Levels of isoforms of fibronectin and α5/CD49e integrin on lymphocytes and in blood plasma in the conditions of chronic diffuse liver diseases
Abstract
Chronic diffuse liver diseases are characterized by accumulation of complex inflammatory infiltrate in the liver tissues, blood, and lympha, and activation of the immune system. Leukocytes become involved in the area of inflammation after the activation of receptors of blood adhesia, particularly integrins and their ligands. Plasma lymphocytes quickly activate the function of integrins by changing their conformation, leading to high affinity and underlying the formation of strong stable connection between the components of extracellular matrix. A vitally important role in the process of liver fibrogenesis is performed by a pro-fibrogenicic protein fibronectin which induces the expresson of collagen genes and precedes the deposition of other components of matrix. The studies were conducted in the group of patients suffering from chronic diffuse liver diseases of non-viral etiology aged 28–60 years, n = 36 and in the group of 15 practically healthy volunteer donors aged 25 to 52 years without a history of liver diseases using the methods of flow cytofluorometry, immunoenzymatic analysis, and quantitative real-time polymerase chain reaction. The patients of the group with chronic diffuse liver diseases were observed to have statistically significant decrease in the concentration of plasmatic form of fibronectin measuring 27.6% compared with the control group. We determined increase in the concentration of cellular fibronectin in blood plasma of patients with the diseases on average accounting for 63.8% compared with the norm, and the highest increase in this parameter equaling 77.2% was seen in patients suffering from drug-induced hepatitis. Significant increase in the level of exposure of cellular FN on blood lymphocytes was determined in patients with chronic diffuse liver diseases, measuring 231.8%, whereas the level of plasmatic form of fibronectin in these cells was decreased (statistically unreliable). For α5-integrin subunit, we determined a 390.8% increase in the level of its exposure in blood lymphocytes in the surveyed groups compared with the control. Level of blood lymphocytes that express the cellular fibronectin significantly decreased by 140.1%. Statistical characteristics of diagnostic possibility of the parameters of the level of plasmatic and cellular fibronectin in blood, determined over the analysis of ROC-curves, demonstrated excellent informativeness of these tests. Analysis of the possibility of predicting the presence of pathology using the model of logistic regression revealed zero error of prediction and maximum efficiency of the tests: intensity of exposure of α5-integrin receptor on the surface of lymphocytes, intensity of exposure of plasmatic fibronectin on the surface of lymphocytes, intensity of exposure of cellular fibronectin on the surface of lymphocytes, concentration of plasmatic fibronectin in blood, concentration of cellular fibronectin in blood plasma. These parameters may be proposed for further surveys for developing serologic biomarkers based on the parameters for diagnostics of chronic diffuse liver diseases.References
Abram, C. L., & Lowell, C. A. (2009). The ins and outs of leukocyte integrin signaling. Annual Review of Immunology, 27, 339–362.
André, L. F., Sampaio, A. L. F., Zahn, G., Leoni, G., Vossmeyer, D., Christner, C., Marshall, J. F., & Perretti, M. (2010). Inflammation‐dependent α5β1 (very late antigen‐5) expression on leukocytes reveals a functional role for this integrin in acute peritonitis. Journal of Leukocyte Biology, 87(5), 877–884.
Aziz-Seible, R. S., & Casey, C. A. (2011). Fibronectin: Functional character and role in alcoholic liver disease. World Journal of Gastroenterology, 17(20), 2482–2499.
Barreiro, O., & Sánchez-Madrid, F. (2009). Molecular basis of leukocyte-endothelium interactions during the inflammatory response. Revista Española de Cardiologia, 62(5), 552–562.
Burns, J. А., Issekutz, T. B., Yagita, H., & Issekutz, A. C. (2001). The α4β1 (very late antigen (VLA)‐4, CD49d/CD29) and α5β1 (VLA‐5, CD49e/CD29) integrins mediate β2 (CD11/CD18) integrin‐independent neutrophil recruitment to endotoxin-induced lung inflammation. The Journal of Immunology, 166, 4644–4649.
Chan, J. R., Hyduk, S. J., & Cybulsky, M. I. (2003). Detecting rapid and transient upregulation of leukocyte integrin affinity induced by chemokines and chemoattractants. Journal of Immunological Method, 273, 43–52.
Cseh, B., Fernandez-Sauze, S., Dominique Grall, D., Schaub, S., Doma, E., & Obberghen-Schilling, E. V. (2010). Autocrine fibronectin directs matrix assembly and crosstalk between cell-matrix and cell-cell adhesion in vascular endothelial cells. Journal of Cell Science, 123, 3989–3999.
Didenko,V. І., Klenіna, І. A., & Oshmyanska, N. Y. (2014). Morfolohicheskaja i byokhimicheskaja otsenka prohressirovanija khronicheskogo hepatita assotsiirovannogo s virusom C [Morphological and biochemical assessment of the progression of chronic hepatitis associated with the virus C]. Gastroenterologija, 52, 37–41 (in Russian).
Dolgikh, A. V., Netronina, O. V., Maslak, A. S., & Abraimova, O. V. (2018). Genetycheski determenirovannye osobennosti vlijanija molekuliarnoj struktury otdel’nykh izoform fibronektina na patogenicheski znachimye protsessy metabolizma v organizme (obzor literatury) [Genetically determined features of the influence of the molecular structure of individual fibronectin isoforms on pathogenically significant metabolic processes in the body (literature review)]. Laboratornaya Diagnostika, Vostochnaya Yevropa, 7(3), 342–359 (in Russian).
