Українська English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2017; 63(3): 90-102


Molecular mechanisms of hepatopulmonary syndrome

I.Ya. Krynytska, M.I. Marushchak, I. M. Klishch, I.V. Birchenko

    I. Horbachevsky Ternopil State Medical University, Ternopil, Ukraine
DOI: https://doi.org/10.15407/fz63.03.090


Abstract

Hepatopulmonary syndrome (HPS) is a severe complication seen in advance liver disease. Its prevalence among cirrhotic patients varies from 4 to 47 percent. HPS exact pathogenesis remains unknown. In this review we summarized existing knowledge on the possible mechanisms and causes of the HPS. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental HPS, and thus might underlie HPS in humans. Despite these insights into the pathogenesis of experimental HPS, there is no established medical therapy, and liver transplantation remains the main treatment.

Keywords: hepatopulmonary syndrome; molecular mechanisms.

References

  1. Fluckiger M. Vorkommen von trommelschagel formigen fingerendphalangen ohne chronische veranderungen an der lungen oder am herzen. Wien Med Wochenschr. 1884; 34:1457–61.
  2.  
  3. Amin Z, Amin HZ, Tedyanto NM. Hepatopulmonary syndrome: a brief review. Romanian Journal of Internal Medicine. 2016; 54(2):93–7. CrossRef PubMed
  4.  
  5. Grace JA, Angus PW. Hepatopulmonary syndrome: update on recent advances in pathophysiology, investigation, and treatment. J Gastroenterol Hepatol. 2013; 28(2):213–19. CrossRef PubMed
  6.  
  7. Rodriguez–Roizin R, Krowka MJ. Hepatopulmonary syndrome – a liver–induced lung vascular disorder. New England Journal of Medicine. 2008; 358:2378–87. CrossRef PubMed
  8.  
  9. Zhang J, Fallon MB. Hepatopulmonary syndrome: update on pathogenesis and clinical features. Nat Rev Gastroenterol Hepatol. 2012; 9(9):539–49. CrossRef PubMed
  10.  
  11. Lima B, Martinelli AA, Franca V. Hepatopulmonary syndrome: pathogenesis, diagnosis and treatment. Arq Gastroenterol. 2004; 41(4):250–58. CrossRef PubMed
  12.  
  13. Goncalves de Macedo L, Pessoa de Almeida Lopes E. Hepatopulmonary syndrome: an update. Sao Paulo Med J. 2009; 127(4):223–30. CrossRef  
  14. Gorgy AI, Jonassaint NL, Stanley SE, Koteish A, DeZern AE, Walter JE, Sopha SC, Hamilton JP, Hoover–Fong J, Chen AR, Anders RA, Kamel IR, Armanios M. Hepatopulmonary syndrome is a frequent cause of dyspnea in the short telomere disorders. Chest. 2015; 148:1019. CrossRef PubMed PubMedCentral
  15.  
  16. Shafiq M, Khan AA, Alam A, Coll J. Frequency of hepatopulmonary syndrome in cirrhotic patients. Physician Surq Rak. 2008; 18(5):278–81.
  17.  
  18. Borkar VV, Poddar U, Kapoor A, Srivastava A, Yachha SK. Hepatopulmonary Syndrome in children: a comparative study of non-cirrhotic vs. cirrhotic portal hypertension. Liver International. 2015; 35(6):1665–72. CrossRef PubMed
  19.  
  20. Cosarderelioglu C, Cosar AM, Gurakar M, Dagher NN, Gurakar A. Hepatopulmonary Syndrome and Liver Transplantation: A Recent Review of the Literature. Journal of Clinical and Translational Hepatology. 2016; 4(1):47. CrossRef PubMed PubMedCentral
  21.  
  22. Zhang Z, Qi X, Li Z, Xu L, Wang F, Wang S, Chang Y, Ma W, Xu M, Yang C. Hepatopulmonary syndrome: the role of intra–abdominal hypertension and a novel mouse model. Int J Clin Exp Pathol. 2014; 7(2):768–73. PubMed PubMedCentral
  23.  
