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Vol. 21, Art. 55 (pp. 669-678)    |    2020       

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Activation of hypoxia-inducible factor in inflammation caused by prolonged exposure to nitrogen dioxide

Kirov Military Medical Academy Russian Federation Defense Ministry, Saint-Petersburg, Russia.

Brief summary

The purpose of the experimental study was to assess the effect of prolonged exposure to nitrogen dioxide on the level of hypoxia-inducible factor activation and the cytoimmunological profile of bronchoalveolar lavage fluid (BALF). Nitrogen dioxide inhalations (30-40 mg/m3) were carried out intermittently (three exposures per day for 30 minutes with a half-hour interval between them) for 60 days. Cell composition, the content of hypoxia-induced factor-1 (HIF-1α), cyclooxygenase-2 (COX-2), interleukin-17 (IL-17), and surfactant protein D (SP-D) were determined in BALF. Under the influence of prolonged exposure to nitrogen dioxide, a persistent inflammatory process was formed in the lungs, as evidenced by the cytoimmunological profile of BALF, and marked activation of hypoxia-induced factor was noted. The results of the study confirm the existence of functional and possibly mutually regulatory relationship of the hypoxic HIF-1α-dependent and pro-inflammatory COX-2-dependent signaling cascades, which can be a therapeutic target for preventing the progression of inflammation and abnormal airway remodeling in many pathological processes associated with the development of inflammatory hypoxia.


Key words

rats, nitrogen dioxide, inflammation, hypoxia-inducible factor, cyclooxygenase-2, interleukin-17, surfactant protein D, lungs.

Reference list

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13. Huang M., Wang L., Chen J., Bai M., Zhou C., Liu S., Lin Q. Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxia-inducible factor-1α is associated with poor prognosis in hepatocellular carcinoma patients post TACE surgery / Int. J. Oncol. 2016. Vol. 48, N 5. P. 2144-2154. doi: 10.3892/ijo.2016.3421.


14. Jiang H., Zhu Y.S., Xu H., Sun Y. Li Q.F. Inflammatory stimulation and hypoxia cooperatively activate HIF-1{alpha} in bronchial epithelial cells: involvement of PI3K and NF-{kappa}B / Am. J. Physiol. Lung Cell Mol. Physiol. 2010. Vol. 298, N 5. P. L660-L669. doi: 10.1152/ajplung.00394.2009.


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16. Lu D., Li N., Yao X., Zhou L. Potential inflammatory markers in obstructive sleep apnea-hypopnea syndrom / Bosn. J. Basic. Med. Sci. 2017. Vol. 17, N 1. P. 47-53. doi: 10.17305/bjbms.2016.1579.


17. Rey S., Semenza G.L. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodeling / Cardiovasc. Res. 2010. Vol. 86, N 2. P. 236-242. doi: 10.1093/cyr/cvq045.


18. Sin D.D., Pahlavan P.S., Man S.F. Surfactant protein D: A lung specific biomarker in COPD? / Ther. Adv. Respir. Dis. 2008. Vol. 2, N 2. P. 65-74. doi: 10.1177/1753465808088903.


19. Zago M., Rico de Souza A., Hecht E., Rousseau S., Hamid Q., Eidelman D.H., Naglole C.J. The NF-κB family member RelB regulates microRNA miR-146a to suppress cigarette smoke-induced COX-2 protein expression in lung fibroblasts / Toxicol. Lett. 2014. Vol. 226, N 2. P. 107-116. doi: 10.1016/j.toxlet.2014.01.020.


20. Zhang M., Fei X., Zhang G.Q., Zhang P.Y., Li F., Bao W.P., Zhang Y.Y., Zhou X. Role of neutralizing anti-murine interleukin-17A monoclonal antibody on chronic ozone-induced airway inflammation in mice / Biomed Pharmacother. 2016. N 83. P. 247-256. doi: 10.1016/j.biopha.2016.06.041.








Reference


1. Dvorakovskaya I.V., Kuzubova N.A., Fionik A.M., Platonova I.S., Lebedeva E.S., Danilov L.N. Pathological anatomy of bronchi and rat respiratory tissue when exposed to nitrogen dioxide. Pulmonology / 2009. 1. P. 54-61. [In Russian].


2. Lyamina S.V., Malyshev I.Yu. Surfactant protein D in norma and lung diseases. Rossiyskiy meditsinskiy zhurnal = Russian Medical Journal / 2012. N 1. P. 50-55. [In Russian].


3. Clerici C., Planès C. Gene regulation in the adaptive process to hypoxia in lung epithelial cells / Am. J. Physiol. Lung Cell Mol. Physiol. 2009. Vol. 296, N 3. P. L267-L274. doi: 10.1152/ajplung.90528.2008.


4. Colgan S.P., Campbell E.L., Kominsky D.J. Hypoxia and mucosal inflammation / Annu. Rev. Pathol. 2016. N 11. P. 77-100. doi: 10.1146/annurev-pathol-012615-044231.


