Влияние системы гормона роста / ИФР-1 на функцию трансплантата и иммунный ответ у детей – реципиентов печени

Гормон роста (ГР) и инсулиноподобный фактор роста 1 (ИФР-1) – важнейшие регуляторы роста, регенерации и метаболизма. Влияние гормона роста и ИФР-1 на результаты трансплантации печени детям опосредовано через регуляцию роста и массы тела, специфические эффекты на функцию гепатоцитов, активность иммунной системы. Последние годы показана связь содержания этих факторов в крови с продолжительностью жизни, как здоровых лиц, так и реципиентов печени. У детей – реципиентов печени нейрогуморальная регуляция функции трансплантата, как и других функций растущего организма, исследованы недостаточно. Результаты исследований содержания и динамики гормона роста и ИФР-1 в крови у реципиентов печени могут служить основой для оценки состояния трансплантата с помощью новых малоинвазивных методов и выявления терапевтических мишеней для персонифицированной терапии. В настоящем обзоре суммированы современные представления о значении гормонов системы ГР/ИФР-1 при заболеваниях гепатобилиарной системы и трансплантации печени детям.

1. Wu YL, Ye J, Zhang S, Zhong J, Xi RP. Clinical significance of serum IGF-I, IGF-II and IGFBP-3 in liver cirrhosis. World J Gastroenterol. 2004; 10 (18): 2740–2743.

2. Меньшиков В. Энциклопедия клинических лабораторных тестов. М., 1997; 960.

3. Leung KC, Ho KK. Measurement of growth hormone, insulin-like growth factor I and their binding proteins: the clinical aspects. Clin Chim Acta. 2001; 313 (1–2): 119–123.

4. Takahashi Y. The Role of Growth Hormone and InsulinLike Growth Factor-I in the Liver. Int J Mol Sci. 2017; 18 (7): 1447. doi: 10.3390/ijms18071447.

5. Bilbao D, Luciani L, Johannesson B, Piszczek A, Rosenthal N. Insulin-like growth factor-1 stimulates regulatory T cells and suppresses autoimmune disease. EMBO Mol Med. 2014; 6 (11): 1423–1435. doi: 10.15252/emmm.201303376.

6. Weigent DA. Lymphocyte GH-axis hormones in immunity. Cell Immunol. 2013; 285 (1–2): 118–132. doi: 10.1016/j.cellimm.2013.10.003.

7. Conover CA, Oxvig C. PAPP-A: a promising therapeutic target for healthy longevity. Aging Cell. 2017; 16 (2): 205–209.

8. Cignarelli A, Genchi VA, Le Grazie G, Caruso I, Marrano N, Biondi G et al. Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis. Front Endocrinol. 2022; 13 (846903). doi: 10.3389/fendo.2022.846903.

9. De Palo EF, Bassanello M, Lancerin F, Spinella P, Gatti R, D’Amico D et al. GH/IGF system, cirrhosis and liver transplantation. Clin Chim Acta. 2001; 310 (1): 31–37.

10. Liu Z, Cordoba-Chacon J, Kineman RD, Cronstein BN, Muzumdar R, Gong Z et al. Growth Hormone Control of Hepatic Lipid Metabolism. Diabetes. 2016; 65 (12): 3598–3609. doi: 10.2337/db16-0649.

11. Cao LH, Lu FM, Lu XJ, Zhu LY. Study on the relationship between insulin growth factor 1 and liver fibrosis in patients with chronic hepatitis C with type 2 diabetes mellitus. J Cell Biochem. 2018; 119 (11): 9513–9518. doi: 10.1002/jcb.27267.

12. Gariani K, Toso C, Philippe J, Orci LA. Effects of liver transplantation on endocrine function: A systematic review. Liver Int. 2016; 10 (10): 13158. doi: 1111/liv.

13. Chishima S, Kogiso T, Matsushita N, Hashimoto E, Tokushige K. The Relationship between the Growth Hormone/Insulin-like Growth Factor System and the Histological Features of Nonalcoholic Fatty Liver Disease. Intern Med. 2017; 56 (5): 473–480. doi: 10.2169/internalmedicine.56.7626.

14. Bonefeld K, Moller S. Insulin-like growth factor-I and the liver. Liver Int. 2011; 31 (7): 911–919. doi:10.1111/j.1478-3231.2010.02428.x.

15. Castro GR, Coelho JC, Parolin MB, Matias JE, de Freitas AC. Insulin-like growth factor I correlates with MELD and returns to normal level after liver transplantation. Ann Transplant. 2013; 18: 57–62. doi: 10.12659/AOT.883819.

