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.
WANG Li,ZHANG Yan-Li,WANG Xiu-Fang et al. Expression and significance of mTOR/4EBP1/HIF-1α/VEGF signaling pathway in lung tissues of asthmatic mice[J]. CJCP, 2017, 19(1): 104-110.
Ferkol T, Schraufnagel D. The global burden of respiratory disease[J]. Ann Am Thorac Soc, 2014, 11(3):404-406.
[2]
Lee GK, Shin H, Lim HJ. Rapamycin influences the efficiency of in vitro fertilization and development in the mouse:a role for autophagic activation[J]. Asian-Australas J Anim Sci, 2016, 29(8):1102-1110.
Mi C, Ma J, Shi H, et al. 4',6-dihydroxy-4-methoxyisoaurone inhibits the HIF-1α pathway through inhibition of Akt/mTOR/p70S6K/4E-BP1 phosphorylation[J]. J Pharmacol Sci, 2014, 125(2):193-201.
[6]
Crotty Alexander LE, Akong-Moore K, Feldstein S, et al. Myeloid cell HIF-1α regulates asthma airway resistance and eosinophil function[J]. J Mol Med (Berl), 2013, 91(5):637-644.
[7]
Kim SR, Lee KS, Park HS, et al. HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium[J]. Eur J Immunol, 2010, 40(10):2858-2869.
[8]
Lee CG, Ma B, Takyar S, et al. Studies of vascular endothelial growth factor in asthma and chronic obstructive pulmonary disease[J]. Proc Am Thorac Soc, 2011, 8(6):512-515.
[9]
Mushaben EM, Kramer EL, Brandt EB, et al. Rapamycin attenuates airway hyperreactivity, goblet cells, and IgE in experimental allergic asthma[J]. J Immunol, 2011, 187(11):5756-5763.
[10]
Kramer EL, Hardie WD, Mushaben EM, et al. Rapamycin decreases airway remodeling and hyperreactivity in a transgenic model of noninflammatory lung disease[J]. J Appl Physiol (1985), 2011, 111(6):1760-1767.
[11]
Eynott PR, Salmon M, Huang TJ, et al. Effects of cyclosporin A and a rapamycin derivative (SAR943) on chronic allergic inflammation in sensitized rats[J]. Immunology, 2003, 109(3):461-467.
[12]
Mo JH, Kim JH, Lim DJ, et al. The role of hypoxia-inducible factor 1α in allergic rhinitis[J]. Am J Rhinol Allergy, 2014, 28(2):e100-e106.
[13]
Huerta-Yepez S, Baay-Guzman GJ, Bebenek IG, et al. Hypoxia inducible factor promotes murine allergic airway inflammation and is increased in asthma and rhinitis[J]. Allergy, 2011, 66(7):909-918.
[14]
Yuksel H, Yilmaz O, Karaman M, et al. Role of vascular endothelial growth factor antagonism on airway remodeling in asthma[J]. Ann Allergy Asthma Immunol, 2013, 110(3):150-155.
[15]
Chen MC, Hsu WL, Hwang PA, et al. Low molecular weight fucoidan inhibits tumor angiogenesis through downregulation of HIF-1/VEGF signaling under hypoxia[J]. Mar Drugs, 2015, 13(7):4436-4451.
[16]
Choi YH, Jin GY, Li LC, et al. Inhibition of protein kinase C delta attenuates allergic airway inflammation through suppression of PI3K/Akt/mTOR/HIF-1 alpha/VEGF pathway[J]. PLoS One, 2013, 8(11):e81773.
