title: [Expression and significance of mTOR/4EBP1/HIF-1α/VEGF signaling pathway in lung tissues of asthmatic mice].
abstract: OBJECTIVE
  To study the expression and significance of the mammalian target of rapamycin (mTOR)/eukaryote initiating factor 4E binding protein 1(4EBP1)/hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway in asthmatic mice.
  
  
  METHODS
  Forty SPF level 6-8 week-old female Balb/C mice were randomly divided into control, asthma, budesonide and mTOR inhibitor (rapamycin) intervention groups (n=10 each). The asthmatic mouse model was prepared via OVA induction and challenge test. The intervention groups were administered with rapamycin at the dosage of 3 mg/kg by an intraperitoneal injection or budesonide suspension at the dosage of l mg by aerosol inhalation respectively 30 minutes before the OVA challenge. The control and asthma groups were treated with normal saline instead. The concentrations of HIF-1α and VEGF in bronchoalveolar lavage fluid (BALF) were examined using ELISA 24 hours after the last challenge. The pathological changes of lung tissue were observed by hematoxylin-eosin (HE) staining. The p-mTOR and p-4EBP1 from the lung tissues were detected by immunohistochemistry and Western blot. Pearson analysis was used to study the correlation between p-mTOR, p-4EBP1, HIF-1α, and VEGF expression.
  
  
  RESULTS
  Compared with the control group, inflammatory cell infiltration and secretions in the trachea increased in the asthma group. The levels of HIF-1α and VEGF in BALF and p-mTOR and p-4EBP1 expression in lung tissues also increased (P<0.01). Compared with the asthma group, inflammatory cell infiltration and secretions in the trachea were reduced in the two intervention groups, and the levels of HIF-1α and VEGF in BALF and p-mTOR and p-4EBP1 expression in lung tissues were also reduced (P<0.01). There were no significant differences in the above changes between the two intervention groups and control group (P>0.05). In the asthma group, there was a pairwise positive correlation between lung p-mTOR and p-4EBP1 expression and HIF-1α and VEGF levels in BALF (P<0.05). However, there were no correlations in the above indexes in the intervention groups and control group.
  
  
  CONCLUSIONS
  p-mTOR, p-4EBP1, HIF-1α and VEGF together are involved in the pathogenesis of asthma. Rapamycin treatment can block this signaling pathway, suggesting that this pathway can be used as a novel target for asthma treatment.
authors.affiliation: Department of Pediatrics, Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. wxf456@126.com.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Zhang
authors.forename: Xiu-Fang
authors.initials: XF
authors.lastname: Wang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Song
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis / Q000502:physiology*; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000502:physiology*; D008168:Lung / Q000737:chemistry* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010750:Phosphoproteins / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000032:analysis / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010750:Phosphoproteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases