Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC128410.15690/vramn1284IMMUNOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ИММУНОЛОГИИResearch ArticleMast Cells Heparin — New Information on the Old Component (Review)Гепарин тучных клеток — новые сведения о старом компоненте (обзор литературы)https://orcid.org/0000-0002-1302-84464421-5225KondashevskayaMarina V.КондашевскаяМарина Владиславовна
Russian Federation

MD, PhD, assistant professor, Leading Researcher, lab. immunomorphology of inflammation “Research Institute of Human Morphology”

доктор биологических наук, доцент, ведущий научный сотрудник лаб. иммуноморфологии воспаления

aktual_probl@mail.ruResearch Institute of Human MorphologyНаучно-исследовательский институт морфологии человека300620217621491581202202029042021Copyright ©; 2021, "Paediatrician" Publishers LLCCopyright ©; 2021, Издательство "Педиатръ"2021"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/article/view/1284

Mast cells (MC) are widely distributed throughout the body of animals and humans, mainly in barrier tissues. This review provides new information on the hematopoietic origin of MCs from early erythromyeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells. As well as information on the maturation of MSs and heparin synthesis already in the embryonic period. Many physiological functions of MCs are determined by the properties of heparin, which forms the basis of the matrix of granules, since the heparin molecule is a strong polyanion, capable to forming complexes with many biologically active substances and regulating their properties. In a new hypothesis about the participation of MCs in pathological processes, it is assumed that this is due to the depletion of the heparin pool. In such cases, injections of exogenous heparin can help replenish MCs heparin stores. As a result of the restoration of the physiological functions of MCs and the action of exogenous heparin, the pathological process will be converted into an adaptive one. In clinical practice, unfractionated heparin (UFH) obtained from natural sources and low molecular weight heparin (LMWH) obtained by the biochemical route are used. Most often, UFH and LMWH are used in the clinic only as anticoagulants. The worldwide spread of a disease named COVID-19 in 2020 showed that UFH and LMWH are multifunctional drugs that have saved many people. The pandemic caused by COVID-19 has been an unprecedented social and health emergency worldwide. Depression, anxiety and post-traumatic stress disorder (PTSD) have been reported in populations of many countries. This review provides new information on experimental studies on the successful treatment of pathology with low doses of UFH in modeling PTSD in animals. Consequently, heparin can be considered as a promising multifunctional drug for effective pharmacological correction of comorbid diseases under the influence of extreme factors.

Тучные клетки (ТК) — это многофункциональная, диффузная, очень широко распространенная в организме животных и человека популяция долгоживущих клеток, которые участвуют в большом разнообразии физиологических и патологических процессов. ТК — практически единственный источник высокомолекулярного гепарина, получаемого для использования в медицинских целях. Структура и многие свойства высокомолекулярного гепарина сходны с эндогенным гепарином ТК. В обзоре представлена новая информация о механизмах влияния эндогенного гепарина на многие функции ТК, так как он играет определяющую регуляторную роль в отношении медиаторов гранул. Наиболее характерным для гепарина механизмом воздействия на многие биологически активные вещества является комплексообразование, изменяющее свойства этих биологически активных веществ в соответствии с потребностями окружающей среды. Приводятся гипотезы, объясняющие роль ТК как в физиологических, так и патологических процессах. Одна из гипотез — элиминация гепарина под влиянием внешних стимулов из матрикса гранул ТК, где он является системообразующим для остальных медиаторов компонентом, что обусловливает неконтролируемый выброс провоспалительных биологически активных веществ. Решением проблемы может быть введение экзогенного гепарина. В клинической практике используют как высокомолекулярный гепарин, так и низкомолекулярные формы гепарина, в основном при антикоагулянтной терапии. Пандемия, объявленная в 2020 г. в связи с широким распространением заболевания, названного COVID-19, заставила оценить гепарин как полифункциональный препарат. Негативные последствия современной пандемии явились причиной развития острого и посттравматического стрессового расстройства. В обзоре представлены сведения экспериментальных работ, доказывающих возможность успешного лечения ПТСР малыми дозами высокомолекулярного гепарина. Следовательно, гепарин можно рассматривать как перспективный полифункциональный препарат для эффективной фармакологической коррекции коморбидных заболеваний.

