Turkiye Klinikleri Archives of Lung

.: REVIEW
Solunum Sistemi Hastalıklarında Kolinerjik Sinir Sisteminin Rolü
The Role of Cholinergic Nervous System in Respiratory System Diseases
Zeynep ÖZDEMİR KÜTAHYAa
aÇukurova Üniversitesi Ceyhan Veteriner Fakültesi, Farmakoloji ve Toksikoloji ABD, Adana, TÜRKİYE
Turkiye Klinikleri Arch Lung. 2021;20(1):19-26
doi: 10.5336/archlung.2019-73146
Article Language: TR
Full Text
ÖZET
 Kronik obstrüktif akciğer hastalığında kolinerjik sistemin aktivitesi artar, bu da solunum yolu düz kaslarını kasarak soluk alışverişini sınırlandırır. Bu nedenle kolinerjik sinir sistemi aktivitesinin arttığı kronik obstrüktif akciğer hastalığı gibi olguların tedavisinde, antikolinerjik ilaçlar kullanılmaktadır. Antikolinerjik ilaçların bu endikasyonda kullanımı, asetilkolinin bronkokonstriksiyon ve mukus salgısını artırıcı etkisinin azaltılmasına dayanmaktadır. Son yapılan deneysel çalışmalar, asetilkolinin yangıda da önemli rol oynadığını ortaya koymuştur. Muskarinik M3 reseptör-noksan fareler ve M3 selektif antagonistler kullanılarak yapılan çalışmalar, parankimal hücrelerdeki M3 reseptörlerinin asetilkolinin proinflamatuar etkisine aracılık ettiğini ortaya koymuştur. Beta-2 (β2) adrenerjik agonist ile muskarinik antagonist kombinasyonlarının kronik obstrüktif akciğer hastalığı tedavisinde kullanılması önerilmektedir. Bu öneri, β2 adrenerjik reseptör uyarımının M3 reseptörlerini antagonize ederek farklı bir yolakla inflamatuar hücrelerde inhibisyona yol açacağına dayanmaktadır ancak bu antiinflamatuar etkiler, kronik obstrüktif akciğer hastalığında açıkça ortaya konulamamıştır. Muskarinik reseptörler aracılığıyla, asetilkolinin proinflamatuar etkilerinin aksine parasempatik sinir sistemini içeren kolinerjik antiinflamatuar yol, doku hasarı ve enfeksiyon durumunda organları korumak için aşırı inflamatuar yanıtları düzenler. Diğer yandan asetilkolinin, α7 nikotinik asetilkolin reseptör aracılığıyla makrofajlar ve Tip 2 doğal lenfoid hücreler dâhil olmak üzere lökositler üzerinde inhibitör etki oluşturduğu ortaya konmuştur. Kronik obstrüktif akciğer hastalığında, asetilkolinin antiinflamatuar hücreler üzerindeki bu inhibe edici etkisi tam olarak ortaya konmasa da kolinerjik antiinflamatuar yolağı içeren nöroimmün etkileşimlerin terapötik bir hedef olabileceği belirtilmektedir.

Anahtar Kelimeler: Solunum sistemi hastalıkları; kolinerjik sinir sistemi
ABSTRACT
 The activity of the cholinergic system increases in chronic obstructive pulmonary disease this restricts breathing exchange by contracting the airway smooth muscles. Therefore, anticholinergic drugs are used in the treatment of chronic obstructive pulmonary disease, which is increased cholinergic nervous system activity. The use of anticholinergic drugs in this indication is based on reducing the effect of acetylcholine on bronchoconstriction and mucus secretion. Recent experimental studies have shown that acetylcholine also plays an important role in inflammation. Studies with muscarinic M3 receptor-deficient mice and M3 selective antagonists have demonstrated that M3 receptors in parenchymal cells mediate the pro-inflammatory effect of acetylcholine. The combination of β2 adrenergic agonist and muscarinic antagonist is recommended in the treatment of chronic obstructive pulmonary disease. This recommendation is based on the fact that β2 adrenergic receptor stimulation will antagonize M3 receptors and leads to inhibition of inflammatory cells in a different way, but these anti-inflammatory effects have not been clearly demonstrated in chronic obstructive pulmonary disease. In contrast to the pro-inflammatory effects of acetylcholine through muscarinic receptors, the cholinergic anti-inflammatory pathway regulates excessive inflammatory responses to protect organs in case of tissue damage and infection. On the other hand, acetylcholine has been shown to have an inhibitory effect on leukocytes, macrophages and type 2 natural lymphoid cells through α7 nicotinic acetylcholine receptor. Although the inhibitory effect of acetylcholine on inflammatory cells in chronic obstructive pulmonary disease has not been fully established, it is stated that neuroimmune interactions involving cholinergic antiinflammatory pathway may be a therapeutic target.

