Skip to main content
SpringerLink
Log in

Activation of Alpha-7 Nicotinic Acetylcholine Receptors (α7nAchR) Promotes the Protective Autophagy in LPS-Induced Acute Lung Injury (ALI) In Vitro and In Vivo

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

The release of inflammatory cytokines and chemokines and autophagy has been reported to be involved in the pathogenic mechanism of acute lung injury (ALI). Reportedly, alpha-7 nicotinic acetylcholine receptors (α7nAchR) might play a protective role in LPS-induced ALI. In the current research, we established LPS-induced ALI model in mice and α7nAchR agonist PNU-282987 improved LPS-induced injury. In MH-S cells, LPS stimulation inhibited, whereas α7nAchR agonist PNU-282987 enhanced the autophagy. α7nAchR agonist PNU-282987 protected MH-S cells from LPS-induced inflammation by reducing the concentrations of IL-6, TNF-α, and IL-1β. Finally, LPS stimulation dramatically inhibited MH-S cell viability but enhanced cell apoptosis, whereas PNU-282987 treatment exerted opposite effects; α7nAchR might regulate the cellular homeostasis via affecting the crosstalk between the autophagy and apoptosis in MH-S cells; in other words, α7nAChR agonist enhances MH-S cell autophagy and inhibits MH-S cell apoptosis. In conclusion, α7nAchR promote the protective autophagy in LPS-induced ALI model in mice and MH-S cells. The application of α7nAchR agonist is considered a potent target for LPS-induced ALI, which needs further clinical investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

Please contact the authors for data requests.

References

  1. Borovikova, L.V., S. Ivanova, M. Zhang, H. Yang, G.I. Botchkina, L.R. Watkins, H. Wang, N. Abumrad, J.W. Eaton, and K.J. Tracey. 2000. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405 (6785): 458–462. https://doi.org/10.1038/35013070.

    Article  CAS  PubMed  Google Scholar 

  2. Chatterjee, P.K., M.M. Yeboah, O. Dowling, X. Xue, S.R. Powell, Y. Al-Abed, and C.N. Metz. 2012. Nicotinic acetylcholine receptor agonists attenuate septic acute kidney injury in mice by suppressing inflammation and proteasome activity. PLoS One 7 (5): e35361. https://doi.org/10.1371/journal.pone.0035361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Choudhary, G.S., S. Al-Harbi, and A. Almasan. 2015. Caspase-3 activation is a critical determinant of genotoxic stress-induced apoptosis. Methods in Molecular Biology 1219: 1–9. https://doi.org/10.1007/978-1-4939-1661-0_1.

    Article  CAS  PubMed  Google Scholar 

  4. Cooper, K.F. 2018. Till death do us part: the marriage of autophagy and apoptosis. Oxidative Medicine and Cellular Longevity 2018: 4701275–4701213. https://doi.org/10.1155/2018/4701275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. de Jonge, W.J., and L. Ulloa. 2007. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. British Journal of Pharmacology 151 (7): 915–929. https://doi.org/10.1038/sj.bjp.0707264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. De Rosa, M.J., C. Esandi Mdel, A. Garelli, D. Rayes, and C. Bouzat. 2005. Relationship between alpha 7 nAChR and apoptosis in human lymphocytes. Journal of Neuroimmunology 160 (1–2): 154–161. https://doi.org/10.1016/j.jneuroim.2004.11.010.

    Article  CAS  PubMed  Google Scholar 

  7. Decuypere, J.P., J.B. Parys, and G. Bultynck. 2012. Regulation of the autophagic bcl-2/beclin 1 interaction. Cells 1 (3): 284–312. https://doi.org/10.3390/cells1030284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Di Paolo, T., L. Gregoire, D. Feuerbach, W. Elbast, M. Weiss, and B. Gomez-Mancilla. 2014. AQW051, a novel and selective nicotinic acetylcholine receptor alpha7 partial agonist, reduces l-Dopa-induced dyskinesias and extends the duration of l-Dopa effects in parkinsonian monkeys. Parkinsonism & Related Disorders 20 (11): 1119–1123. https://doi.org/10.1016/j.parkreldis.2014.05.007.