  24. Espinosa MD, Nogueras F, Olmedo C, Macias R, Muffak– Granero K, Comino A, Villegas T, Ramirez JA, De Teresa J, Garrote D, Bueno P. Hepatopulmonary syndrome among cirrhotic candidates for liver transplantation. Transplantation Proceedings. 2012; 44(6):1508–9. CrossRef PubMed
  25.  
  26. Krowka MJ. Management of pulmonary complications in pretransplant patients. Clin Liver Dis. 2011; 15(4):765–77. CrossRef PubMed
  27.  
  28. Machicao VI, Fallon MB. Hepatopulmonary syndrome. Semin Respi. Cri Care Med. 2012; 33(1):11–6.
  29.  
  30. Younis I, Sarwar S, Butt Z, Tanveer S, Qaadir A, Jadoon NA. Clinical characteristics, predictors, and survival among patients with hepatopulmonary syndrome. Ann Hepatol. 2015; 14:354. PubMed
  31.  
  32. Taille S, Cadranel J, Bellocq A. Liver transplantation for hepatopulmonary syndrome: a ten–year experience in Paris, France. Transplantation. 2003; 75(9):1482–89. CrossRef PubMed
  33.  
  34. Nayyar D, Man HS, Granton J, Lilly LB, Gupta S. Proposed management algorithm for severe hypoxemia after liver transplantation in the hepatopulmonary syndrome. Am J Transplant. 2015; 15(4):903–13. CrossRef PubMed PubMedCentral
  35.  
  36. Dziedziczko A, Bartuzi Z. Hepatopulmonary syndrome– known symptoms and new name. Case Rep. Clin Pract Rev. 2002; (3):121–7.
  37.  
  38. Dinh–Xuan AT, Naeije R. The hepatopulmonary syndrome: NO way out? European Respiratory Journal. 2004; 23(5):661–2. CrossRef PubMed
  39.  
  40. Kalinichenko OV, Myshunina TM, Tron'ko MD. Nitric oxide synthase activity and its concentration in the tissues of human thyroid carcinomas. Fiziol Zh. 2016; 62(3):9–19. [Ukrainian]. CrossRef  
  41. Strutynska NA, Kotsiuruba aV, Budko AYu, Mys LA, Sagach VF. Mitochondrial dysfunction in the aging heart is accompanied by constitutive no-synthases uncoupling on the background of oxidative and nitrosative stress. Fiziol Zh. 2016; 62(2):3–11. [Ukrainian]. CrossRef  
  42. Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. European Heart Journal. 2012; 33(7):829–37. CrossRef PubMed PubMedCentral
  43.  
  44. Fallon MB. Mechanisms of pulmonary vascular complications of liver disease: hepatopulmonary syndrome. Journal of Clinical Gastroenterology. 2005; 39(4):S138–42. CrossRef PubMed
  45.  
  46. Hamamoto J, Toba S, Hirosako S, Nakamura K, Fujii K, Kohrogi H. A case of hepatopulmonary syndrome with elevated exhaled nitric oxide. Nihon Kokyuki Gakkai Zasshi. 2010; 48(5):379–84. PubMed
  47.  
  48. Rolla G, Brussino L, Colagrande P. Exhaled nitric oxide and impaired oxygenation in cirrhotic patients before and after liver transplantation. Ann Intern Med. 1998; 129(5):375–78. CrossRef PubMed
  49.  
  50. Degano B, Mittaine M, Hervé P, Rami J, Kamar N, Suc B, Rivière D, Rostaing L. Nitric oxide production by the alveolar compartment of the lungs in cirrhotic patients. European Respiratory Journal. 2009; 34(1):138–44. CrossRef PubMed
  51.  
  52. Delclaux C, Mahut B, Zerah–Lancner F, Delacourt C, Laoud S, Cherqui D, Duvoux C, Mallat A, Harf A. Increased nitric oxide output from alveolar origin during liver cirrhosis versus bronchial source during asthma. American Journal of Respiratory and Critical Care Medicine. 2002; 165(3):332–7. CrossRef PubMed
  53.  