Keywords: Respiratory system diseases; cholinergic nervous system
REFERENCES:
  1. Mak JC, Barnes PJ. Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung. Am Rev Respir Dis. 1990;141(6):1559-68.[Crossref] [PubMed] 
  2. Proskocil BJ, Sekhon HS, Jia Y, Savchenko V, Blakely RD, Lindstrom J, et al. Acetylcholine is an autocrine or paracrine hormone synthesized and secreted by airway bronchial epithelial cells. Endocrinology. 2004;145(5):2498-506.[Crossref] [PubMed] 
  3. Kummer W, Krasteva-Christ G. Non-neuronal cholinergic airway epithelium biology. Curr Opin Pharmacol. 2014;16:43-9.[Crossref] [PubMed] 
  4. Wessler I, Kirkpatrick CJ. Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol. 2008;154(8):1558-71.[Crossref] [PubMed] [PMC] 
  5. Profita M, Bonanno A, Siena L, Ferraro M, Montalbano AM, Pompeo F, et al. Acetylcholine mediates the release of IL-8 in human bronchial epithelial cells by a NFkB/ERK-dependent mechanism. Eur J Pharmacol. 2008;582(1-3):145-53.[Crossref] [PubMed] 
  6. Gosens R, Rieks D, Meurs H, Ninaber DK, Rabe KF, Nanninga J, et al. Muscarinic M3 receptor stimulation increases cigarette smoke-induced IL-8 secretion by human airway smooth muscle cells. Eur Respir J. 2009;34(6):1436-43.[Crossref] [PubMed] 
  7. Gross NJ, Skorodin MS. Role of the parasympathetic system in airway obstruction due to emphysema. N Engl J Med. 1984;311(7):421-5.[Crossref] [PubMed] 
  8. Nathan C. Points of control in inflammation. Nature. 2002;420(6917):846-52.[Crossref] [PubMed] 
  9. Rosas-Ballina M, Olofsson PS, Ochani M, Valdés-Ferrer SI, Levine YA, Reardon C, et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011;334(6052):98-101.[Crossref] [PubMed] [PMC] 
  10. Wu H, Li L, Su X. Vagus nerve through α7 nAChR modulates lung infection and inflammation: models, cells, and signals. Biomed Res Int. 2014;2014:283525.[Crossref] [PubMed] [PMC] 
  11. Yang X, Zhao C, Gao Z, Su X. A novel regulator of lung inflammation and immunity: pulmonary parasympathetic inflammatory reflex. QJM. 2014;107(10):789-92.[Crossref] [PubMed] 
  12. Huston JM, Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M, et al. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit Care Med. 2007;35(12):2762-8.[Crossref] [PubMed] 
  13. Yang X, Zhao C, Chen X, Jiang L, Su X. Monocytes primed with GTS-21/α7 nAChR (nicotinic acetylcholine receptor) agonist develop anti-inflammatory memory. QJM. 2017;110(7):437-45.[Crossref] [PubMed] 
  14. Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells: 10 years on. Cell. 2018;174(5):1054-66.[Crossref] [PubMed] 
  15. Wollin L, Pieper MP. Tiotropium bromide exerts anti-inflammatory activity in a cigarette smoke mouse model of COPD. Pulm Pharmacol Ther. 2010;23(4):345-54.[Crossref] [PubMed] 
  16. Bucher H, Duechs MJ, Tilp C, Jung B, Erb KJ. Tiotropium attenuates virus-induced pulmonary inflammation in cigarette smoke-exposed mice. J Pharmacol Exp Ther. 2016;357(3):606-18.[Crossref] [PubMed] [PMC] 
  17. Shen LL, Liu YN, Shen HJ, Wen C, Jia YL, Dong XW,et al. Inhalation of glycopyrronium inhibits cigarette smoke-induced acute lung inflammation in a murine model of COPD. Int Immunopharmacol. 2014;18(2):358-64.[Crossref] [PubMed] 
  18. Hsiao YH, Tseng CM, Su KC, Chen WC, Wu MT, Wu YC, et al. Glycopyrronium bromide inhibits lung inflammation and small airway remodeling induced by subchronic cigarette smoke exposure in mice. Respir Physiol Neurobiol. 2018;249:16-22.[Crossref] [PubMed] 
