Erythromycin attenuates oxidative stress-induced cellular senescence via the PI3K-mTOR signaling pathway in chronic obstructive pulmonary disease

Background and Purpose: Chronic obstructive pulmonary disease (COPD) is proposed to hasten lung aging. Erythromycin protects against oxidative stress and inflammatory responses. However, the potential anti-senescence effect of erythromycin remains disclosed. In the present study, we investigated whether erythromycin influenced oxidative stress-induced cellular senescence and investigated its related mechanisms. Methods: A cigarrete smoke (CS) -induced emphysema mouse model and a H2O2-induced premature senescence model in human bronchial epithelial cell line (BEAS-2B) were established. Senescence-related markers (P53, P21 and SA-β-Gal activity), and levels of oxidative stress biomarkers (MDA, SOD and ROS) were measured. Additionally, cells were pretreated with rapamycin (mTOR inhibitor) or erythromycin, and the expression levels of components of the PI3K-mTOR signaling pathway were measured in BEAS-2B cells. Results: Exposed to H2O2, increased SA-β-gal activity was observed in BEAS-2B cells suggesting premature senescence. Erythromycin inhibited the expression of P53 and P21 in the CS-induced emphysema mouse model. MDA levels significantly increased and SOD levels decreased in the CS-exposed mice and H2O2-induced BEAS-2B cells. Rapamycin and erythromycin significantly suppressed the expression of P53 and P21. Additionally, rapamycin and erythromycin inhibited the PI3K-mTOR signaling pathway. Conclusion: Our findings suggest that erythromycin ameliorates oxidative stress-induced cellular senescence via the PI3K-mTOR signaling pathway. Hence, we establish a theoretical foundation for the clinical application of erythromycin for COPD prevention and treatment.

[1]  E. Pace,et al.  Cellular and Molecular Signatures of Oxidative Stress in Bronchial Epithelial Cell Models Injured by Cigarette Smoke Extract , 2022, International journal of molecular sciences.

[2]  J. Travers,et al.  Creatine and Nicotinamide Prevent Oxidant-Induced Senescence in Human Fibroblasts , 2021, Nutrients.

[3]  Jianquan Zhang,et al.  Erythromycin inhibits cigarette smoke-induced inflammation through regulating the PPARγ/NF-κB signaling pathway in macrophages. , 2021, International immunopharmacology.

[4]  J. Bai,et al.  Histone Deacetylase 2 Suppresses Skeletal Muscle Atrophy and Senescence via NF-κB Signaling Pathway in Cigarette Smoke-Induced Mice with Emphysema , 2021, International journal of chronic obstructive pulmonary disease.

[5]  Sang-Hyug Park,et al.  Sargahydroquinoic acid (SHQA) suppresses cellular senescence through Akt/mTOR signaling pathway , 2021, Experimental Gerontology.

[6]  A. Sharpe,et al.  The aging lung: Physiology, disease, and immunity , 2021, Cell.

[7]  T. Takata,et al.  FK866 Protects Human Dental Pulp Cells against Oxidative Stress-Induced Cellular Senescence , 2021, Antioxidants.

[8]  Yanhong Gao,et al.  The p53/miR-145a Axis Promotes Cellular Senescence and Inhibits Osteogenic Differentiation by Targeting Cbfb in Mesenchymal Stem Cells , 2021, Frontiers in Endocrinology.

[9]  F. Martinez,et al.  Global Initiative for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease. The 2020 GOLD Science Committee Report on COVID-19 and Chronic Obstructive Pulmonary Disease , 2020, American journal of respiratory and critical care medicine.

[10]  W. Labaki,et al.  Chronic Obstructive Pulmonary Disease , 2020, Annals of Internal Medicine.

[11]  B. Kennedy,et al.  The quest to slow ageing through drug discovery , 2020, Nature Reviews Drug Discovery.

[12]  P. Barnes.  Oxidative stress-based therapeutics in COPD , 2020, Redox biology.