  54. Nunes H, Lebrec D, Mazmanian M, Capron F, Heller J, Tazi KA, Zerbib E, Dulmet E, Moreau R, Dinh–Xuan AT, Simonneau G, Hervé P. Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats. Am J Respir Crit Care Med. 2001; 164(5):879–85. CrossRef PubMed
  55.  
  56. Zhang J, Ling Y, Luo B, Tang L, Ryter SW, Stockard CR, Grizzle WE, Fallon MB. Analysis of pulmonary heme oxygenase–1 and nitric oxide synthase alterations in experimental hepatopulmonary syndrome. Gastroenterology. 2003; 125:1441–51. CrossRef PubMed
  57.  
  58. Brussino L, Bucca C, Morello M, Scappaticci E, Mauro M, Rolla G. Effect on dyspnoea and hypoxaemia of inhaled N G–nitro–L–arginine methyl ester in hepatopulmonary syndrome. The Lancet. 2003; 362(9377):43–4. CrossRef  
  59. Aksu B, Umit H, Kanter M, Guzel A, Aktas C, Civelek S, Uzun H. Effects of methylene blue in reducing cholestatic oxidative stress and hepatic damage after bile–duct ligation in rats. Acta Histochemica. 2010; 112(3):259–69. CrossRef PubMed
  60.  
  61. Schenk P, Madl C, Rezaie–Majd S, Lehr S, Müller C. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med. 2000; 133(9):701–6. CrossRef PubMed
  62.  
  63. Gómez FP, Barberà JA, Roca J, Burgos F, Gistau C, Rodríguez–Roisin R. Effects of nebulized NG–nitro–L– arginine methyl ester in patients with hepatopulmonary syndrome. Hepatology. 2006; 43(5):1084–91. CrossRef PubMed
  64.  
  65. Luo B, Liu L, Tang L, Zhang J, Ling Y, Fallon MB. Et–1 and TNF–alpha in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats. Am J Physiol Gastrointest Liver Physiol. 2004; 286(2):G294–G303. CrossRef PubMed
  66.  
  67. Liu L, Liu N, Zhao Z, Liu J, Feng Y, Jiang H, Han D. TNF–α neutralization improves experimental hepatopulmonary syndrome in rats. Liver International. 2012; 32(6):1018–26. CrossRef PubMed
  68.   Olmos G, Lladó J. Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity. Mediators of Inflammation [serial on the Internet]. 2014 May [cited 2016 Sept 21];2014:[about 12 p.]. Available from: https:.www.hindawi.com/journals/ mi/2014/861231/cta/  
  69. Panasyukova OR, Kadan LP. The role of inflammatory mediators in the pathogenesis of COPD (Literature Review). Ukr Chemioter J. 2009; (3):15–20. [Ukrainian].
  70.  
  71. Prokhorenko TS, Saprina TV, Lazarenko FE, Ryazantseva NV, Vorozhtsova IN, Novitsky VV. The system of tumor necrosis factor α in the pathogenesis of autoimmune diabetes mellitus. Bulletin of Siberian Medicine. 2011; 10(1):64–9. [Russian].
  72.  
  73. Sztrymf B, Rabiller A, Nunes H, Savale L, Lebrec D, Le Pape A, de Montpreville V, Mazmanian M, Humbert M, Hervé P. Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats. Eur Respir J. 2004; 23(5):752–58. CrossRef PubMed
  74.  
  75. Garbuzenko DV. The pathophysiological mechanisms and new areas of treatment of portal hypertension in liver cirrhosis. Clin Perspectives of Gastroenterol, Gepatol. 2010; (6):11–20. [Russian].
  76.  
  77. Van Landeghem L, Laleman W, Vander EI, Zeegers M, van Pelt J, Cassiman D, Nevens F. Carbon monoxide produced by intrasinusoidally located haemoxygenase–1 regulates the vascular tone in cirrhotic rat liver. Liver Int. 2009; 29(5):650–60. CrossRef PubMed
  78.  