  19. Domínguez-Fandos D, Ferrer E, Puig-Pey R, Carre-o C, Prats N, Aparici M, et al. Effects of aclidinium bromide in a cigarette smoke-exposed Guinea pig model of chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2014;50(2):337-46.[PubMed] 
  20. Kistemaker LE, Bos IS, Hylkema MN, Nawijn MC, Hiemstra PS, Wess J, et al. Muscarinic receptor subtype-specific effects on cigarette smoke-induced inflammation in mice. Eur Respir J. 2013;42(6):1677-88.[Crossref] [PubMed] 
  21. Profita M, Bonanno A, Montalbano AM, Ferraro M, Siena L, Bruno A, et al. Cigarette smoke extract activates human bronchial epithelial cells affecting non-neuronal cholinergic system signalling in vitro. Life Sci. 2011;89(1-2):36-43.[Crossref] [PubMed] 
  22. Anzalone G, Gagliardo R, Bucchieri F, Albano GD, Siena L, Montalbano AM, et al. IL-17A induces chromatin remodeling promoting IL-8 release in bronchial epithelial cells: Effect of Tiotropium. Life Sci. 2016;152:107-16.[Crossref] [PubMed] 
  23. Costa L, Roth M, Miglino N, Keglowich L, Zhong J, Lardinois D, et al. Tiotropium sustains the anti-inflammatory action of olodaterol via the cyclic AMP pathway. Pulm Pharmacol Ther. 2014;27(1):29-37.[Crossref] [PubMed] 
  24. Sato E, Koyama S, Okubo Y, Kubo K, Sekiguchi M. Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity. Am J Physiol. 1998;274(6):L970-9.[Crossref] [PubMed] 
  25. Bühling F, Lieder N, Kühlmann UC, Waldburg N, Welte T. Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro. Respir Med. 2007;101(11):2386-94.[Crossref] [PubMed] 
  26. Koarai A, Traves SL, Fenwick PS, Brown SM, Chana KK, Russell RE, et al. Expression of muscarinic receptors by human macrophages. Eur Respir J. 2012;39(3):698-704.[Crossref] [PubMed] 
  27. Milara J, Cervera A, de Diego A, Sanz C, Juan G, Gavaldà A, et al. Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients. Respir Res. 2016;17(1):145.[Crossref] [PubMed] [PMC] 
  28. Reinheimer T, Möhlig T, Zimmermann S, Höhle KD, Wessler I. Muscarinic control of histamine release from airways. Inhibitory M1-receptors in human bronchi but absence in rat trachea. Am J Respir Crit Care Med. 2000;162(2 Pt 1):534-8.[Crossref] [PubMed] 
  29. Fujii YX, Tashiro A, Arimoto K, Fujigaya H, Moriwaki Y, Misawa H, et al. Diminished antigen-specific IgG1 and interleukin-6 production and acetylcholinesterase expression in combined M1 and M5 muscarinic acetylcholine receptor knockout mice. J Neuroimmunol. 2007;188(1-2):80-5.[Crossref] [PubMed] 
  30. Kistemaker LE, van Os RP, Dethmers-Ausema A, Bos IS, Hylkema MN, van den Berge M, et al. Muscarinic M3 receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice. Am J Physiol Lung Cell Mol Physiol. 2015;308(1):L96-103.[Crossref] [PubMed] [PMC] 
  31. Powrie DJ, Wilkinson TM, Donaldson GC, Jones P, Scrine K, Viel K, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J. 2007;30(3):472-8.[Crossref] [PubMed] 
  32. Perng DW, Tao CW, Su KC, Tsai CC, Liu LY, Lee YC. Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD. Eur Respir J. 2009;33(4):778-84.[Crossref] [PubMed] 
  33. Yamada M, Ichinose M. The cholinergic pathways in inflammation: a potential pharmacotherapeutic target for COPD. Front Pharmacol. 2018;9:1426.[Crossref] [PubMed] [PMC] 