16. Dichtel LE, Cordoba-Chacon J, Kineman RD. Growth hormone and insulin-like growth factor I regulation of nonalcoholic fatty liver disease. J Clin Endocrinol Metab. 2022; 16 (10). doi: 1210/clinem/dgac088.

17. Sobrevals L, Rodriguez C, Romero-Trevejo JL, Gondi G, Monreal I, Paneda A et al. Insulin-like growth factor I gene transfer to cirrhotic liver induces fibrolysis and reduces fibrogenesis leading to cirrhosis reversion in rats. Hepatology. 2010; 51 (3): 912–921. doi: 10.1002/hep.23412.

18. de la Garza RG, Morales-Garza LA, Martin-Estal I, Castilla-Cortazar I. Insulin-Like Growth Factor-1 Deficiency and Cirrhosis Establishment. J Clin Med Res. 2017; 9 (4): 233–247. doi: 10.14740/jocmr2761w.

19. Kawai M, Harada N, Takeyama H, Okajima K. Neutrophil elastase contributes to the development of ischemia/ reperfusion-induced liver injury by decreasing the production of insulin-like growth factor-I in rats. Transl Res. 2010; 155 (6): 294–304. doi: 10.1016/j.trsl.2010.02.003.

20. Meng F, Zhang Z, Chen C, Liu Y, Yuan D, Hei Z et al. PI3K/AKT activation attenuates acute kidney injury following liver transplantation by inducing FoxO3a nuclear export and deacetylation. Life Sci. 2021; 272 (119119):26. doi: 10.1016/j.lfs.2021.119119.

21. Conchillo M, de Knegt RJ, Payeras M, Quiroga J, Sangro B, Herrero JI et al. Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: results of a pilot randomized controlled clinical trial. J Hepatol. 2005; 43 (4): 630–636. doi:10.1016/j.jhep.2005.03.025.

22. Шевченко ОП, Цирульникова ОМ, Цирульникова ИЕ, Курабекова РМ, Олефиренко ГА, Степанова ОИ и др. Динамика инсулиноподобного фактора роста 1 (ИФР-1) при трансплантации печени детям от донора, не совместимого по группе крови. Вестник трансплантологии и искусственных органов. 2014; XVI (2): 46–51.

23. Stefano JT, Correa-Giannella ML, Ribeiro CM, Alves VA, Massarollo PC, Machado MC et al. Increased hepatic expression of insulin-like growth factor-I receptor in chronic hepatitis C. World J Gastroenterol. 2006; 12 (24): 3821–3828.

24. Nishizawa H, Iguchi G, Fukuoka H, Takahashi M, Suda K, Bando H et al. IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner. Sci Rep. 2016; 6 (34605). doi: 10.1038/srep34605.

25. Choi JS, Park YJ, Kim SW. Three-dimensional Differentiated Human Mesenchymal Stem Cells Exhibit Robust Antifibrotic Potential and Ameliorates Mouse Liver Fibrosis. Cell Transplant. 2021; 30 (963689720987525): 0963689720987525.

26. Lee SJ, Kim KH, Park KK. Mechanisms of fibrogenesis in liver cirrhosis: The molecular aspects of epithelialmesenchymal transition. World J Hepatol. 2014; 6 (4): 207–216. doi: 10.4254/wjh.v6.i4.207.

27. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008; 134 (4): 657–667. doi:10.1016/j.cell.2008.06.049.

28. Nicolini D, Mocchegiani F, Palmonella G, Coletta M, Brugia M, Montalti R et al. Postoperative Insulin-Like Growth Factor 1 Levels Reflect the Graft’s Function and Predict Survival after Liver Transplantation. PLoS One. 2015; 10 (7). doi: 10.1371/journal.pone.0133153.

29. Abdel-Wahab R, Hassan MM, George B, Carmagnani Pestana R, Xiao L, Lacin S et al. Impact of Integrating Insulin-Like Growth Factor 1 Levels into Model for End-Stage Liver Disease Score for Survival Prediction in Hepatocellular Carcinoma Patients. Oncology. 2020; 98 (12): 836–846. doi: 10.1159/000502482.

30. Курабекова РМ, Цирульникова ОМ, Пашкова ИЕ, Макарова ЛВ, Можейко НП, Монахов АР, Шевченко ОП. Связь уровней гормона роста и инсулиноподобного фактора роста 1 (ИФР-1) с функцией печени и краткосрочной выживаемостью детей – реципиентов печени. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2020; 30 (4): 44–51. doi: 10.22416/1382-4376-2020-30-4-44-51.