  79. Félétou M. The endothelium. Part I: Multiple functions of the endothelial cells–focus on endothelium–derived vasoactive mediators. In Colloquium Series on Integrated Systems Physiology: From Molecule to Function. 2011; 3(4):1–306.
  80.  
  81. Nechyporuk VM, Korda MM. Modern aspects of metabolism of sulfur–containing amino acids. Med Chemistry. 2010; (12):126–32. [Ukrainian].
  82.  
  83. Drachuk KO, Dorofeyeva NA, Sagach VF. The role of hydrogen sulfide in diastolic function restoration during aging. Fiziol Zh. 2016; 62(6):9–18. CrossRef  
  84. Yanchuk PI, Slobodianyk LA. The role of hydrogen sulfide in regulation of circulation blood liver. Fiziol Zh. 2015; 61(3):28–34. [Ukrainian]. CrossRef PubMed
  85.  
  86. Li L, Bhatia M, Moore PK. Hydrogen sulphide – a novel mediator of inflammation? Curr Opin Pharmacol. 2006; 6(2):125–9. CrossRef PubMed
  87.  
  88. Waqner CA. Hydrogen sulfide: a new gaseous signal molecule and blood pressure regulator. J Nephrol. 2009; 2(22):173–76.
  89.  
  90. Atucha NM, Ortíz MC, Fortepiani LA, Nadal FJ, Martínez– Prieto C, García–Esta- J. Mesenteric hyporesponsiveness in cirrhotic rats with ascites: role of cGMP and K+ channels. Clinical Science. 2000; 99(5):455–60. CrossRef PubMed
  91.  
  92. Hennenberg M, Trebicka J, Sauerbruch T, Heller J. Mechanisms of extrahepatic vasodilation in portal hypertension. Gut. 2008; 57(9):1300–14. CrossRef PubMed
  93.  
  94. Hennenberg M, Biecker E, Trebicka J, Jochem K, Zhou Q, Schmidt M, Jakobs KH, Sauerbruch T, Heller J. Defective RhoA/Rho–kinase signaling contributes to vascular hypocontractility and vasodilatation in cirrhotic rats. Gastroenterology. 2006; 130(2):838–54. CrossRef PubMed
  95.  
  96. Hennenberg M, Trebicka J, Biecker E. Vascular dysfunction in human and rat cirrhosis: role of receptor–desensitizing and calcium–sensitizing proteins. Hepatology. 2007; 45(2):495–506. CrossRef PubMed
  97.  
  98. Castro A, Jiménez W, Clária J, Ros J, Martínez JM, Bosch M, Arroyo V, Piulats J, River F, Rodés J. Impaired responsiveness to angiotensin II in experimental cirrhosis: role of nitric oxide. Hepatology. 1993; 18(2):367–72. PubMed
  99.  
  100. Chang SW, Ohara N. Pulmonary circulatory dysfunction in rats with biliary cirrhosis. Am Rev Respir Dis. 1992; 148:798–805. CrossRef PubMed
  101.  
  102. Ho V. Current concepts in the management of hepatopulmonary syndrome. Vascular Health and Risk Management. 2008; 4(5):1035–41. CrossRef PubMed PubMedCentral
  103.  
  104. Gill SS, Suri SS, Janardhan KS, Caldwell S, Duke T, Singh B. Role of pulmonary intravascular macrophages in endotoxin–induced lung inflammation and mortality in a rat model. Respiratory Research. 2008; 9(1):1. CrossRef PubMed PubMedCentral
  105.  
  106. Iwatsuki K, Tanaka K, Kaneko T, Kazama R, Okamoto S, Nakayama Y, Ito Y, Satake M, Takahashi S, Miyajima A, Watanabe T, Hara T. Runx1 promotes angiogenesis by down–regulation of insulin–like growth factor–binding protein–3. Oncogene. 2005; 24(7):1129–37. CrossRef PubMed
  107.  