[13]  S. Cessie,et al.  Ageing, age-related diseases and oxidative stress: What to do next? , 2019, Ageing Research Reviews.

[14]  Yi Liang,et al.  Erythromycin reverses cigarette smoke extract-induced corticosteroid insensitivity by inhibition of the JNK/c-Jun pathway. , 2019, Free radical biology & medicine.

[15]  H. Stout-Delgado,et al.  Aging and Lung Disease. , 2019, Annual review of physiology.

[16]  Yi Liang,et al.  Erythromycin suppresses neutrophil extracellular traps in smoking-related chronic pulmonary inflammation , 2019, Cell Death & Disease.

[17]  P. Barnes,et al.  Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases. , 2019, American journal of respiratory and critical care medicine.

[18]  A. Bhushan,et al.  Activation of the mTORC1/PGC-1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium. , 2019, American journal of physiology. Lung cellular and molecular physiology.

[19]  A. Akha,et al.  Aging and the immune system: An overview. , 2018, Journal of immunological methods.

[20]  P. Maurya,et al.  Biomarkers of oxidative stress and protein–protein interaction in chronic obstructive pulmonary disease , 2018, Archives of physiology and biochemistry.

[21]  P. Abete,et al.  Oxidative stress, aging, and diseases , 2018, Clinical interventions in aging.

[22]  P. Validire,et al.  mTOR pathway activation drives lung cell senescence and emphysema. , 2018, JCI insight.

[23]  N. Vij,et al.  Cigarette smoke-induced autophagy impairment accelerates lung aging, COPD-emphysema exacerbations and pathogenesis. , 2018, American journal of physiology. Cell physiology.

[24]  P. Barnes.  Senescence in COPD and Its Comorbidities. , 2017, Annual review of physiology.

[25]  G. Criner,et al.  Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. , 2015, Chest.

[26]  G. Criner,et al.  Executive summary: prevention of acute exacerbation of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. , 2015, Chest.

[27]  O. Gavrilova,et al.  Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. , 2013, Cell reports.

[28]  P. Rabinovitch,et al.  mTOR is a key modulator of ageing and age-related disease , 2013, Nature.

[29]  F. Martinez,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. , 2007, American journal of respiratory and critical care medicine.

[30]  L. Fabbri,et al.  Long-term macrolide treatment for chronic respiratory disease , 2012, European Respiratory Journal.

[31]  James B. Mitchell,et al.  mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. , 2012, Cell stem cell.

[32]  N. Thomson,et al.  Long‐term macrolide treatment of chronic inflammatory airway diseases: risks, benefits and future developments , 2012, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[33]  D. Peeper,et al.  The essence of senescence. , 2010, Genes & development.

[34]  Kunlin Jin,et al.  Modern Biological Theories of Aging. , 2010, Aging and disease.

[35]  W. MacNee,et al.  Effect of 6 Months of Erythromycin Treatment on Inflammatory Cells in Induced Sputum and Exacerbations in Chronic Obstructive Pulmonary Disease , 2010, Respiration.

[36]  N. Zhong,et al.  Suppression of Oxidant-Induced Glutathione Synthesis by Erythromycin in Human Bronchial Epithelial Cells , 2007, Respiration.

[37]  Matt Kaeberlein,et al.  Extension of chronological life span in yeast by decreased TOR pathway signaling. , 2006, Genes & development.

[38]  Matt Kaeberlein,et al.  Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients , 2005, Science.

[39]  Di Chen,et al.  The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span , 2004, Development.

[40]  S. Benzer,et al.  Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway , 2004, Current Biology.

[41]  R. Pauwels,et al.  Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: GOLD Executive Summary Updated 2003 , 2004, COPD.

[42]  A. Lloyd,et al.  Milestones in cell division: Cell senescence and cancer , 2001, Nature Reviews Cancer.

[43]  W. MacNee,et al.  Role of oxidants/antioxidants in smoking-induced lung diseases. , 1996, Free radical biology & medicine.

[44]  D. Harman.  Aging: a theory based on free radical and radiation chemistry. , 1956, Journal of gerontology.