Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

Liu,Tie; Wu,Bin; Wang,Yahong; He,Huijuan; Lin,Ziying; Tan,Jianxin; Yang,Lawei; Kamp,David  W.; Zhou,Xu; Tang,Jinfeng; Huang,Haili; Zhang,Liangqing; Bin,Liu; Liu,Gang

doi:10.3892/mmr.2015.3577

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

Authors:
- Tie Liu
- Bin Wu
- Yahong Wang
- Huijuan He
- Ziying Lin
- Jianxin Tan
- Lawei Yang
- David W. Kamp
- Xu Zhou
- Jinfeng Tang
- Haili Huang
- Liangqing Zhang
- Liu Bin
- Gang Liu
View Affiliations

Affiliations: Clinical Research Center, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China, Department of Respiratory Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine and Jesse Brown VA Medical Center, Chicago, IL 60611, USA, Department of Immunology and Tumor Research Institute, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shanxi 710061, P.R. China
Published online on: March 31, 2015 https://doi.org/10.3892/mmr.2015.3577
Pages: 1914-1922

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Particulate matter 2.5 (PM2.5) is a significant risk factor for asthma. A recent study revealed that autophagy was associated with asthma pathogenesis. However, the specific mechanisms underlying PM2.5‑induced autophagy in asthma have remained elusive. In the present study, PM2.5‑induced autophagy was evaluated in Beas‑2B human bronchial epithelial cells and the potential molecular mechanisms were investigated. Using electron microscopy, immunofluorescence staining and immunoblot studies, it was confirmed that PM2.5 induced autophagy in Beas‑2B cells as a result of PM2.5‑mediated inhibition of the phosphatidylinositol 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in Beas‑2B cells. LY294002, a PI3K inhibitor, reduced the accumulation of microtubule‑associated protein 1 light chain 3 II and attenuated the effect of PM2.5. Phosphorylated (p‑)p38, p‑extracellular signal‑regulated kinase and p‑c‑Jun N‑terminal kinase were dephosphorylated following exposure to PM2.5. The roles of p53, reactive oxygen species scavenger tetramethylthiourea and autophagy inhibitor 3‑methyladenine in PM2.5‑induced autophagy in Beas‑2B cells were also investigated. The results suggested that the PI3K/Akt/mTOR signaling pathway may be a key contributor to PM2.5‑induced autophagy in Beas‑2B cells. The results of the present study therefore provided an a insight into potential future clinical applications targeting these signaling pathways, for the prevention and/or treatment of PM2.5‑induced lung diseases.

