New Insights into the Nrf-2/HO-1 Signaling Axis and Its Application in Pediatric Respiratory Diseases

Respiratory diseases are one of the most common pediatric diseases in clinical practice. Their pathogenesis, diagnosis, and treatment are thus worthy of further investigation. The nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling axis is a multiple organ protection chain that protects against oxidative stress injury. This signaling axis regulates anti-inflammation and antioxidation by regulating calcium ions, mitochondrial oxidative stress, autophagy, ferroptosis, pyroptosis, apoptosis, alkaliptosis, and clockophagy. This review presents an overview of the role of the Nrf2/HO-1 signaling axis in the pathogenesis of pediatric respiratory diseases and the latest research progress on this subject. Overall, the Nrf2/HO-1 signaling axis has an important clinical value in pediatric respiratory diseases, and its protective effect needs further exploration.

[1]  S. Kook,et al.  Irradiation inhibits the maturation and mineralization of osteoblasts via the activation of Nrf2/HO-1 pathway , 2015, Molecular and Cellular Biochemistry.

[2]  S. Epiphanio,et al.  Could Heme Oxygenase-1 Be a New Target for Therapeutic Intervention in Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome? , 2018, Front. Cell. Infect. Microbiol..

[3]  Chaoqian Li,et al.  Nrf2 Activator RTA-408 Protects Against Ozone-Induced Acute Asthma Exacerbation by Suppressing ROS and γδT17 Cells , 2019, Inflammation.

[4]  G. Hong,et al.  The reversal of paraquat-induced mitochondria-mediated apoptosis by cycloartenyl ferulate, the important role of Nrf2 pathway. , 2013, Experimental cell research.

[5]  Masayuki Yamamoto,et al.  Inflammation and airway hyperresponsiveness after chlorine exposure are prolonged by Nrf2 deficiency in mice , 2017, Free radical biology & medicine.

[6]  Sankar Ghosh,et al.  NF-κB, the first quarter-century: remarkable progress and outstanding questions. , 2012, Genes & development.

[7]  Do-Hee Kim,et al.  Cellular adaptation mediated through Nrf2-induced glutamate cysteine ligase up-regulation against oxidative stress caused by iron overload in β-thalassemia/HbE patients , 2019, Free radical research.

[8]  M. Balaan,et al.  Acute Respiratory Distress Syndrome , 2016, Critical care nursing quarterly.

[9]  A. Józkowicz,et al.  Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism , 2016, Cellular and Molecular Life Sciences.

[10]  L. Duan,et al.  Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-β1 , 2019, Journal of Inflammation.

[11]  Caroline Dive,et al.  Progress and prospects of early detection in lung cancer , 2017, Open Biology.

[12]  Rong Zeng,et al.  Sulforaphane reverses glucocorticoid-induced apoptosis in osteoblastic cells through regulation of the Nrf2 pathway , 2014, Drug design, development and therapy.

[13]  S. Giordano,et al.  The Dual Roles of NRF2 in Cancer. , 2016, Trends in molecular medicine.

[14]  G. Scapagnini,et al.  Modulation of Nrf2/ARE Pathway by Food Polyphenols: A Nutritional Neuroprotective Strategy for Cognitive and Neurodegenerative Disorders , 2011, Molecular Neurobiology.

[15]  C. Chien,et al.  Activating Nrf-2 Signaling Depresses Unilateral Ureteral Obstruction-Evoked Mitochondrial Stress-Related Autophagy, Apoptosis and Pyroptosis in Kidney , 2012, PloS one.

[16]  Gail Davey.  Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016 , 2017 .

[17]  A. Veskoukis,et al.  A battery of translational biomarkers for the assessment of the in vitro and in vivo antioxidant action of plant polyphenolic compounds: The biomarker issue , 2019, Current Opinion in Toxicology.

[18]  Y. Jiao,et al.  Metformin Sensitizes Non-small Cell Lung Cancer Cells to an Epigallocatechin-3-Gallate (EGCG) Treatment by Suppressing the Nrf2/HO-1 Signaling Pathway , 2017, International journal of biological sciences.

[19]  A. Choi,et al.  Nrf2, a Cap’n’Collar Transcription Factor, Regulates Induction of the Heme Oxygenase-1 Gene* , 1999, The Journal of Biological Chemistry.

