芳香烃受体与急性肺损伤的研究进展
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摘要
急性肺损伤(acute lung injury, ALI)是临床上常见的危重症疾病之一,其患病率和死亡率高,严重威胁着患者生命健康。芳香烃受体(aryl hydrocarbon receptor, AhR)是一种配体激活的转录因子,通过转录调控作用,在代谢毒物及化学物质、调节生物节律、生殖、氧化应激等方面发挥重要的作用。近年来研究发现,芳香烃受体在各种原因导致的ALI中发挥了重要的作用,AhR或许为治疗ALI的潜在靶点。本文就AhR在ALI发生发展中的机制及其在ALI的药物治疗作用进行归纳总结。
Acute lung injury(ALI) is one of the most common critical illnesses in the clinic. Its prevalence and mortality are high, which seriously threatens patients' life and health. Aryl hydrocarbon receptor(AhR) is a ligand-activated transcription factor that plays an important role in metabolic toxicants and chemicals, regulation of biological rhythms, reproduction, and oxidative stress through transcriptional regulation. In recent years,studies have found that aromatic hydrocarbon receptors play an important role in ALI caused by various causes,and AhR might be a potential target for the treatment of ALI. This article summarizes the mechanism of AhR in the development of ALI and its pharmacological effects in ALI.
Acute lung injury(ALI) is one of the most common critical illnesses in the clinic. Its prevalence and mortality are high, which seriously threatens patients' life and health. Aryl hydrocarbon receptor(AhR) is a ligand-activated transcription factor that plays an important role in metabolic toxicants and chemicals, regulation of biological rhythms, reproduction, and oxidative stress through transcriptional regulation. In recent years,studies have found that aromatic hydrocarbon receptors play an important role in ALI caused by various causes,and AhR might be a potential target for the treatment of ALI. This article summarizes the mechanism of AhR in the development of ALI and its pharmacological effects in ALI.
引文
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[2]Busbee PB,Rouse M,Nagarkatti M,et al.Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders.Nutr Rev,2013,71(6):353-369
[3]Bessede A,Gargaro M,Pallotta MT,et al.Aryl hydrocarbon receptor control of a disease tolerance defence pathway.Nature,2014,511(7508):184-190
[4]Quintana FJ,Sherr DH.Aryl hydrocarbon receptor control of adaptive immunity.Pharmacol Rev,2013,65(4):1148-1161
[5]Oesch-Bartlomowicz B,Huelster A,Wiss O,et al.Aryl hydrocarbon receptor activation by cAMP vs.dioxin:divergent signaling pathways.Proc Natl Acad Sci USA,2005,102(26):9218-9223
[6]Formosa R,Vassallo J.The complex biology of the aryl hydrocarbon receptor and its role in the pituitary gland.Horm Cancer,2017,8(4):197-210
[7]Sakurai S,Shimizu T,Ohto U.The crystal structure of the AhRR-ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription.J Biol Chem,2017,292(43):17609-17616
[8]Amara IE,Anwar-Mohamed A,El-Kadi AO.Posttranslational mechanisms modulating the expression of the cytochrome P450 1A1 gene by methylmercury in HepG2cells:a role of heme oxygenase-1.Toxicol Lett,2013,219(3):239-247
[9]Fujii-Kuriyama Y,Kawajiri K.Molecular mechanisms of the physiological functions of the aryl hydrocarbon(dioxin)receptor,a multifunctional regulator that senses and responds to environmental stimuli.Proc Jpn Acad Ser BPhys Biol Sci,2010,86(1):40-53
[10]Pinaire JA,Xiao GH,Falkner KC,et al.Regulation of NAD(P)H:quinone oxidoreductase 1 gene expression by CYP1A1 Activity.Toxicol Appl Pharmacol,2004,199(3):344-353
