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Visfatin Plays a Significant Role in Alleviating Lipopolysaccharide-Induced Apoptosis and Autophagy Through PI3K/AKT Signaling Pathway During Acute Lung Injury in Mice

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Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Visfatin is involved in the body’s inflammation and immune response. Inflammation could promote, while visfatin may directly or indirectly mitigate the effects of apoptosis and autophagy. Whether visfatin lessens the detrimental effects of lipopolysaccharide (LPS)-induced mouse acute lung injury (ALI) is poorly understood yet. Therefore, in the current study, the regulation mechanism of visfatin on apoptosis and autophagy was explored in Kunming mice by replicating LPS-induced inflammatory ALI model. Based on the mouse model of ALI, HE staining, TUNEL, transmission electron microscopy, immunohistochemical staining, real-time fluorescence quantitative PCR and western blot were used and the results showed that the alveolar septum was thinner than that of the LPS group, slight lung interstitial and alveolar exudation appeared, and a small number of inflammatory cell infiltration was found in the visfatin intervention group, indicating reduced tissue damage in lungs. After visfatin treatment, the expression of pro-apoptotic genes Bax, Bik, and p53 decreased and the expression of anti-apoptotic genes Bcl-2 and Bcl-xl increased, and expression of autophagy factors LC3 and Beclin1 decreased, indicating that visfatin inhibits apoptosis and reduces autophagy. The expression of PI3K and p-AKT was upregulated in the visfatin intervention group, the expression of AKT was downregulated, and the PI3K/AKT signaling pathway was activated. Hence, visfatin could activate the PI3K/AKT signaling pathway, reduce the apoptotic rate in alveolar epithelial cells and the level of autophagy in ALI by regulating the expression of autophagy factors, ultimately causing a protective effect on lung tissue.

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References

  • Adya R, Tan BK, Punn A et al (2008) Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis. Cardiovasc Res 78:356–365

    Article  CAS  PubMed  Google Scholar 

  • Ashkenazi A, Fairbrother WJ, Leverson JD et al (2017) From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov 16:273–284

    Article  CAS  PubMed  Google Scholar 

  • Bao S, Wang Y, Sweeney P et al (2005) Keratinocyte growth factor induces Akt kinase activity and inhibits Fas-mediated apoptosis in A549 lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 288:L36–L42

    Article  CAS  PubMed  Google Scholar 

  • Bi TQ, Che XM (2010) Nampt/PBEF/visfatin and cancer. Cancer Biol Ther 10:119–125

    Article  CAS  PubMed  Google Scholar 

  • Brunet A, Bonni A, Zigmond MJ et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868

    Article  CAS  PubMed  Google Scholar 

  • Caroppi P, Sinibaldi F, Fiorucci L et al (2009) Apoptosis and human diseases: mitochondrion damage and lethal role of released cytochrome c as proapoptotic protein. Curr Med Chem 16:4058–4065

    Article  CAS  PubMed  Google Scholar 

  • Chen T, Mou Y, Tan J et al (2015) The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol 25:55–64

    Article  CAS  PubMed  Google Scholar 

  • Crapo JD (1986) Morphologic changes in pulmonary oxygen toxicity. Annu Rev Physiol 48:721–731

    Article  CAS  PubMed  Google Scholar 

  • Crighton D, Wilkinson S, O’Prey J et al (2006) DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126:121–134

    Article  CAS  PubMed  Google Scholar 

  • Czabotar PE, Lessene G, Strasser A et al (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63

    Article  CAS  PubMed  Google Scholar 

  • Doherty J, Baehrecke EH (2018) Life, death and autophagy. Nat Cell Biol 20:1110–1117

    Article  CAS  PubMed  Google Scholar 

  • Eisenberg-Lerner A, Bialik S, Simon HU et al (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16:966–975

    Article  CAS  PubMed  Google Scholar 

  • Emani S, Ramlawi B, Sodha NR et al (2009) Increased vascular permeability after cardiopulmonary bypass in patients with diabetes is associated with increased expression of vascular endothelial growth factor and hepatocyte growth factor. J Thorac Cardiovasc Surg 138:185–191