    Article  Google Scholar 

  9. Fan, H., R. Gu, and D. Wei. 2015. The alpha7 nAChR selective agonists as drug candidates for Alzheimer’s disease. Advances in Experimental Medicine and Biology 827: 353–365. https://doi.org/10.1007/978-94-017-9245-5_21.

    Article  CAS  PubMed  Google Scholar 

  10. Fan, K., L. Lin, Q. Ai, J. Wan, J. Dai, G. Liu, L. Tang, Y. Yang, P. Ge, R. Jiang, and L. Zhang. 2018. Lipopolysaccharide-induced dephosphorylation of AMPK-activated protein kinase potentiates inflammatory injury via repression of ULK1-dependent autophagy. Frontiers in Immunology 9: 1464. https://doi.org/10.3389/fimmu.2018.01464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Han, S., and R.K. Mallampalli. 2015. The acute respiratory distress syndrome: from mechanism to translation. Journal of Immunology 194 (3): 855–860. https://doi.org/10.4049/jimmunol.1402513.

    Article  CAS  Google Scholar 

  12. Harris, J., M. Hartman, C. Roche, S.G. Zeng, A. O'Shea, F.A. Sharp, E.M. Lambe, E.M. Creagh, D.T. Golenbock, J. Tschopp, H. Kornfeld, K.A. Fitzgerald, and E.C. Lavelle. 2011. Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. The Journal of Biological Chemistry 286 (11): 9587–9597. https://doi.org/10.1074/jbc.M110.202911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hu, Y., J. Lou, Y.Y. Mao, T.W. Lai, L.Y. Liu, C. Zhu, C. Zhang, J. Liu, Y.Y. Li, F. Zhang, W. Li, S.M. Ying, Z.H. Chen, and H.H. Shen. 2016. Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury. Autophagy 12 (12): 2286–2299. https://doi.org/10.1080/15548627.2016.1230584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huang, L., C. Hu, H. Cao, X. Wu, R. Wang, H. Lu, H. Li, and H. Chen. 2018. MicroRNA-29c increases the chemosensitivity of pancreatic cancer cells by inhibiting USP22 mediated autophagy. Cellular Physiology and Biochemistry 47 (2): 747–758. https://doi.org/10.1159/000490027.

    Article  CAS  PubMed  Google Scholar 

  15. Jeong, J.K., and S.Y. Park. 2015. Neuroprotective effect of cellular prion protein (PrPC) is related with activation of alpha7 nicotinic acetylcholine receptor (alpha7nAchR)-mediated autophagy flux. Oncotarget 6 (28): 24660–24674. https://doi.org/10.18632/oncotarget.4953.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jiang, Y., A. Dai, Y. Zhou, G. Peng, G. Hu, B. Li, J.S. Sham, and P. Ran. 2014. Nicotine elevated intracellular Ca(2)(+) in rat airway smooth muscle cells via activating and up-regulating alpha7-nicotinic acetylcholine receptor. Cellular Physiology and Biochemistry 33 (2): 389–401. https://doi.org/10.1159/000356678.

    Article  CAS  PubMed  Google Scholar 

  17. Jiang, Y., M. Gao, W. Wang, Y. Lang, Z. Tong, K. Wang, H. Zhang, G. Chen, M. Liu, Y. Yao, and X. Xiao. 2015. Sinomenine hydrochloride protects against polymicrobial sepsis via autophagy. International Journal of Molecular Sciences 16 (2): 2559–2573. https://doi.org/10.3390/ijms16022559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kilbride, S.M., and J.H. Prehn. 2013. Central roles of apoptotic proteins in mitochondrial function. Oncogene 32 (22): 2703–2711. https://doi.org/10.1038/onc.2012.348.

    Article  CAS  PubMed  Google Scholar 

  19. Kundu, M., and C.B. Thompson. 2005. Macroautophagy versus mitochondrial autophagy: a question of fate? Cell Death and Differentiation 12 (Suppl 2): 1484–1489. https://doi.org/10.1038/sj.cdd.4401780.