[20]  Jun Xia,et al.  Lycopene Triggers Nrf2-AMPK Cross Talk to Alleviate Atrazine-Induced Nephrotoxicity in Mice. , 2018, Journal of agricultural and food chemistry.

[21]  A. Jaiswal.  Regulation of genes encoding NAD(P)H:quinone oxidoreductases. , 2000, Free radical biology & medicine.

[22]  J. Gaudart,et al.  Air pollution and children’s asthma-related emergency hospital visits in southeastern France , 2017, European Journal of Pediatrics.

[23]  P. Sil,et al.  Mangiferin alleviates arsenic induced oxidative lung injury via upregulation of the Nrf2-HO1 axis. , 2019, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[24]  E. Martín-Montañez,et al.  The S1P mimetic fingolimod phosphate regulates mitochondrial oxidative stress in neuronal cells. , 2019, Free radical biology & medicine.

[25]  L. Pan,et al.  Pulmonary , gastrointestinal and urogenital pharmacology Protective e ff ect of forsythiaside A on OVA-induced asthma in mice , 2017 .

[26]  A. Ferrante,et al.  Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation , 2018, Nature Communications.

[27]  Lu He,et al.  Modulation of autophagy in traumatic brain injury , 2020, Journal of cellular physiology.

[28]  Mingyi Zhao,et al.  Functional Immunoregulation by Heme Oxygenase 1 in Juvenile Autoimmune Diseases. , 2019, Current gene therapy.

[29]  Tanshi Li,et al.  Acacetin attenuates mice endotoxin-induced acute lung injury via augmentation of heme oxygenase-1 activity , 2018, Inflammopharmacology.

[30]  A. Mahmoud,et al.  Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPARγ, and suppression of NF-κB/NLRP3 inflammasome axis. , 2019, Food & function.

[31]  D. Klionsky,et al.  Clockophagy is a novel selective autophagy process favoring ferroptosis , 2019, Science Advances.

[32]  L. Muscarella,et al.  Nrf2 and Notch Signaling in Lung Cancer: Near the Crossroad , 2016, Oxidative medicine and cellular longevity.

[33]  M. Carraway,et al.  Heme Oxygenase-1 Regulates Cardiac Mitochondrial Biogenesis via Nrf2-Mediated Transcriptional Control of Nuclear Respiratory Factor-1 , 2008, Circulation research.

[34]  D. Tang,et al.  Activation of the p62‐Keap1‐NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells , 2016, Hepatology.

[35]  H. Yao,et al.  Nrf2 attenuates inflammatory response in COPD/emphysema: Crosstalk with Wnt3a/β‐catenin and AMPK pathways , 2018, Journal of cellular and molecular medicine.

[36]  L. Yao,et al.  Activation of the Nrf2‐ARE Signaling Pathway Prevents Hyperphosphatemia‐Induced Vascular Calcification by Inducing Autophagy in Renal Vascular Smooth Muscle Cells , 2017, Journal of cellular biochemistry.

[37]  M. Massiah,et al.  Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Fahey,et al.  Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. , 2001, The Journal of nutrition.

[39]  Chih-Yang Huang,et al.  Neferine modulates IGF‐1R/Nrf2 signaling in doxorubicin treated H9c2 cardiomyoblasts , 2018, Journal of cellular biochemistry.

[40]  W. Tai,et al.  Rapamycin attenuates the paraquat‐induced pulmonary fibrosis through activating Nrf2 pathway , 2019, Journal of cellular physiology.

[41]  X. Ci,et al.  Role of Nrf2 and Its Activators in Respiratory Diseases , 2019, Oxidative medicine and cellular longevity.

[42]  Laura Contreras,et al.  Glutamate excitotoxicity and Ca2+-regulation of respiration: Role of the Ca2+ activated mitochondrial transporters (CaMCs). , 2016, Biochimica et biophysica acta.

[43]  V. Krajka-Kuźniak,et al.  The Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment. , 2017 .

[44]  P. Vandenabeele,et al.  The molecular machinery of regulated cell death , 2019, Cell Research.

[45]  J. Reutershan,et al.  Tissue heme oxygenase-1 exerts anti-inflammatory effects on LPS-induced pulmonary inflammation , 2015, Mucosal Immunology.