    Article  PubMed  PubMed Central  Google Scholar 

  • Erfani S, Aboutaleb N, Oryan S et al (2015) Visfatin inhibits apoptosis and necrosis of hippocampus CA3 cells following transient global ischemia/reperfusion in rats. Int J Pept Res Ther 21:223–228

    Article  CAS  Google Scholar 

  • Eskelinen EL (2008) To be or not to be? Examples of incorrect identification of autophagic compartments in conventional transmission electron microscopy of mammalian cells. Autophagy 4:257–260

    Article  PubMed  Google Scholar 

  • Feng X, Jia A (2014) Protective effect of carvacrol on acute lung injury induced by lipopolysaccharide in mice. Inflammation 37:1091–1101

    Article  CAS  PubMed  Google Scholar 

  • Ferrara N, Gerber H-P, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  CAS  PubMed  Google Scholar 

  • Gao W, Shen Z, Shang L et al (2011) Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor p53 contributes to DNA-damage-induced cell death. Cell Death Differ 18:1598–1607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Griet M, Zelaya H, Mateos MV et al (2014) Soluble factors from Lactobacillus reuteri CRL1098 have anti-inflammatory effects in acute lung injury induced by lipopolysaccharide in mice. PLoS One 9:e110027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo Q, Jin J, Yuan JX et al (2011) VEGF, Bcl-2 and Bad regulated by angiopoietin-1 in oleic acid induced acute lung injury. Biochem Biophys Res Commun 413:630–636

    Article  CAS  PubMed  Google Scholar 

  • Haupt S, Berger M, Goldberg Z et al (2003) Apoptosis—the p53 network. J Cell Sci 116:4077–4085

    Article  CAS  PubMed  Google Scholar 

  • Henshall DC, Araki T, Schindler CK et al (2002) Activation of Bcl-2-associated death protein and counter-response of Akt within cell populations during seizure-induced neuronal death. J Neurosci 22:8458–8465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itakura E, Mizushima N (2009) Atg14 and UVRAG: mutually exclusive subunits of mammalian Beclin 1-PI3K complexes. Autophagy 5:534–536

    Article  CAS  PubMed  Google Scholar 

  • Jia SH, Li Y, Parodo J et al (2004) Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis. J Clin Investig 113:1318–1327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jieyu H, Chao T, Mengjun L et al (2012) Nampt/Visfatin/PBEF: a functionally multi-faceted protein with a pivotal role in malignant tumors. Curr Pharm Des 18:6123–6132

    Article  PubMed  Google Scholar 

  • Jin S, Levine AJ (2001) The p53 functional circuit. J Cell Sci 114(Pt 23):4139–4140

    CAS  PubMed  Google Scholar 

  • Kang R, Zeh H, Lotze M et al (2011) The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 18:571–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ke HL, Lin HH, Li WM et al (2015) High visfatin expression predicts poor prognosis of upper tract urothelial carcinoma patients. Am J Cancer Res 5:2447–2454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levine AJ, Feng Z, Mak TW et al (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20:267–275

    Article  CAS  PubMed  Google Scholar 

  • Li G, Zhou C, Zhou Q et al (2016) Galantamine protects against lipopolysaccharide-induced acute lung injury in rats. Braz J Med Biol Res 49:e5008

    CAS  PubMed  Google Scholar 

  • Li DX, Hu HY, Li G et al (2017) Calcium controls the formation of vacuoles from mitochondria to regulate microspore development in wheat. Plant Reprod 30:131–139

    Article  CAS  PubMed  Google Scholar 

  • Lim SY, Davidson SM, Paramanathan AJ et al (2008) The novel adipocytokine visfatin exerts direct cardioprotective effects. J Cell Mol Med 12:1395–1403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu F, Sun GQ, Gao HY et al (2013) Angelicin regulates LPS-induced inflammation via inhibiting MAPK/NF-κB pathways. J Surg Res 185:300–309

    Article  CAS  PubMed  Google Scholar 

  • Lockshin RA, Zakeri Z (2004) Apoptosis, autophagy, and more. Int J Biochem Cell Biol 36:2405–2419