  108. Reichetzeder C, Tsuprykov O, Hocher B. Endothelin receptor antagonists in clinical research – Lessons learned from preclinical and clinical kidney studies. Life Sciences. 2014; 118(2):141–48. CrossRef PubMed
  109.  
  110. Zhang ZJ, Chang–Qing Y. Progress in investigating the pathogenesis of hepatopulmonary syndrome. Hepatobiliary Pancreat Dis Int. 2010; 9(4):355–60. PubMed
  111.  
  112. Vercelino R, Tieppo J, Forgiarini Junior LA, Dias AS, Marroni CA, Marroni NP. Experimental models for assessment of pulmonary alterations in hepatopulmonary syndrome. J Bras Pneumol. 2008; 34(7):453–60. CrossRef PubMed
  113.  
  114. Ling Y, Zhang J, Luo B, Song D, Liu L, Tang L, Stockard CR, Grizzle WE, Ku DD, Fallon MB. The role of endothelin–1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the rat. Hepatology. 2004; 39(6):1593–1602. CrossRef PubMed
  115.  
  116. Zhang J, Ling Y, Tang L, Luo B, Pollock DM, Fallon MB. Attenuation of experimental hepatopulmonary syndrome in endothelin B receptor–deficient rats. Am J Phisiol Gastrointest Liver Physiol. 2009; 296(4):G704–G708. CrossRef PubMed PubMedCentral
  117.  
  118. Yan Y, Bao XQ, Wang Y. Roles of vascular mediators in the pathogenesis of hepatopulmonary syndrome in rats. Shijie Huaren Xiaohua Zazhi. 2008; 16:1053–58.
  119.  
  120. Luo B, Abrams GA, Fallon MB. Endothelin–1 in the rat bile duct ligation model of hepatopulmonary syndrome: correlation with pulmonary dysfunction. J Hepatology. 1998; 29(4):571–78. CrossRef  
  121. Pinzani M, Milani S, De Franco R, Grappone C, Caligiuri A, Gentilini A, Tosti–Guerra C, Maggi M, Failli P, Ruocco C, Gentilini P. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology. 1996; 110(2):534–48. CrossRef PubMed
  122.  
  123. Silva HM, Reis G, Guedes M, Cleto E, Vizcaíno JR, Kelly D, Gennery AR, Silva ES. A case of hepatopulmonary syndrome solved by mycophenolate mofetil (an inhibitor of angiogenesis and nitric oxide production). J Hepatol. 2013; 58(3):630–33. CrossRef PubMed
  124.  
  125. Zhang J, Luo B, Tang L, Wang Y, Stockard CR, Kadish I, Van Groen T, Grizzle WE, Ponnazhagan S, Fallon MB. Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome. Gastroenterology. 2009; 136(3):1070–80. CrossRef PubMed PubMedCentral
  126.  
  127. Sprindzhuk MV. Angiogenesis. Annals of Restorative Medicine. 2010; (5):15–20. [Russian].
  128.  
  129. Tsokolaeva ZI. Stimulation of angiogenesis in ischemic myocardium and skeletal muscles by transient transgenic expression of urokinase [disertation], Moscow; 2006. [Russian].
  130.  
  131. Fallon MB, Abrams GA, McGrath JW, Hou Z, Luo B. Common bile duct ligation in the rat: a model of intrapulmonary vasodilatation and hepatopulmonary syndrome. Am J Physiol Gastrointest Liver Physiol. 1997; 272(4):G779–84.
  132.  
  133. Bosch J. Vascular deterioration in cirrhosis: the big picture. Journal of Clinical Gastroenterology. 2007; 41:S247–53. CrossRef PubMed
  134.  
  135. Neugebauer H, Hartmann P, Krenn S, Glück T, Schölmerich J, Straub R, Wiest R. Bacterial translocation increases phagocytic activity of polymorphonuclear leucocytes in portal hypertension: priming independent of liver cirrhosis. Liver Int. 2008; 28(8):1149–57. CrossRef PubMed
  136.  