[11]Shrestha AK,Patel A,Menon RT,et al.Leflunomide induces NAD(P)H quinone dehydrogense 1 enzyme via the aryl hydrocarbon receptor in neonatal mice.Biochem Biophys Res Commun,2017,485(1):195-200
[12]Marshall NB,Kerkvliet NI.Dioxin and immune regulation:emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells.Ann N Y Acad Sci,2010,1183:25-37
[13]Kerkvliet NI.AHR-mediated immunomodulation:the role of altered gene transcription.Biochem Pharmacol,2009,77(4):746-760
[14]de Souza AR,Zago M,Eidelman DH,et al.Aryl hydrocarbon receptor(AhR)attenuation of subchronic cigarette smoke-induced pulmonary neutrophilia is associated with retention of nuclear RelB and suppression of intercellular adhesion molecule-1(ICAM-1).Toxicol Sci,2014,140(1):204-223
[15]Vogel CF,Khan EM,Leung PS,et al.Cross-talk between aryl hydrocarbon receptor and the inflammatory response:a role for nuclear factor-κB.J Biol Chem,2014,289(3):1866-1875
[16]Jacob A,Tomkiewicz-Raulet C,Jamet C,et al.Aryl hydrocarbon receptor upregulates IL-1βexpression in hCMEC/D3 humancerebral microvascular endothelial cells after TCDD exposure.Toxicol In Vitro,2017,41:200-204
[17]Xue P,Fu J,Zhou Y.The aryl hydrocarbon receptor and tumor immunity.Front Immunol,2018,9:286
[18]Kolluri SK,Jin UH,Safe S.Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target.Arch Toxicol,2017,91(7):2497-2513
[19]Hsieh TH,Tsai CF,Hsu CY,et al.Phthalates induce proliferation and invasiveness of estrogen receptor-negativebreast cancer through the AhR/HDAC6/c-Myc signaling pathway.FASEB J,2012,26(2):778-787
[20]Huang CR,Lee CT,Chang KY,et al.Down-regulation of ARNT promotes cancer metastasis by activating the fibronectin/integrinβ1/FAK axis.Oncotarget,2015,6(13):11530-11546
[21]Tomkiewicz C,Herry L,Bui LC,et al.The aryl hydrocarbon receptor regulates focal adhesion sites through a non-genomic FAK/Src pathway.Oncogene,2013,32(14):1811-1820
[22]Maybauer MO,Maybauer DM,Herndon DN.Incidence and outcomes of acute lung injury.N Engl J Med,2006,354(4):416-417
[23]Fan E,Brodie D,Slutsky AS.Acute respiratory distress syndrome:advances in diagnosis and treatment.JAMA,2018,319(7):698-710
[24]Bellani G,Laffey JG,Pham T,et al.Epidemiology,patterns of care,and mortality for patients with acute respiratory distress syndrome in intensive care units in 50countries.JAMA,2016,315(8):788-800
[25]Mantell LL,Lee PJ.Signal transduction pathways in hyperoxia-induced lung cell death.Mol Genet Metab,2000,71(1-2):359-370
[26]Shivanna B,Zhang W,Jiang W,et al.Functional deficiency of aryl hydrocarbon receptor augments oxygen toxicity-induced alveolar simplification in newborn mice.Toxicol Appl Pharmacol,2013,267:209-217
[27]Brahmajothi MV,Tinch BT,Wempe MF,et al.Hyperoxia inhibits nitric oxide treatment effects in alveolar epithelial cells via effects on L-type amino acid transporter-1.Antioxid Redox Signal,2014,21:1823-1836
[28]Richter J,Jimenez J,Nagatomo T,et al.Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury.J Translat Med,2016,14(1):247
[29]Cheng J,Li W,Kang B,et al.Tryptophan derivatives regulate the transcription of Oct4 in stem-like cancer cells.Nat Commun,2015,6:7209
[30]Zordoky BN,El-Kadi AO.Role of NF-κB in the regulation of cytochrome p450 enzymes.Curr Drug Metab,2009,10(2):164-178