    Article  CAS  PubMed  Google Scholar 

  • Luk T, Malam Z, Marshall JC (2008) Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity. J Leukoc Biol 83:804–816

    Article  CAS  PubMed  Google Scholar 

  • Maiuri MC, Zalckvar E, Kimchi A et al (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8:741–752

    Article  CAS  PubMed  Google Scholar 

  • Maloney JP, Ambruso DR, Voelkel NF et al (2014) Platelet vascular endothelial growth factor is a potential mediator of transfusion-related acute lung injury. J Pulm Respir Med 4:212. https://doi.org/10.4172/2161-105X.1000212

    Article  Google Scholar 

  • Martin TR, Nakamura M, Matute-Bello G (2003) The role of apoptosis in acute lung injury. Crit Care Med 31(4 Suppl):S184–S188

    Article  PubMed  Google Scholar 

  • Meijer AJ, Codogno P (2004) Regulation and role of autophagy in mammalian cells. Int J Biochem Cell Biol 36:2445–2462

    Article  CAS  PubMed  Google Scholar 

  • Mizushima N, Levine B, Cuervo AM et al (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132

    Article  CAS  PubMed  Google Scholar 

  • Moll UM, Wolff S, Speidel D et al (2005) Transcription-independent pro-apoptotic functions of p53. Curr Opin Cell Biol 17:631–636

    Article  CAS  PubMed  Google Scholar 

  • Moloney ED, Griffiths MJD (2004) Protective ventilation of patients with acute respiratory distress syndrome. Br J Anaesth 92:261–270

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay S, Panda PK, Sinha N et al (2014) Autophagy and apoptosis: where do they meet? Apoptosis 19:555–566

    Article  CAS  PubMed  Google Scholar 

  • Mura M, Santos CCd, Stewart D et al (2004) Vascular endothelial growth factor and related molecules in acute lung injury. J Appl Physiol 97:1605–1617

    Article  CAS  PubMed  Google Scholar 

  • Okuda S, Sherman DJ, Silhavy TJ et al (2016) Lipopolysaccharide transport and assembly at the outer membrane: the PEZ model. Nat Rev Microbiol 14:337–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orfanos SE, Mavrommati I, Korovesi I et al (2004) Pulmonary endothelium in acute lung injury: from basic science to the critically ill. Intensive Care Med 30:1702–1714

    Article  CAS  PubMed  Google Scholar 

  • Ouyang L, Shi Z, Zhao S et al (2012) Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 45:487–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parekh D, Dancer RC, Thickett DR (2011) Acute lung injury. Clin Med 11:615–618

    Article  Google Scholar 

  • Pattingre S, Levine B (2006) Bcl-2 inhibition of autophagy: a new route to cancer? Cancer Res 66:2885–2888

    Article  CAS  PubMed  Google Scholar 

  • Pattingre S, Tassa A, Qu X et al (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927–939

    Article  CAS  PubMed  Google Scholar 

  • Pohl-Schickinger A, Koehne P, Schmitz T et al (2010) Vascular endothelial growth factor and its soluble receptor in infants with congenital cardiac disease. Cardiol Young 20:505–508

    Article  PubMed  Google Scholar 

  • Qi D, He J, Wang D et al (2014) 17β-estradiol suppresses lipopolysaccharide-induced acute lung injury through PI3K/Akt/SGK1 mediated up-regulation of epithelial sodium channel (ENaC) in vivo and in vitro. Respir Res 15:159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reddy NM, Suryanaraya V, Yates MS et al (2009) The triterpenoid CDDO-imidazolide confers potent protection against hyperoxic acute lung injury in mice. Am J Respir Crit Care Med 180:867–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reutershan J, Saprito MS, Wu D et al (2010) Phosphoinositide 3-kinase γ required for lipopolysaccharide-induced transepithelial neutrophil trafficking in the lung. Eur Respir J 35:1137–1147

    Article  CAS  PubMed  Google Scholar 

  • Rzymski T, Milani M, Pike L et al (2010) Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene 29:4424–4435