5. Corcoran S.E., O?Neill L.A. HIF1α and metabolic reprogramming in inflammation / J. Clin. Invest. 2016. Vol. 126, N 10. P. 3699-3707. doi: 10.1172/JCI84431.


6. Cummins E.P., Keogh C.E., Crean D., Taylor C.T. The role of HIF in immunity and inflammation / Mol. Aspects Med. 2016. N 47-48. P. 24-34. doi: 10.1016/j.mam.2015.12.004.


7. Eurlings I.M., Reynaert N.L., van den Beucken T., Gosker H.R., de Theije C.C., Verhamme F.M., Bracke K.R., Wouters E.F., Dentener M.A. Cigarette smoke extract induces a phenotypic shift in epithelial cells; involvement of HIF1α in mesenchymal transition / PLoS One. 2014. Vol. 9, N 10. e107757. doi: 10.1371/journal.pone.0107757.


8. D?Ignazio L., Bandarra D., Rocha S. NF-κB and HIF crosstalk in immune responses / FEBS J. 2016. Vol. 283, N 3. P. 413-424. doi: 10.1111/febs.13578.


9. Duan M.C., Zhang J.Q., Liang Y., Liu G.N., Xiao J., Tang H.J., Liang Y. Infiltration of IL-17-producing T cells and Treg cells in a mouse model of smoke-induced emphysema / Inflammation. 2016. Vol. 39, N 4. P. 1334-1344. doi: 10.1007/s10753-016-0365-8.


10. Gao W., Li L., Wang Y., Zhang S., Adcock I.M., Barnes P.J., Huang M., Yao X. Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease? / Respirology. 2015. Vol. 20, N 5. P. 722-729. doi: 10.1111/resp.12542.


11. Gu W., Song L., Li X.M., Wang D., Guo X.J., Xu W.G. Mesenchymal stem cells alleviate airway inflammation and emphysema in COPD through down-regulation of cyclooxygenase-2 via p38 and ERK MAPK pathways / Sci. Rep. 2015. N 5. P. 8733. doi: 10.1038/srep08733.


12. He X.Y., Shi X.Y., Yuan H.B., Xu H.T., Li Y.K., Zou Z. Propofol attenuates hypoxia-induced apoptosis in alveolar epithelial type II cells through down-regulating hypoxia-inducible factor-1α / Injury. 2012. Vol. 43, N 3. P. 279-283. doi: 10.1016/j.injury.2011.05.037.


13. Huang M., Wang L., Chen J., Bai M., Zhou C., Liu S., Lin Q. Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxia-inducible factor-1α is associated with poor prognosis in hepatocellular carcinoma patients post TACE surgery / Int. J. Oncol. 2016. Vol. 48, N 5. P. 2144-2154. doi: 10.3892/ijo.2016.3421.


14. Jiang H., Zhu Y.S., Xu H., Sun Y. Li Q.F. Inflammatory stimulation and hypoxia cooperatively activate HIF-1{alpha} in bronchial epithelial cells: involvement of PI3K and NF-{kappa}B / Am. J. Physiol. Lung Cell Mol. Physiol. 2010. Vol. 298, N 5. P. L660-L669. doi: 10.1152/ajplung.00394.2009.


15. Levänen B., Glader P., Dahlén B., Billing B., Qvarfordt I.,Palmberg L., Larsson K., Lindén A. Impact of tobacco smoking on cytokine signaling via interleukin-17A in the peripheral airways / Int. J. Chron. Obstruct. Pulmon. Dis. 2016. N 11. P. 2109-2116. doi: 10.2147/COPD.S99900.


16. Lu D., Li N., Yao X., Zhou L. Potential inflammatory markers in obstructive sleep apnea-hypopnea syndrom / Bosn. J. Basic. Med. Sci. 2017. Vol. 17, N 1. P. 47-53. doi: 10.17305/bjbms.2016.1579.


17. Rey S., Semenza G.L. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodeling / Cardiovasc. Res. 2010. Vol. 86, N 2. P. 236-242. doi: 10.1093/cyr/cvq045.


18. Sin D.D., Pahlavan P.S., Man S.F. Surfactant protein D: A lung specific biomarker in COPD? / Ther. Adv. Respir. Dis. 2008. Vol. 2, N 2. P. 65-74. doi: 10.1177/1753465808088903.


19. Zago M., Rico de Souza A., Hecht E., Rousseau S., Hamid Q., Eidelman D.H., Naglole C.J. The NF-κB family member RelB regulates microRNA miR-146a to suppress cigarette smoke-induced COX-2 protein expression in lung fibroblasts / Toxicol. Lett. 2014. Vol. 226, N 2. P. 107-116. doi: 10.1016/j.toxlet.2014.01.020.


20. Zhang M., Fei X., Zhang G.Q., Zhang P.Y., Li F., Bao W.P., Zhang Y.Y., Zhou X. Role of neutralizing anti-murine interleukin-17A monoclonal antibody on chronic ozone-induced airway inflammation in mice / Biomed Pharmacother. 2016. N 83. P. 247-256. doi: 10.1016/j.biopha.2016.06.041.