[31]Cheon H,Woo YS,Lee JY,et al.Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-alphaproduction in differentiated THP-1 human macrophages.Exp Mol Med,2007,39(4):524-534
[32]Huai W,Zhao R,Song H,et al.Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription.Nat Commun,2014,5:4738
[33]Vogel CF,Wu D,Goth SR,et al.Aryl hydrocarbon receptor signaling regulates NF-κB RelB activation during dendritic-cell differentiation.Immunol Cell Biol,2013,91(9):568-575
[34]Kimura A,Naka T,Nakahama T,et al.Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses.J Exp Med,2009,206(9):2027-2035
[35]Masuda K,Kimura A,Hanieh H,et al.Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages.Int Immunol,2011,23(10):637-645
[36]Stockinger B,Di Meglio P,Gialitakis M,et al.The aryl hydrocarbon receptor:multitasking in the immune system.Annu Rev Immunol,2014,32:403-432
[2]Busbee PB,Rouse M,Nagarkatti M,et al.Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders.Nutr Rev,2013,71(6):353-369
[3]Bessede A,Gargaro M,Pallotta MT,et al.Aryl hydrocarbon receptor control of a disease tolerance defence pathway.Nature,2014,511(7508):184-190
[4]Quintana FJ,Sherr DH.Aryl hydrocarbon receptor control of adaptive immunity.Pharmacol Rev,2013,65(4):1148-1161
[5]Oesch-Bartlomowicz B,Huelster A,Wiss O,et al.Aryl hydrocarbon receptor activation by cAMP vs.dioxin:divergent signaling pathways.Proc Natl Acad Sci USA,2005,102(26):9218-9223
[6]Formosa R,Vassallo J.The complex biology of the aryl hydrocarbon receptor and its role in the pituitary gland.Horm Cancer,2017,8(4):197-210
[7]Sakurai S,Shimizu T,Ohto U.The crystal structure of the AhRR-ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription.J Biol Chem,2017,292(43):17609-17616
[8]Amara IE,Anwar-Mohamed A,El-Kadi AO.Posttranslational mechanisms modulating the expression of the cytochrome P450 1A1 gene by methylmercury in HepG2cells:a role of heme oxygenase-1.Toxicol Lett,2013,219(3):239-247
[9]Fujii-Kuriyama Y,Kawajiri K.Molecular mechanisms of the physiological functions of the aryl hydrocarbon(dioxin)receptor,a multifunctional regulator that senses and responds to environmental stimuli.Proc Jpn Acad Ser BPhys Biol Sci,2010,86(1):40-53
[10]Pinaire JA,Xiao GH,Falkner KC,et al.Regulation of NAD(P)H:quinone oxidoreductase 1 gene expression by CYP1A1 Activity.Toxicol Appl Pharmacol,2004,199(3):344-353
[11]Shrestha AK,Patel A,Menon RT,et al.Leflunomide induces NAD(P)H quinone dehydrogense 1 enzyme via the aryl hydrocarbon receptor in neonatal mice.Biochem Biophys Res Commun,2017,485(1):195-200
[12]Marshall NB,Kerkvliet NI.Dioxin and immune regulation:emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells.Ann N Y Acad Sci,2010,1183:25-37
[13]Kerkvliet NI.AHR-mediated immunomodulation:the role of altered gene transcription.Biochem Pharmacol,2009,77(4):746-760
[14]de Souza AR,Zago M,Eidelman DH,et al.Aryl hydrocarbon receptor(AhR)attenuation of subchronic cigarette smoke-induced pulmonary neutrophilia is associated with retention of nuclear RelB and suppression of intercellular adhesion molecule-1(ICAM-1).Toxicol Sci,2014,140(1):204-223
[15]Vogel CF,Khan EM,Leung PS,et al.Cross-talk between aryl hydrocarbon receptor and the inflammatory response:a role for nuclear factor-κB.J Biol Chem,2014,289(3):1866-1875
