title: Hypoxia induces cysteine-rich 61, vascular endothelial growth factor, and interleukin-8 expressions in human nasal polyp fibroblasts: An implication of neutrophils in the pathogenesis of nasal polyposis.
abstract: BACKGROUND
  The purpose of this article was to elucidate the roles of neutrophils and angiogenesis factors in the pathogenesis of nasal polyposis. The effect of hypoxia on the expressions of angiogenesis factors as cysteine-rich 61 (Cyr61) and vascular endothelial growth factor (VEGF) and neutrophil chemoattractant as interleukin (IL)-8 in nasal polyp fibroblasts (NPFs), and the role of nuclear factor kappa B (NF-kappaB) in this reaction were investigated. The action of Cyr61 on the synthesis of VEGF and IL-8 in NPFs was also examined.
  
  
  METHODS
  Primary cultures of NPFs were established from nasal polyps (NPs). Productions of Cyr61, VEGF, and IL-8 by NPFs under hypoxia were detected by Western blot (Cyr61 and VEGF) or enzyme-linked immunosorbent assay (ELISA; IL-8). Immunohistochemical staining was used to examine the relation between fibroblastic expression of Cyr61 and neovascularization/neutrophil infiltration in NPs.
  
  
  RESULTS
  Western blot showed that the hypoxia inducer CoCl(2) stimulated Cyr61 synthesis in NPFs in a time-dependent manner, reaching a peak at 24 hours. Bay-117082 (a specific NF-kappaB inhibitor) attenuated the levels of Cyr61 stimulated by hypoxia. Cyr61 induced IL-8 secretion and VEGF synthesis by NPFs, as evidenced by Western blot and ELISA analysis. Bay-117082 abolished hypoxia-stimulated IL-8 and VEGF synthesis, whereas Cyr61 restored the stimulative effect of hypoxia readily. Immunohistochemical staining revealed the presence of Cyr61 and IL-8 in NPFs. Neutrophils and capillaries aggregating around these NPFs were frequently found.
  
  
  CONCLUSIONS
  Under hypoxia, NPFs contribute to NP propagation by expressing Cyr61, which subsequently stimulates VEGF and IL-8 production, leading to angiogenesis and activating neutrophil infiltration in NPs.
authors.affiliation: Department of Forensic Medicine and Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.forename: Sze-Kwan
authors.initials: SK
authors.lastname: Lin
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Hong
authors.forename: Hung-Meng
authors.initials: HM
authors.lastname: Huang
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Liu
mesh_terms: D002465:Cell Movement; D002478:Cells, Cultured; D002908:Chronic Disease; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009297:Nasal Mucosa / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D009298:Nasal Polyps; D009389:Neovascularization, Pathologic; D009504:Neutrophils / Q000276:immunology; D009570:Nitriles / Q000494:pharmacology; D012220:Rhinitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012852:Sinusitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013450:Sulfones / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D055515:Cysteine-Rich Protein 61; D016209:Interleukin-8; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A