    Article  CAS  PubMed  Google Scholar 

  20. Levin, E.D., F.J. McClernon, and A.H. Rezvani. 2006. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology 184 (3–4): 523–539. https://doi.org/10.1007/s00213-005-0164-7.

    Article  CAS  PubMed  Google Scholar 

  21. Li, X.W., and H. Wang. 2006. Non-neuronal nicotinic alpha 7 receptor, a new endothelial target for revascularization. Life Sciences 78 (16): 1863–1870. https://doi.org/10.1016/j.lfs.2005.08.031.

    Article  CAS  PubMed  Google Scholar 

  22. Li, Z.Y., Y.F. Wu, X.C. Xu, J.S. Zhou, Y. Wang, H.H. Shen, and Z.H. Chen. 2017. Autophagy as a double-edged sword in pulmonary epithelial injury: a review and perspective. American Journal of Physiology. Lung Cellular and Molecular Physiology 313 (2): L207–L217. https://doi.org/10.1152/ajplung.00562.2016.

    Article  PubMed  Google Scholar 

  23. Lin, C.W., S. Lo, C. Hsu, C.H. Hsieh, Y.F. Chang, B.S. Hou, Y.H. Kao, C.C. Lin, M.L. Yu, S.S. Yuan, and Y.C. Hsieh. 2014. T-cell autophagy deficiency increases mortality and suppresses immune responses after sepsis. PLoS One 9 (7): e102066. https://doi.org/10.1371/journal.pone.0102066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu, H., Y.M. Yao, Y. Yu, N. Dong, H.N. Yin, and Z.Y. Sheng. 2007. Role of Janus kinase/signal transducer and activator of transcription pathway in regulation of expression and inflammation-promoting activity of high mobility group box protein 1 in rat peritoneal macrophages. Shock 27 (1): 55–60. https://doi.org/10.1097/01.shk.0000233197.40989.31.

    Article  CAS  PubMed  Google Scholar 

  25. Liu, Y., X. Zeng, Y. Hui, C. Zhu, J. Wu, D.H. Taylor, J. Ji, W. Fan, Z. Huang, and J. Hu. 2015. Activation of alpha7 nicotinic acetylcholine receptors protects astrocytes against oxidative stress-induced apoptosis: implications for Parkinson’s disease. Neuropharmacology 91: 87–96. https://doi.org/10.1016/j.neuropharm.2014.11.028.

    Article  CAS  PubMed  Google Scholar 

  26. Lo, S., S.S. Yuan, C. Hsu, Y.J. Cheng, Y.F. Chang, H.W. Hsueh, P.H. Lee, and Y.C. Hsieh. 2013. Lc3 over-expression improves survival and attenuates lung injury through increasing autophagosomal clearance in septic mice. Annals of Surgery 257 (2): 352–363. https://doi.org/10.1097/SLA.0b013e318269d0e2.

    Article  PubMed  Google Scholar 

  27. Lorne, E., X. Zhao, J.W. Zmijewski, G. Liu, Y.J. Park, Y. Tsuruta, and E. Abraham. 2009. Participation of mammalian target of rapamycin complex 1 in Toll-like receptor 2- and 4-induced neutrophil activation and acute lung injury. American Journal of Respiratory Cell and Molecular Biology 41 (2): 237–245. https://doi.org/10.1165/rcmb.2008-0290OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Marquez, R.T., and L. Xu. 2012. Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch. American Journal of Cancer Research 2 (2): 214–221.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Nakahira, K., J.A. Haspel, V.A. Rathinam, S.J. Lee, T. Dolinay, H.C. Lam, J.A. Englert, et al. 2011. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nature Immunology 12 (3): 222–230. https://doi.org/10.1038/ni.1980.

    Article  CAS  PubMed  Google Scholar 

  30. Okajima, K. 2008. Regulation of inflammatory responses by endothelial cells--understanding the molecular mechanism(s) and its therapeutic application to sepsis. Masui 57 (3): 311–320.

    PubMed  Google Scholar 

  31. Phua, J., J.R. Badia, N.K. Adhikari, J.O. Friedrich, R.A. Fowler, J.M. Singh, D.C. Scales, et al. 2009. Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review. American Journal of Respiratory and Critical Care Medicine 179 (3): 220–227. https://doi.org/10.1164/rccm.200805-722OC.

    Article  PubMed  Google Scholar 

  32. Pinelli, V., C.L. Marchica, and M.S. Ludwig. 2009. Allergen-induced asthma in C57Bl/6 mice: hyper-responsiveness, inflammation and remodelling. Respiratory Physiology & Neurobiology 169 (1): 36–43. https://doi.org/10.1016/j.resp.2009.08.005.

    Article  Google Scholar 

  33. Ren, C., H. Zhang, T.T. Wu, and Y.M. Yao. 2017. Autophagy: a potential therapeutic target for reversing sepsis-induced immunosuppression. Frontiers in Immunology 8: 1832. https://doi.org/10.3389/fimmu.2017.01832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ren, C., X.H. Li, S.B. Wang, L.X. Wang, N. Dong, Y. Wu, and Y.M. Yao. 2018. Activation of central alpha 7 nicotinic acetylcholine receptor reverses suppressed immune function of T lymphocytes and protects against sepsis lethality. International Journal of Biological Sciences 14 (7): 748–759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Romanov, J., M. Walczak, I. Ibiricu, S. Schuchner, E. Ogris, C. Kraft, and S. Martens. 2012. Mechanism and functions of membrane binding by the Atg5-Atg12/Atg16 complex during autophagosome formation. The EMBO Journal 31 (22): 4304–4317. https://doi.org/10.1038/emboj.2012.278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Salminen, A., K. Kaarniranta, and A. Kauppinen. 2013. Beclin 1 interactome controls the crosstalk between apoptosis, autophagy and inflammasome activation: impact on the aging process. Ageing Research Reviews 12 (2): 520–534. https://doi.org/10.1016/j.arr.2012.11.004.

    Article  CAS  PubMed  Google Scholar 

  37. Sanchez-Valle, V., N.C. Chavez-Tapia, M. Uribe, and N. Mendez-Sanchez. 2012. Role of oxidative stress and molecular changes in liver fibrosis: a review. Current Medicinal Chemistry 19 (28): 4850–4860.

    Article  CAS  PubMed  Google Scholar 

  38. Slimen, I.B., T. Najar, A. Ghram, H. Dabbebi, M. Ben Mrad, and M. Abdrabbah. 2014. Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review. Int J Hyperthermia 30 (7): 513–523. https://doi.org/10.3109/02656736.2014.971446.

    Article  CAS  PubMed  Google Scholar 

  39. Su, X., J.W. Lee, Z.A. Matthay, G. Mednick, T. Uchida, X. Fang, N. Gupta, and M.A. Matthay. 2007. Activation of the alpha7 nAChR reduces acid-induced acute lung injury in mice and rats. American Journal of Respiratory Cell and Molecular Biology 37 (2): 186–192. https://doi.org/10.1165/rcmb.2006-0240OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Thomsen, M.S., H.H. Hansen, D.B. Timmerman, and J.D. Mikkelsen. 2010. Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Current Pharmaceutical Design 16 (3): 323–343.

    Article  CAS  PubMed  Google Scholar 

  41. Tracey, K.J. 2007. Physiology and immunology of the cholinergic antiinflammatory pathway. The Journal of Clinical Investigation 117 (2): 289–296. https://doi.org/10.1172/JCI30555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tsuneki, H., R. Klink, C. Lena, H. Korn, and J.P. Changeux. 2000. Calcium mobilization elicited by two types of nicotinic acetylcholine receptors in mouse substantia nigra pars compacta. The European Journal of Neuroscience 12 (7): 2475–2485.

    Article  CAS  PubMed  Google Scholar 

  43. Wang, H., H. Liao, M. Ochani, M. Justiniani, X. Lin, L. Yang, Y. Al-Abed, et al. 2004. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Medicine 10 (11): 1216–1221. https://doi.org/10.1038/nm1124.

    Article  CAS  PubMed  Google Scholar 

  44. Wu, M., T. Sherwin, W.L. Brown, and P.G. Stockley. 2005. Delivery of antisense oligonucleotides to leukemia cells by RNA bacteriophage capsids. Nanomedicine 1 (1): 67–76. https://doi.org/10.1016/j.nano.2004.11.011.

    Article  CAS  PubMed  Google Scholar 

  45. Yang, R., L. Yang, X. Shen, W. Cheng, B. Zhao, K.H. Ali, Z. Qian, and H. Ji. 2012. Suppression of NF-kappaB pathway by crocetin contributes to attenuation of lipopolysaccharide-induced acute lung injury in mice. European Journal of Pharmacology 674 (2–3): 391–396. https://doi.org/10.1016/j.ejphar.2011.08.029.

    Article  CAS  PubMed  Google Scholar 

  46. Yen, Y.T., H.R. Yang, H.C. Lo, Y.C. Hsieh, S.C. Tsai, C.W. Hong, and C.H. Hsieh. 2013. Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury. Surgery 153 (5): 689–698. https://doi.org/10.1016/j.surg.2012.11.021.

    Article  PubMed  Google Scholar 

  47. Zapelini, P.H., G.T. Rezin, M.R. Cardoso, C. Ritter, F. Klamt, J.C. Moreira, E.L. Streck, and F. Dal-Pizzol. 2008. Antioxidant treatment reverses mitochondrial dysfunction in a sepsis animal model. Mitochondrion 8 (3): 211–218. https://doi.org/10.1016/j.mito.2008.03.002.

    Article  CAS  PubMed  Google Scholar 

  48. Zhang, Qichun, Ying Lu, Huimin Bian, Liwei Guo, and Huaxu Zhu. 2017. Activation of the α7 nicotinic receptor promotes lipopolysaccharide-induced conversion of M1 microglia to M2. American Journal of Translational Research 9 (3): 971–985.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhaohui, Du, Yanlin Wang, and Li Jianguo. 2007. Effect of electrical stimulation of efferent vagus nerve on acute lung injury in septic shock rats. Chinese Journal of Experimental Surgery 24 (9): 1096–1098.

    Google Scholar 

  50. Zhaohui, Fu, Yuan Yu, Yuan Shiying, and Shanglong Yao. 2015. a7 nicotinic acetylcholine receptor mediates lipopolysaccharide-induced inflammatory response in the mouse macrophages. Chinese Journal of Experimental Surgery 32 (12): 3082–3085.

    Google Scholar 

  51. Zhu, H., and L. He. 2015. Beclin 1 biology and its role in heart disease. Current Cardiology Reviews 11 (3): 229–237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhu, Y., L. Zhao, L. Liu, P. Gao, W. Tian, X. Wang, H. Jin, H. Xu, and Q. Chen. 2010. Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis. Protein & Cell 1 (5): 468–477. https://doi.org/10.1007/s13238-010-0048-4.

    Article  CAS  Google Scholar 

  53. Zia, S., A. Ndoye, V.T. Nguyen, and S.A. Grando. 1997. Nicotine enhances expression of the alpha 3, alpha 4, alpha 5, and alpha 7 nicotinic receptors modulating calcium metabolism and regulating adhesion and motility of respiratory epithelial cells. Research Communications in Molecular Pathology and Pharmacology 97 (3): 243–262.

    CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Xin Zhao, Zhizhong Yu and Zheng Lv contributed equally to this work.

Authors and Affiliations

  1. Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Jiefang Avenue, Wuhan, Hubei, People’s Republic of China

    Xin Zhao, Zhizhong Yu, Zheng Lv, Lei Meng, Jiaxin Xu, Shiying Yuan & Zhaohui Fu

  2. Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Xin Zhao, Zhizhong Yu, Zheng Lv, Lei Meng, Jiaxin Xu, Shiying Yuan & Zhaohui Fu

Authors
  1. Xin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhizhong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zheng Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lei Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiaxin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shiying Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhaohui Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhaohui Fu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, X., Yu, Z., Lv, Z. et al. Activation of Alpha-7 Nicotinic Acetylcholine Receptors (α7nAchR) Promotes the Protective Autophagy in LPS-Induced Acute Lung Injury (ALI) In Vitro and In Vivo. Inflammation 42, 2236–2245 (2019). https://doi.org/10.1007/s10753-019-01088-w

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-019-01088-w

KEY WORDS

Search

Navigation