    Article  CAS  PubMed  Google Scholar 

  • Schwechheimer C, Kuehn MJ (2015) Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat Rev Microbiol 13:605–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siddiqa A, Long LM, Li L et al (2008) Expression of HER-2 in MCF-7 breast cancer cells modulates anti-apoptotic proteins Survivin and Bcl-2 via the extracellular signal-related kinase (ERK) and phosphoinositide-3 kinase (PI3K) signalling pathways. BMC Cancer 8:129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sitarek P, Skała E, Toma M et al (2016) A preliminary study of apoptosis induction in glioma cells via alteration of the Bax/Bcl-2-p53 axis by transformed and non-transformed root extracts of Leonurus sibiricus L. Tumor Biol 37:8753–8764

    Article  CAS  Google Scholar 

  • Sonoli S, Shivprasad S, Prasad C et al (2011) Visfatin—a review. Eur Rev Med Pharmacol Sci 15:9–14

    CAS  PubMed  Google Scholar 

  • Sun Z, Lei H, Zhang Z (2013) Pre-B cell colony enhancing factor (PBEF), a cytokine with multiple physiological functions. Cytokine Growth Factor Rev 24:433–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tacar O, Sriamornsak P, Dass CR (2013) Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol 65:157–170

    Article  CAS  PubMed  Google Scholar 

  • Tanida I, Ueno T, Kominami E (2004) LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 36:2503–2518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Zheng X, Cheng Y et al (2014) Resolvin D1 stimulates alveolar fluid clearance through alveolar epithelial sodium channel, Na, K-ATPase via ALX/cAMP/PI3K pathway in lipopolysaccharide-induced acute lung injury. J Immunol 192:3765–3777

    Article  CAS  PubMed  Google Scholar 

  • Wu XT, Yang Z, Ansari AR et al (2018) Visfatin regulates the production of lipopolysaccharide-induced inflammatory cytokines through p38 signaling in murine macrophages. Microb Pathog 117:55–59

    Article  CAS  PubMed  Google Scholar 

  • Xiao K, Zou WH, Yang Z et al (2015) The role of visfatin on the regulation of inflammation and apoptosis in the spleen of LPS-treated rats. Cell Tissue Res 359:605–618

    Article  CAS  PubMed  Google Scholar 

  • Xin M, Deng X (2005) Nicotine inactivation of the proapoptotic function of Bax through phosphorylation. J Biol Chem 280:10781–10789

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Zeng Y, Li B et al (2015) Pre-B-cell colony enhancing factor (PBEF) increases endothelial permeability in hypoxia/re-oxygenation model. Int J Clin Exp Med 8:8842–8847

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yen YT, Yang HR, Lo HC et al (2013) Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury. Surgery 153:689–698

    Article  PubMed  Google Scholar 

  • Zhou Y, Yuan HR, Cui L et al (2017) Effects of visfatin on the apoptosis of intestinal mucosal cells in immunological stressed rats. Acta Histochem 119:26–31

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by National Natural Science Fund Project of China (no. 31772687) and Fundamental Research Funds for the Central Universities (no. 2662015PY063) and National Natural Science Fund Project of China (no. 31101776).

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Authors and Affiliations

  1. College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China

    Xin-Tong Wu, Xin-Xin Pang, Hui-Zhen Li, Zhe-Wei Zhang, You Luo & Hui Song

  2. Section of Anatomy and Histology, Department of Basic Sciences, College of Veterinary and Animal Sciences (CVAS) Jhang, University of Veterinary and Animal Sciences (UVAS), Lahore, Pakistan

    Abdur Rahman Ansari

  3. Section of Biochemistry, Department of Basic Sciences, College of Veterinary and Animal Sciences (CVAS) Jhang, University of Veterinary and Animal Sciences (UVAS), Lahore, Pakistan

    Muhammad Arshad

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  1. Xin-Tong Wu
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Wu, XT., Ansari, A.R., Pang, XX. et al. Visfatin Plays a Significant Role in Alleviating Lipopolysaccharide-Induced Apoptosis and Autophagy Through PI3K/AKT Signaling Pathway During Acute Lung Injury in Mice. Arch. Immunol. Ther. Exp. 67, 249–261 (2019). https://doi.org/10.1007/s00005-019-00544-7

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