Dolgikh, H. V., Maslak, H. S., Didenko, V. I., Klenina, I. A., & Abraimova O. E. (2020). Aktyvnist’ katepsyniv B, L ta H v plazmi krovi u patsyentiv z khronichnymy dyfuznymy zakhvoriuvanniamy pechinky [Activity of catepsins B, L and H in blood plasma in patients with chronic diffusive liver diseases]. Medychna ta Klinichna Khimiia, 1, 23–35 (in Ukranian).
Hu, P., & Luo, B. H. (2013). Integrin bi-directional signaling across the plasma membrane. Journal of Cellular Physiology, 228, 306–312.
Huveneers, S., Truong, H., Fässler, R., Sonnenberg, A., & Danen, E. (2008). Binding of soluble fibronectin to integrin α5β1 – link to focal adhesion redistribution and contractile shape. Journal of Cell Science, 121, 2452–2462.
Kinashi, T. (2005). Intracellular signalling controlling integrin activation in lymphocytes. Nature Reviews Immunology, 5(7), 546–559.
Koh, T. J., & DiPietro, L. A. (2011). Inflammation and wound healing: The role of the macrophage. Expert Reviews in Molecular Medicine, 13, e23.
Koivisto, L., Heino, J., Häkkinen, L., & Larjava, H. (2014). Integrins in wound healing. Advances in Wound Care, 3(12), 762–783.
Kulinich, A. O., Minchenko, D. O., Maslak, H. S., Shevtsova, A. I., Brazaluk, O. Z., & Minchenko, O. H. (2010). Fibronectin-1 expression in lymphocytes of patients with erythremia. Ukrains’kyi Biokhimichnyi Zhurnal, 482(4), 53–99 (in Ukranian).
Lang, T. A., & Sesik, M. (2011). Kak opisyvat’ statistiku v meditsine. Rukovodstvo dlya avtorov, redaktorov i retsenzentov [How to describe the statistics in medicine. A guide for authors, editors and reviewers]. Prakticheskaya Meditsina, Moscow (in Russian).
Lee, U. Е., & Fridman, S. L. (2011). Mechanisms of hepatic fibrogenesis. Best Practice and Research: Clinical Gastroenterology, 25(2), 195–206.
Levitan, B. N., & Astakhin, A. V. (2012). Diagnosticheskoye i prognosticheskoye znacheniye plazmennogo fibronektina pri khronicheskikh diffuznykh zabolevaniyakh pecheni [Diagnostic and prognostic value of plasma fibronectin in chronic diffuse liver diseases]. Rossiyskiy Gastroenterologicheskiy Zhurnal, 99, 1– 6 (in Russian).
Machado-Pineda, Y., Cardeñes, B., Raquel Reyes, R., López-Martín, S., Toribio, V., Sánchez-Organero, P., Suarez, H., Joachim Grötzinger, J., Lorenzen, I., Yáñez-Mó, M., & Cabañas, C. (2018). CD9 controls integrin α5β1-mediated cell adhesion by modulating its association with the metalloproteinase ADAM17. Frontiers in Immunology, 9, 1–14.
Mandrekar, J. N. (2010). Simple statistical measures for diagnostic accuracy assessment. Journal of Thoracic Oncology, 5(6), 763–764.
Netronina, O. V., Maslak, A. S., & Novik, E. U. (2018). Uroven’ lektin-svyazyvayu-shchikh leykotsitov v krovi bol’nykh dobrokachestvennymi pervichnymi opu-kholyami [Level of lectin binding white blood cells in patients with benign pri-mary tumors]. Zhurnal Grodnenskogo Gosudarstvennogo Mediczinskogo Universiteta, 45(4), 570–572 (in Russian).
Novikov, D. K., & Novikova, V. I. (1996). Otsenka immunnogo statusa [Evaluation of the immune status]. Meditsina, Moscow (in Russian).
Rodríguez-Juan, C., de la Torre, P., García-Ruiz, I., Díaz-Sanjuán, T., Muñoz-Yagüe, T., Gómez-Izquierdo., E., Solís-Muñoz, P., & Solís-Herruzo, J. A. (2009). Fibronectin increases survival of rat hepatic stellate cells – a novel profibrogenic mechanism of fibronectin. Cellular Physiology and Biochemistry, 24, 271–282.
Schwarzbauer, J. E., & DeSimone, D. W. (2011). Fibronectins, their fibrillogenesis, and in vivo functions. Cold Spring Harbor Perspectives in Biology, 3(7), а005041.
Springer, T. A. (1995). Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annual Review of Physiology, 57, 827–872.
Svegliati-Baroni, G., De Minicis, S., & Marzioni, M. (2008). Hepatic fibrogenesis in response to chronic liver injury: Novel insights on the role of cell-to-cell interaction and transition. Liver International, 28(8), 1052–1064.
To, W. S., & Midwood, K. S. (2011). Plasma and cellular fibronectin: Distinct and independent functions during tissue repair. Fibrogenesis and Tissue Repair, 21, 4–21.
Tomasini-Johansson, B. R., Annis, D. S., & Mosher, D. F. (2006). The N-terminal 70-kDa fragment of fibronectin binds to cell surface fibronectin assembly sites in the absence of intact fibronectin. Matrix Biology, 25, 282–293.
Zhou, X., Rowe, R. G., Hiraoka, N., George, J. P., Wirtz, D., Mosher, D. F., Virtanen, I., Chernousov, M. A., & Weiss, S. J. (2008). Fibronectin fibrillogenesis regulates three-dimensional neovessel formation. Genes and Development, 22(9), 1231–1243.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons «Attribution» 4.0 License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