  137. Seo YS, Shah VH. The role of gut–liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol. 2012; 18(4):337–46. CrossRef PubMed PubMedCentral
  138.  
  139. Sztrymf B, Libert JM, Mougeot C, Lebrec D, Mazmanian M, Humbert M, Herve P. Cirrhotic rats with bacterial translocation have higher incidence and severity of hepatopulmonary syndrome. J Gastroenterol Hepatol. 2005; 20(10):1538–44. CrossRef PubMed
  140.  
  141. Zhang HY, Han DW, Su AR, Zhang LT, Zhao ZF, Ji JQ, Li BH, Ji C. Intestinal endotoxemia plays a central role in development of hepatopulmonary syndrome in a cirrhotic rat model induced by multiple pathogenic factors. World J Gastroenterol. 2007; 13(47):6385–95. CrossRef PubMed PubMedCentral
  142.  
  143. Titov VN, Dugin SF. Translocation syndrome, bacterial lipopolysaccharide, inflammation disorders of biological reactions and blood pressure. Clin Lab Diagn. 2010; (4):21–37. [Russian].
  144.  
  145. Garbuzenko DV. The role of intestine microflora in the development of portal hypertension in hepatic cirrhosis. Clin Medicine. 2007; (8):15–9. [Russian].
  146.  
  147. Vallance P, Moncada S. Hypothesis: induction of nitric oxide synthase in the vasculature underlies the hyperdynamic circulation of cirrhosis. Lancet. 1991; 337:776–78. CrossRef  
  148. Micurov AA, Garbuzenko DV. The comparative analysis of level endotoxemia at patients of the cirrhosis of the liver with the portal hypertensia. Fundamental Reseach. 2011; (6):126–8. [Russian].
  149.  
  150. Gehring S, Dickson EM, San Martin ME, van Rooijen N, Papa EF, Harty MW, Tracy TF, Gregory SH. Kupffer cells abrogate cholestatic liver injury in mice. Gastroenterology. 2006; 130(3):810–22. CrossRef PubMed
  151.  
  152. Teuber G, Teupe C, Dietrich CF. Pulmonary dysfunction in non–cirrhotic patients with chronic viral hepatitis. Eur J Intern Med. 2002; 13(5):311–18. CrossRef  
  153. O'Grady J. Hepatopulmonary Syndrome: Is It Naïve or Enlightening When Genetic Associations Match Clinical Perspective? Gastroenterology. 2010; 139(1):20–2. CrossRef PubMed
  154.  
  155. Roberts KE, Kawut SM, Krowka MJ, Brown RS, Trotter JF, Shah V, Peter I, Tighiouart H, Mitra N, Handorf E, Knowles JA, Zacks S, Fallon MB. Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease. Gastroenterology. 2010; 139(1):130–39. CrossRef PubMed PubMedCentral
  156.  
  157. Digtyar AV, Pozdnyakova NV, Feldman NB, Lutsenko SV, Severin SE. Endostatin: current concepts about its biological role and mechanisms of action. Biochemistry (Moscow). 2007; 72(3):235–46. CrossRef  
  158. McAllister KA, Grogg KM, Johnson DW. Endoglin, a TGF–beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8(4):345–51. CrossRef PubMed
  159.  
  160. Sabbà C, Pasculli G, Lenato GM, Suppressa P, Lastella P, Memeo M, Dicuonzo F, Guant G. Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost. 2007; 5(6):1149–57. CrossRef PubMed
  161.  
  162. Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JG, Semenza GL. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF–1. Blood. 2005; 105(2):659–69. CrossRef PubMed
  163.  
  164. Ismail S, Sturrock A, Wu P, Cahill B, Norman K, Huecksteadt T, Sanders K, Kennedy T, Hoidal J. NOX4 mediates hypoxia–induced proliferation of human pulmonary artery smooth muscle cells: the role of autocrine production of transforming growth factor–β1 and insulin– like growth factor binding protein–3. Am J Physiol Lung Cell Mol Physiol. 2009; 296(3):L489–L499. CrossRef PubMed PubMedCentral

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2024.