  34. Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandström T, Taylor AF, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med. 2013;1(3):199-209.[Crossref] [PubMed] 
  35. Calverley PMA, Anzueto AR, Carter K, Grönke L, Hallmann C, Jenkins C, et al. Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial. Lancet Respir Med. 2018;6(5):337-44.[Crossref] [PubMed] 
  36. Beeh KM, Korn S, Beier J, Jadayel D, Henley M, D'Andrea P, et al. Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study. Respir Med. 2014;108(4):584-92.[Crossref] [PubMed] 
  37. Vincken W, Aumann J, Chen H, Henley M, McBryan D, Goyal P. Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study. Int J Chron Obstruct Pulmon Dis. 2014;9:215-28.[Crossref] [PubMed] [PMC] 
  38. Mahler DA, Decramer M, D'Urzo A, Worth H, White T, Alagappan VK, et al. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J. 2014;43(6):1599-609.[Crossref] [PubMed] 
  39. Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4). Eur Respir J. 2015;45(4):969-79. Erratum in: Eur Respir J. 2015;45(6):1763.[Crossref] [PubMed] [PMC] 
  40. Oba Y, Sarva ST, Dias S. Efficacy and safety of long-acting β-agonist/long-acting muscarinic antagonist combinations in COPD: a network meta-analysis. Thorax. 2016;71(1):15-25.[Crossref] [PubMed] 
  41. Meyer T, Reitmeir P, Brand P, Herpich C, Sommerer K, Schulze A, et al. Effects of formoterol and tiotropium bromide on mucus clearance in patients with COPD. Respir Med. 2011;105(6):900-6.[Crossref] [PubMed] 
  42. Tagaya E, Yagi O, Sato A, Arimura K, Takeyama K, Kondo M, et al. Effect of tiotropium on mucus hypersecretion and airway clearance in patients with COPD. Pulm Pharmacol Ther. 2016;39:81-4.[Crossref] [PubMed] 
  43. Cazzola M, Calzetta L, Puxeddu E, Ora J, Facciolo F, Rogliani P, et al. Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells. Respir Res. 2016;17(1):70.[Crossref] [PubMed] [PMC] 
  44. Albano GD, Bonanno A, Moscato M, Anzalone G, Di Sano C, Riccobono L, et al. Crosstalk between mAChRM3 and β2AR, via acetylcholine PI3/PKC/PBEP1/Raf-1 MEK1/2/ERK1/2 pathway activation, in human bronchial epithelial cells after long-term cigarette smoke exposure. Life Sci. 2018;192:99-109.[Crossref] [PubMed] 
  45. Wex E, Kollak I, Duechs MJ, Naline E, Wollin L, Devillier P. The long-acting β2 -adrenoceptor agonist olodaterol attenuates pulmonary inflammation. Br J Pharmacol. 2015;172(14):3537-47.[Crossref] [PubMed] [PMC] 
  46. Keränen T, Hömmö T, Hämäläinen M, Moilanen E, Korhonen R. Anti-inflammatory effects of β2-receptor agonists salbutamol and terbutaline are mediated by MKP-1. PLoS One. 2016;11(2):e0148144.[Crossref] [PubMed] [PMC] 
  47. Keränen T, Hömmö T, Moilanen E, Korhonen R. β2-receptor agonists salbutamol and terbutaline attenuated cytokine production by suppressing ERK pathway through cAMP in macrophages. Cytokine. 2017;94:1-7.[Crossref] [PubMed] 
  48. Xu ZP, Yang K, Xu GN, Zhu L, Hou LN, Zhang WH, et al. Role of M3 mAChR in in vivo and in vitro models of LPS-induced inflammatory response. Int Immunopharmacol. 2012;14(3):320-7.[Crossref] [PubMed] 
  49. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421(6921):384-8.[Crossref] [PubMed] 
  50. Su X, Lee JW, Matthay ZA, Mednick G, Uchida T, Fang X, et al. Activation of the alpha7 nAChR reduces acid-induced acute lung injury in mice and rats. Am J Respir Cell Mol Biol. 2007;37(2):186-92.[Crossref] [PubMed] [PMC] 