View Figures

View References

1	Zanobetti A, Franklin M, Koutrakis P and Schwartz J: Fine particulate air pollution and its components in association with cause-specific emergency admissions. Environ Health. 8:582009. View Article : Google Scholar : PubMed/NCBI
2	Delfino RJ, Sioutas C and Malik S: Potential role of ultrafine particles in associations between airborne particle mass and cardiovascular health. Environ Health Perspect. 113:934–946. 2005. View Article : Google Scholar : PubMed/NCBI
3	Dockery DW, Pope CA III, Xu X, et al: An association between air pollution and mortality in six U.S. cities. N Engl J Med. 329:1753–1759. 1993. View Article : Google Scholar : PubMed/NCBI
4	Trejo Bittar HE, Yousem SA and Wenzel SE: Pathobiology of severe asthma. Annu Rev Pathol. 10:511–545. 2015. View Article : Google Scholar
5	Mehta M, Chen LC, Gordon T, Rom W and Tang MS: Particulate matter inhibits DNA repair and enhances mutagenesis. Mutat Res. 657:116–121. 2008. View Article : Google Scholar : PubMed/NCBI
6	Nordling E, Berglind N, Melén E, et al: Traffic-related air pollution and childhood respiratory symptoms, function and allergies. Epidemiology. 19:401–408. 2008. View Article : Google Scholar : PubMed/NCBI
7	Anderson HR, Favarato G and Atkinson RW: Long-term exposure to air pollution and the incidence of asthma: meta-analysis of cohort studies. Air Qual Atmos Health. 6:47–56. 2013. View Article : Google Scholar
8	Zeng Y, Yang X, Wang J, Fan J, Kong Q and Yu X: Aristolochic acid I induced autophagy extenuates cell apoptosis via ERK 1/2 pathway in renal tubular epithelial cells. PloS One. 7:e303122012. View Article : Google Scholar : PubMed/NCBI
9	Poon AH, Chouiali F, Tse SM, et al: Genetic and histologic evidence for autophagy in asthma pathogenesis. J Allergy Clin Immunol. 129:569–571. 2012. View Article : Google Scholar :
10	Maiuri MC, Galluzzi L, Morselli E, Kepp O, Malik SA and Kroemer G: Autophagy regulation by p53. Curr Opin Cell Biol. 22:181–185. 2010. View Article : Google Scholar : PubMed/NCBI
11	Glick D, Barth S and Macleod KF: Autophagy: cellular and molecular mechanisms. J Pathol. 221:3–12. 2010. View Article : Google Scholar : PubMed/NCBI
12	Akhtar S, Yousif MH, Chandrasekhar B and Benter IF: Activation of EGFR/ERBB2 via pathways involving ERK1/2, P38 MAPK, AKT and FOXO enhances recovery of diabetic hearts from ischemia-reperfusion injury. PloS One. 7:e390662012. View Article : Google Scholar : PubMed/NCBI
13	Soberanes S, Panduri V, Mutlu GM, Ghio A, Bundinger GR and Kamp DW: p53 mediates particulate matter-induced alveolar epithelial cell mitochondria-regulated apoptosis. Am J Respir Crit Care Med. 174:1229–1238. 2006. View Article : Google Scholar : PubMed/NCBI
14	Lin Z, Liu T, et al: AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy. Free Radic Biol Med. 72:296–307. 2014. View Article : Google Scholar : PubMed/NCBI
15	Yang L, Liu G, Lin Z, et al: Pro-inflammatory response and oxidative stress induced by specific components in ambient particulate matter in human bronchial epithelial cells. Environ Toxicol. Dec 23–2014.Epub ahead of print. View Article : Google Scholar
16	Wiltfang J, Smirnov A, Schnierstein B, et al: Improved electrophoretic separation and immunoblotting of beta-amyloid (A beta) peptides 1–40, 1–42, and 1–43. Electrophoresis. 18:527–532. 1997. View Article : Google Scholar : PubMed/NCBI
17	Zhou C, Zhong W, Zhou J, et al: Monitoring autophagic flux by an improved tandem fluorescent-tagged LC3 (mTagRFP-mWasabi-LC3) reveals that high-dose rapamycin impairs autophagic flux in cancer cells. Autophagy. 8:1215–1226. 2012. View Article : Google Scholar : PubMed/NCBI
18	Bolster DR, Crozier SJ, Kimball SR and Jefferson LS: AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem. 277:23977–23980. 2002. View Article : Google Scholar : PubMed/NCBI