31. Kelley KW, Weigent DA, Kooijman R. Protein hormones and immunity. Brain Behav Immun. 2007; 21 (4): 384–392. doi: 10.1016/j.bbi.2006.11.010.

32. Gong FY, Deng JY, Shi YF. Stimulatory effect of interleukin-1beta on growth hormone gene expression and growth hormone release from rat GH3 cells. Neuroendocrinology. 2005; 81 (4): 217–228. doi:10.1159/000087160.

33. Derfalvi B, Szalai C, Mandi Y, Kiraly A, Falus A. Growth hormone receptor gene expression on human lymphocytic and monocytic cell lines. Cell Biol Int. 1998; 22 (11–12): 849–853. doi: 10.1006/cbir.1998.0324.

34. Dardenne M, Smaniotto S, de Mello-Coelho V, Villa-Verde DM, Savino W. Growth hormone modulates migration of developing T cells. Ann N Y Acad Sci. 2009. doi: 10.1111/j.1749-6632.2008.03977.x.

35. Farmer JT, Weigent DA. TGF-beta1 expression in EL4 lymphoma cells overexpressing growth hormone. Cell Immunol. 2006; 240 (1): 22–30. doi: 10.1016/j.cellimm.2006.06.003.

36. Wang K, Wang M, Gannon M, Holterman A. Growth Hormone Mediates Its Protective Effect in Hepatic Apoptosis through Hnf6. PLoS One. 2016; 11 (12). doi: 10.1371/journal.pone.0167085.

37. Walsh PT, Smith LM, O’Connor R. Insulin-like growth factor-1 activates Akt and Jun N-terminal kinases (JNKs) in promoting the survival of T lymphocytes. Immunology. 2002; 107 (4): 461–471.

38. Clark R, Strasser J, McCabe S, Robbins K, Jardieu P. Insulin-like growth factor-1 stimulation of lymphopoiesis. J Clin Invest. 1993; 92 (2): 540–548.

39. Xu J, Wang X, Chen J, Chen S, Li Z, Liu H et al. Embryonic stem cell-derived mesenchymal stem cells promote colon epithelial integrity and regeneration by elevating circulating IGF-1 in colitis mice. Theranostics. 2020; 10(26): 12204–12222. doi: 10.7150/thno.47683.

40. Keshvari S, Caruso M, Teakle N, Batoon L, Sehgal A, Patkar OL et al. CSF1R-dependent macrophages control postnatal somatic growth and organ maturation. PLoS Genet. 2021; 17 (6). doi: 10.1371/journal.pgen.1009605.

41. Dehghani SM, Karamifar H, Hamzavi SS, Haghighat M, Malek-Hosseini SA. Serum insulinlike growth factor-1 and its binding protein-3 levels in children with cirrhosis waiting for a liver transplant. Exp Clin Transplant. 2012; 10 (3): 252–257.

42. Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007; 28 (1): 20–47.

43. Qiao C, Huang W, Chen J, Feng W, Zhang T, Wang Y et al. IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R. Cell Death Dis. 2021; 12 (6): 021-03833. doi: 10.1038/s41419-2.

44. González-Juanatey JR, Piñeiro R, Iglesias MJ, Gualillo O, Kelly PA, Diéguez C et al. GH prevents apoptosis in cardiomyocytes cultured in vitro through a calcineurin-dependent mechanism. J Endocrinol. 2004; 180 (2): 325–335. doi: 10.1677/joe.0.1800325.

45. Li SY, Fang CX, Aberle NS, 2nd, Ren BH, Ceylan-Isik AF, Ren J. Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function. J Endocrinol. 2005; 186 (3): 491–503. doi: 10.1677/joe.1.06168.

46. Kawamura I, Takeshita S, Fushimi M, Mabuchi M, Seki J, Goto T. Induction of choleresis by immunosuppressant FK506 through stimulation of insulin-like growth factor-I production in the liver of rats. Eur J Pharmacol. 2001; 419 (1): 99–105. doi: 10.1016/s0014-2999(01)00961-x.

47. Курабекова РМ, Цирульникова ОМ, Гичкун ОЕ, Олефиренко ГА, Пашкова ИЕ, Бельченков АА и др. Взаимосвязь уровня инсулиноподобного фактора роста 1 с дозой такролимуса у детей – реципиентов печени. Вестник трансплантологии и искусственных органов. 2021; 23 (2): 13–20. doi: 10.15825/1995-1191-2021-2-13-20.