[16]Jacob A,Tomkiewicz-Raulet C,Jamet C,et al.Aryl hydrocarbon receptor upregulates IL-1βexpression in hCMEC/D3 humancerebral microvascular endothelial cells after TCDD exposure.Toxicol In Vitro,2017,41:200-204
[17]Xue P,Fu J,Zhou Y.The aryl hydrocarbon receptor and tumor immunity.Front Immunol,2018,9:286
[18]Kolluri SK,Jin UH,Safe S.Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target.Arch Toxicol,2017,91(7):2497-2513
[19]Hsieh TH,Tsai CF,Hsu CY,et al.Phthalates induce proliferation and invasiveness of estrogen receptor-negativebreast cancer through the AhR/HDAC6/c-Myc signaling pathway.FASEB J,2012,26(2):778-787
[20]Huang CR,Lee CT,Chang KY,et al.Down-regulation of ARNT promotes cancer metastasis by activating the fibronectin/integrinβ1/FAK axis.Oncotarget,2015,6(13):11530-11546
[21]Tomkiewicz C,Herry L,Bui LC,et al.The aryl hydrocarbon receptor regulates focal adhesion sites through a non-genomic FAK/Src pathway.Oncogene,2013,32(14):1811-1820
[22]Maybauer MO,Maybauer DM,Herndon DN.Incidence and outcomes of acute lung injury.N Engl J Med,2006,354(4):416-417
[23]Fan E,Brodie D,Slutsky AS.Acute respiratory distress syndrome:advances in diagnosis and treatment.JAMA,2018,319(7):698-710
[24]Bellani G,Laffey JG,Pham T,et al.Epidemiology,patterns of care,and mortality for patients with acute respiratory distress syndrome in intensive care units in 50countries.JAMA,2016,315(8):788-800
[25]Mantell LL,Lee PJ.Signal transduction pathways in hyperoxia-induced lung cell death.Mol Genet Metab,2000,71(1-2):359-370
[26]Shivanna B,Zhang W,Jiang W,et al.Functional deficiency of aryl hydrocarbon receptor augments oxygen toxicity-induced alveolar simplification in newborn mice.Toxicol Appl Pharmacol,2013,267:209-217
[27]Brahmajothi MV,Tinch BT,Wempe MF,et al.Hyperoxia inhibits nitric oxide treatment effects in alveolar epithelial cells via effects on L-type amino acid transporter-1.Antioxid Redox Signal,2014,21:1823-1836
[28]Richter J,Jimenez J,Nagatomo T,et al.Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury.J Translat Med,2016,14(1):247
[29]Cheng J,Li W,Kang B,et al.Tryptophan derivatives regulate the transcription of Oct4 in stem-like cancer cells.Nat Commun,2015,6:7209
[30]Zordoky BN,El-Kadi AO.Role of NF-κB in the regulation of cytochrome p450 enzymes.Curr Drug Metab,2009,10(2):164-178
[31]Cheon H,Woo YS,Lee JY,et al.Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-alphaproduction in differentiated THP-1 human macrophages.Exp Mol Med,2007,39(4):524-534
[32]Huai W,Zhao R,Song H,et al.Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription.Nat Commun,2014,5:4738
[33]Vogel CF,Wu D,Goth SR,et al.Aryl hydrocarbon receptor signaling regulates NF-κB RelB activation during dendritic-cell differentiation.Immunol Cell Biol,2013,91(9):568-575
[34]Kimura A,Naka T,Nakahama T,et al.Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses.J Exp Med,2009,206(9):2027-2035
[35]Masuda K,Kimura A,Hanieh H,et al.Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages.Int Immunol,2011,23(10):637-645
[36]Stockinger B,Di Meglio P,Gialitakis M,et al.The aryl hydrocarbon receptor:multitasking in the immune system.Annu Rev Immunol,2014,32:403-432