  51. Su X, Matthay MA, Malik AB. Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury. J Immunol. 2010;184(1):401-10.[Crossref] [PubMed] [PMC] 
  52. dos Santos CC, Shan Y, Akram A, Slutsky AS, Haitsma JJ. Neuroimmune regulation of ventilator-induced lung injury. Am J Respir Crit Care Med. 2011;183(4):471-82.[Crossref] [PubMed] 
  53. He Y, Ye ZQ, Li X, Zhu GS, Liu Y, Yao WF, et al. Alpha7 nicotinic acetylcholine receptor activation attenuated intestine-derived acute lung injury. J Surg Res. 2016;201(2):258-65.[Crossref] [PubMed] 
  54. Ma P, Yu K, Yu J, Wang W, Ding Y, Chen C, et al. Effects of nicotine and vagus nerve in severe acute pancreatitis-associated lung injury in rats. Pancreas. 2016;45(4):552-60.[Crossref] [PubMed] 
  55. Ge J, Tian J, Yang H, Hou L, Wang Z, He Z, et al. Alpha7 Nicotine acetylcholine receptor agonist PNU-282987 attenuates acute lung injury in a cardiopulmonary bypass model in rats. Shock. 2017;47(4):474-9.[Crossref] [PubMed] 
  56. Zhao C, Yang X, Su EM, Huang Y, Li L, Matthay MA, et al. Signals of vagal circuits engaging with AKT1 in α7 nAChR+CD11b+ cells lessen E. coli and LPS-induced acute inflammatory injury. Cell Discov. 2017;3:17009.[Crossref] [PubMed] [PMC] 
  57. Pinheiro NM, Santana FP, Almeida RR, Guerreiro M, Martins MA, Caperuto LC, et al. Acute lung injury is reduced by the α7nAChR agonist PNU-282987 through changes in the macrophage profile. FASEB J. 2017;31(1):320-32.[Crossref] [PubMed] 
  58. Wang J, Li R, Peng Z, Zhou W, Hu B, Rao X, et al. GTS-21 Reduces inflammation in acute lung injury by regulating M1 polarization and function of alveolar macrophages. Shock. 2019;51(3):389-400.[Crossref] [PubMed] 
  59. Sun P, Li L, Zhao C, Pan M, Qian Z, Su X. Deficiency of α7 nicotinic acetylcholine receptor attenuates bleomycin-induced lung fibrosis in mice. Mol Med. 2017;23:34-9.[Crossref] [PubMed] [PMC] 
  60. Vicary GW, Ritzenthaler JD, Panchabhai TS, Torres-González E, Roman J. Nicotine stimulates collagen type I expression in lung via α7 nicotinic acetylcholine receptors. Respir Res. 2017;18(1):115.[Crossref] [PubMed] [PMC] 
  61. Gahring LC, Myers EJ, Dunn DM, Weiss RB, Rogers SW. Nicotinic alpha 7 receptor expression and modulation of the lung epithelial response to lipopolysaccharide. PLoS One. 2017;12(4):e0175367.[Crossref] [PubMed] [PMC] 
  62. Nastrucci C, Russo P. α7 nAChR in airway respiratory epithelial cells. Curr Drug Targets. 2012;13(5):666-70.[Crossref] [PubMed] 
  63. Maouche K, Medjber K, Zahm JM, Delavoie F, Terryn C, Coraux C, et al. Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure. Proc Natl Acad Sci U S A. 2013;110(10):4099-104.[Crossref] [PubMed] [PMC] 
  64. Chernyavsky AI, Shchepotin IB, Galitovkiy V, Grando SA. Mechanisms of tumor-promoting activities of nicotine in lung cancer: synergistic effects of cell membrane and mitochondrial nicotinic acetylcholine receptors. BMC Cancer. 2015;15:152.[Crossref] [PubMed] [PMC] 
  65. Schaal C, Chellappan S. Nicotine-mediated regulation of nicotinic acetylcholine receptors in non-small cell lung adenocarcinoma by E2F1 and STAT1 transcription factors. PLoS One. 2016;11(5):e0156451.[Crossref] [PubMed] [PMC] 
  66. Schuller HM. Regulatory role of the α7nAChR in cancer. Curr Drug Targets. 2012;13(5):680-7.[Crossref] [PubMed] 