19	Corcelle EA, Puustinen P and Jäättelä M: Apoptosis and autophagy: Targeting autophagy signalling in cancer cells – ‘trick or treats’? FEBS J. 276:6084–6096. 2009. View Article : Google Scholar : PubMed/NCBI
20	Jung CH, Ro SH, Cao J, Otto NM and Kim DH: mTOR regulation of autophagy. FEBS Lett. 584:1287–1295. 2010. View Article : Google Scholar : PubMed/NCBI
21	Codogno P and Meijer AJ: Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ. 12(Suppl 2): 1509–1518. 2005. View Article : Google Scholar : PubMed/NCBI
22	Roy B, Pattanaik AK, Das J, et al: Role of PI3K/Akt/mTOR and MEK/ERK pathway in Concanavalin A induced autophagy in HeLa cells. Chem Biol Interact. 210:96–102. 2014. View Article : Google Scholar : PubMed/NCBI
23	Hamamura K, Goldring MB and Yokota H: Involvement of p38 MAPK in regulation of MMP13 mRNA in chondrocytes in response to surviving stress to endoplasmic reticulum. Arch Oral Biol. 54:279–286. 2009. View Article : Google Scholar :
24	Dougherty R and Fahy JV: Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clin Exp Allergy. 39:193–202. 2009. View Article : Google Scholar : PubMed/NCBI
25	Delfino RJ, Wu J, Tjoa T, Gullesserian SK, Nickerson B and Gillen DL: Asthma morbidity and ambient air pollution: effect modification by residential traffic-related air pollution. Epidemiology. 25:48–57. 2014. View Article : Google Scholar
26	Jyothula SS and Eissa NT: Autophagy and role in asthma. Curr Opin Pulm Med. 19:30–35. 2013. View Article : Google Scholar
27	Martin LJ, Gupta J, Jyothula SS, et al: Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma. PLoS One. 7:e334542012. View Article : Google Scholar : PubMed/NCBI
28	Poon A, Eidelman D, Laprise C and Hamid Q: ATG5, autophagy and lung function in asthma. Autophagy. 8:694–695. 2012. View Article : Google Scholar : PubMed/NCBI
29	Albert L, Karsy M, Murali R and Jhanwar-Uniyal M: Inhibition of mTOR activates the MAPK pathway in glioblastoma multiforme. Cancer Genomics Proteomics. 6:255–261. 2009.PubMed/NCBI
30	Hazzalin CA and Mahadevan LC: MAPK-regulated transcription: a continuously variable gene switch? Nat Rev Mol Cell Biol. 3:30–40. 2002. View Article : Google Scholar : PubMed/NCBI
31	Webber JL and Tooze SA: Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP. EMBO J. 29:27–40. 2010. View Article : Google Scholar :
32	de la Cruz-Morcillo MA, Valero ML, Callejas-Valera JL, et al: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance. Oncogene. 31:1073–1085. 2012. View Article : Google Scholar
33	Brigelius-Flohé R: Commentary: oxidative stress reconsidered. Genes Nutr. 4:161–163. 2009. View Article : Google Scholar : PubMed/NCBI
34	Cheng Y, Qiu F, Tashiro S, Onodera S and Ikejima T: ERK and JNK mediate TNFalpha-induced p53 activation in apoptotic and autophagic L929 cell death. Biochem Biophys Res Commun. 376:483–488. 2008. View Article : Google Scholar : PubMed/NCBI
35	Kabesch M and Adcock IM: Epigenetics in asthma and COPD. Biochimie. 94:2231–2241. 2012. View Article : Google Scholar : PubMed/NCBI
36	Urich D, Soberanes S, Burgess Z, et al: Proapoptotic Noxa is required for particulate matter-induced cell death and lung inflammation. FASEB J. 23:2055–2064. 2009. View Article : Google Scholar : PubMed/NCBI
37	McCarthy N: Autophagy: Directed development. Nat Rev Cancer. 14:74–75. 2014. View Article : Google Scholar : PubMed/NCBI
38	Green DR and Kroemer G: Cytoplasmic functions of the tumour suppressor p53. Nature. 458:1127–1130. 2009. View Article : Google Scholar : PubMed/NCBI
39	Kim MN, Lee KE, Hong JY, et al: Involvement of the MAPK and PI3K pathways in chitinase 3-like 1-regulated hyperoxia-induced airway epithelial cell death. Biochem Biophys Res Commun. 421:790–796. 2012. View Article : Google Scholar : PubMed/NCBI
40	Takada E, Furuhata M, Nakae S, Ichijo H, Sudo K and Mizuguchi J: Requirement of apoptosis-inducing kinase 1 for the induction of bronchial asthma following stimulation with ovalbumin. Int Arch Allergy Immunol. 162:104–114. 2013. View Article : Google Scholar : PubMed/NCBI