[46]  S. Niture,et al.  Regulation of Nrf2-an update. , 2014, Free radical biology & medicine.

[47]  K. Larsson,et al.  Organic dust, causing both oxidative stress and Nrf2 activation, is phagocytized by bronchial epithelial cells. , 2019, American journal of physiology. Lung cellular and molecular physiology.

[48]  A. Kong,et al.  The nuclear cofactor RAC3/AIB1/SRC-3 enhances Nrf2 signaling by interacting with transactivation domains , 2012, Oncogene.

[49]  A. Jaiswal,et al.  Nrf2 and c-Jun regulation of antioxidant response element (ARE)-mediated expression and induction of gamma-glutamylcysteine synthetase heavy subunit gene. , 2000, Biochemical pharmacology.

[50]  Daniela Debone,et al.  Association of Heme Oxygenase 1 with Lung Protection in Malaria-Associated ALI/ARDS , 2016, Mediators of inflammation.

[51]  Dean P. Jones.  Redefining oxidative stress. , 2006, Antioxidants & redox signaling.

[52]  G. Kroemer,et al.  JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice. , 2017, Gastroenterology.

[53]  Zhongwei Xu,et al.  HO‑1 alleviates cholesterol‑induced oxidative stress through activation of Nrf2/ERK and inhibition of PI3K/AKT pathways in endothelial cells. , 2017, Molecular medicine reports.

[54]  B. Li,et al.  Cyanidin-3-O-glucoside attenuates amyloid-beta (1–40)-induced oxidative stress and apoptosis in SH-SY5Y cells through a Nrf2 mechanism , 2017 .

[55]  J. Reutershan,et al.  Anti-inflammatory Effects of Heme Oxygenase-1 Depend on Adenosine A2A- and A2B-Receptor Signaling in Acute Pulmonary Inflammation , 2017, Front. Immunol..

[56]  C. Wolf,et al.  Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. , 2002, The Biochemical journal.

[57]  Tingting Yang,et al.  Nrf2/Keap1/ARE Signaling Mediated an Antioxidative Protection of Human Placental Mesenchymal Stem Cells of Fetal Origin in Alveolar Epithelial Cells , 2019, Oxidative medicine and cellular longevity.

[58]  W. Ouyang,et al.  Neuroprotective Effects of Kinetin Against Glutamate-Induced Oxidative Cytotoxicity in HT22 Cells: Involvement of Nrf2 and Heme Oxygenase-1 , 2018, Neurotoxicity Research.

[59]  Q. Wang,et al.  Oxidative stress activates the TRPM2-Ca2+-CaMKII-ROS signaling loop to induce cell death in cancer cells. , 2017, Biochimica et biophysica acta. Molecular cell research.

[60]  K. Itoh,et al.  Role of Nrf2 in Host Defense against Influenza Virus in Cigarette Smoke-Exposed Mice , 2011, Journal of Virology.

[61]  K. Mills,et al.  The Role of Regulatory T Cells in Respiratory Infections and Allergy and Asthma , 2010, Current allergy and asthma reports.

[62]  Mohammad Hossein Khosravi,et al.  Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016 , 2017, Lancet.

[63]  Michelle R. Campbell,et al.  Beyond antioxidant genes in the ancient Nrf2 regulatory network. , 2015, Free radical biology & medicine.

[64]  L. French,et al.  The Crosstalk between Nrf2 and Inflammasomes , 2018, International journal of molecular sciences.

[65]  G. Latunde-Dada,et al.  Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. , 2017, Biochimica et biophysica acta. General subjects.

[66]  M. Nitti,et al.  The Nrf2/HO-1 Axis in Cancer Cell Growth and Chemoresistance , 2015, Oxidative medicine and cellular longevity.

[67]  O. Kochetova,et al.  Associations of the NRF2/KEAP1 pathway and antioxidant defense gene polymorphisms with chronic obstructive pulmonary disease. , 2019, Gene.

[68]  G. Sudhandiran,et al.  Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-κB dependant TGF-β activation: a biphasic experimental study. , 2013, Toxicology letters.

[69]  Tangchun Wu,et al.  Prevalence, risk factors, and management of asthma in China: a national cross-sectional study , 2019, The Lancet.