  67. Schuller HM, Orloff M. Tobacco-specific carcinogenic nitrosamines. Ligands for nicotinic acetylcholine receptors in human lung cancer cells. Biochem Pharmacol. 1998;55(9):1377-84.[Crossref] [PubMed] 
  68. Bordas A, Cedillo JL, Arnalich F, Esteban-Rodriguez I, Guerra-Pastrián L, de Castro J, et al. Expression patterns for nicotinic acetylcholine receptor subunit genes in smoking-related lung cancers. Oncotarget. 2017;8(40):67878-90.[Crossref] [PubMed] [PMC] 
  69. Russo P, Del Bufalo A, Milic M, Salinaro G, Fini M, Cesario A. Cholinergic receptors as target for cancer therapy in a systems medicine perspective. Curr Mol Med. 2014;14(9):1126-38.[Crossref] [PubMed] 
  70. Cardoso V, Chesné J, Ribeiro H, García-Cassani B, Carvalho T, Bouchery T, et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature. 2017;549(7671):277-81.[Crossref] [PubMed] [PMC] 
  71. Klose CSN, Mahlakõiv T, Moeller JB, Rankin LC, Flamar AL, Kabata H, et al. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature. 2017;549(7671):282-6.[Crossref] [PubMed] [PMC] 
  72. Wallrapp A, Riesenfeld SJ, Burkett PR, Abdulnour RE, Nyman J, Dionne D, et al. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature. 2017;549(7672):351-6. Erratum in: Nature. 2017.[Crossref] [PubMed] [PMC] 
  73. Moriyama S, Brestoff JR, Flamar AL, Moeller JB, Klose CSN, Rankin LC, et al. β2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science. 2018;359(6379):1056-61.[Crossref] [PubMed] 
  74. Gu X, Karp PH, Brody SL, Pierce RA, Welsh MJ, Holtzman MJ, et al. Chemosensory functions for pulmonary neuroendocrine cells. Am J Respir Cell Mol Biol. 2014;50(3):637-46.[Crossref] [PubMed] [PMC] 
  75. Cutz E, Perrin DG, Pan J, Haas EA, Krous HF. Pulmonary neuroendocrine cells and neuroepithelial bodies in sudden infant death syndrome: potential markers of airway chemoreceptor dysfunction. Pediatr Dev Pathol. 2007;10(2):106-16.[Crossref] [PubMed] 
  76. Gillan JE, Cutz E. Abnormal pulmonary bombesin immunoreactive cells in Wilson-Mikity syndrome (pulmonary dysmaturity) and bronchopulmonary dysplasia. Pediatr Pathol. 1993;13(2):165-80.[Crossref] [PubMed] 
  77. Young LR, Brody AS, Inge TH, Acton JD, Bokulic RE, Langston C, et al. Neuroendocrine cell distribution and frequency distinguish neuroendocrine cell hyperplasia of infancy from other pulmonary disorders. Chest. 2011;139(5):1060-71.[Crossref] [PubMed] 
  78. van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet. 2011;378(9804):1741-55.[Crossref] [PubMed] 
  79. Sui P, Wiesner DL, Xu J, Zhang Y, Lee J, Van Dyken S, et al. Pulmonary neuroendocrine cells amplify allergic asthma responses. Science. 2018;360(6393):eaan8546.[Crossref] [PubMed] [PMC] 
  80. Linnoila RI. Functional facets of the pulmonary neuroendocrine system. Lab Invest. 2006;86(5):425-44.[Crossref] [PubMed] 
  81. Barrios J, Patel KR, Aven L, Achey R, Minns MS, Lee Y, et al. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. FASEB J. 2017;31(9):4117-28.[Crossref] [PubMed] [PMC] 
  82. Ibiza S, García-Cassani B, Ribeiro H, Carvalho T, Almeida L, Marques R, et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature. 2016;535(7612):440-3.[Crossref] [PubMed] [PMC] 

.: Up To Date

.: Process List

Login

 Forgot your password?

 New Registration  

Contact

Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com