subjects and may play different roles (e.g. epithelial proliferation [33]). CF subjects at transplantation were younger than control subjects.…”

Section: Discussionmentioning

confidence: 99%

CFTR dysfunction induces vascular endothelial growth factor synthesis in airway epithelium

Martin

Coolen

et al. 2013

Eur Respir J

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Peribronchial angiogenesis may occur in cystic fibrosis and vascular endothelial growth factor (VEGF)-A regulates angiogenesis in airways.Peribronchial vascularity and VEGF-A expression were examined using immunocytochemistry and morphometric analysis in lung sections obtained in 10 cystic fibrosis patients at transplantationversus10 control nonsmokers, and in two strains of Cftr-deficient mice versus wild-type littermates. Airway epithelial NCI-H292 cells and primary cultures of noncystic fibrosis human airway epithelial cells were treated with cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors (CFTR-inh172or PPQ-102) or transfected with a CFTR small interfering (si)RNA with or without a selective epidermal growth factor receptor tyrosine kinase inhibitor. Concentrations of VEGF-A and phosphorylated epidermal growth factor receptor were measured by ELISA.Peribronchial vascularity was increased in cystic fibrosis patients, but not inCftr-deficient mice. VEGF-A immunostaining was localised to airway epithelium and was increased in cystic fibrosis patients and inCftr-deficient mice. In cultured airway epithelial cells, treatment with CFTR inhibitors or transfection with CFTR siRNA induced a twofold increase in VEGF-A production. CFTR inhibitors triggered epidermal growth factor receptor phosphorylation that was required for VEGF-A synthesis.Cystic fibrosis airways at transplantation showed increased peribronchial vascularity and epithelial VEGF-A expression. CFTR dysfunction triggered epithelial synthesis of VEGF-A, which may contribute to vascular remodelling.

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Vascular Endothelial Growth Factor Drives Autocrine Epithelial Cell Proliferation and Survival in Chronic Rhinosinusitis with Nasal Polyposis

Cited by 60 publications

References 72 publications

Investigation of angiogenetic pathways in nasal polyposis

Investigation of angiogenetic pathways in nasal polyposis

Mucous Cytokine Levels in Chronic Rhinosinusitis–Associated Olfactory Loss

CFTR dysfunction induces vascular endothelial growth factor synthesis in airway epithelium

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