mast cellsheparinmediatorsmatrix of granulespharmacological correction of diseasesтучные клеткигепаринмедиаторыматрикс гранулфармакологическая коррекция заболеванийФГБНУ «НИИ морфологии человека»SRI of Human MorphologyАААА-А19-119021490067-4Traina G. Mast cells in gut and brain and their potential role as an emerging therapeutic target for neural diseases. Front Cell Neurosci. 2019;13(345):1–13. doi: https://doi.org/10.3389/fncel.2019.00345Stassen M, Hartmann AK, Delgado SJ, et al. Mast cells within cellular networks. J Allergy Clin Immunol. 2019;144(4S):S46–S54. doi: https://doi.org/10.1016/j.jaci.2019.01.031Albert-Bayo M, Paracuellos I, Gonzlez-Cfstro AM, et al. Intestinal mucosal mast cells: key modulators of barrier function and homeostasis. Cells. 2019; 8(2):pii:E135. doi: https://doi.org/10.3390/cells8020135Ishihara M, Nakamura S, Sato Y, et al. Heparinoid complex-based heparin-binding cytokines and cell delivery carriers. Molecules. 2019;24(24). pii: E4630. doi: https://doi.org/10.3390/molecules24244630Lima M, Rudd T, Yates E New applications of heparin and other glycosaminoglycans. Molecules. 2017;22(5). pii: E749. doi: https://doi.org/10.3390/molecules22050749Weiss RJ, Esko JD, Tor Y. Targeting heparin and heparan sulfate protein interactions. Org Biomol Chem. 2017;15(27):5656–5668. doi: https://doi.org/10.1039/c7ob01058cMulloy B, Lever R, Page CP. Mast cell glycosaminoglycans. Glycoconj J. 2017;34(3):351–361. doi: https://doi.org/10.1007/s10719-016-9749-0Кондашевская М.В. Экосистема тучных клеток — ключевой полифункциональный компонент организма животных и человека. — М.: Группа МДВ, 2019. — 92 c. [Kondashevskaya MV. The mast cell ecosystem is a key multifunctional component of animals and humans. Moscow: MDV Group. Moscow; 2019. 92 р. (In Russ.)]Questrada I, Chin WC, Verdugo P. ATP-independent luminal oscillations and release of Ca2+ and H+ from mast cell secretory granules: implications for signal transduction. Biophys J. 2003;85(2):963–970. doi: https://doi.org/10.1016/S0006-3495(03)74535-4Dagälv A, Holmborn K, Kjellén L, Abrink M. Lowered expression of heparan sulfate/heparin biosynthesis enzyme N-deacetylase/n-sulfotransferase 1 results in increased sulfation of mast cell heparin. J Biol Chem. 2011;286(52):44433–4440. doi: https://doi.org/10.1074/jbc.M111.303891Fornaro R, Caristo G, Stratta E, et al. Thrombotic complications in inflammatory bowel diseases. G Chir. 2019;40(1):14–19.Avila ML, Shah PS, Brandão LR. Different unfractionated heparin doses for preventing arterial thrombosis in children undergoing cardiac catheterization. Cochrane Database Syst Rev. 2020; 2:CD010196. doi: https://doi.org/10.1002/14651858.CD010196.pub3Prechel MM, Walenga JM. Complexes of platelet factor 4 and heparin activate Toll-like receptor 4. J Thromb Haemost. 2015;13(4):665–670. doi: https://doi.org/10.1111/jth.12847Bruder M, Won SY, Kashefiolasl S, et al. Effect of heparin on secondary brain injury in patients with subarachnoid hemorrahage: an additional ‘H’ therapy in vasospasm treatment. J Neurointerv Surg. 2017;9(7):659–663. Epub 2017 Feb 2. doi: https://doi.org/10.1136/neurintsurg-2016-012925Altay O, Suzuki H, Hasegawa Y, et al. Effects of Low-Dose Unfractionated Heparin Pretreatment on Early Brain Injury after Subarachnoid Hemorrhage in Mice. Acta Neurochir Suppl. 2016;121:127–1230. doi: https://doi.org/10.1007/978-3-319-18497-5_22Hayman EG, Patel AP, James RF, Simard JM. Heparin and Heparin-Derivatives in Post-Subarachnoid Hemorrhage Brain Injury: A Multimodal Therapy for a Multimodal Disease. Molecules. 2017;22(5). pii: E724. doi: https://doi.org/10.3390/molecules22050724Kondashevskaya MV. Experimental evaluation of the effects of low-dose heparin on the behavior and morphofunctional status of the liver in Wistar rats with posttraumatic stress disorders. Bulletin of Experimental Biology and Medicine. 2018;164(10):490–494. doi: https://doi.org/10.1007/s10517-018-4018-9Кондашевская М.В., Цейликман В.Э., Цейликман О.Б., и др. Эффекты гепарина при посттравматическом стрессовом расстройстве в эксперименте // Российский физиологический журнал имени И.М. Сеченова. — 2018. — Т. 104. — № 7. — С. 817–826. [Kondashevskaya MV, Tseilikman VE, Tseilikman OB, et al. Effects of heparin in post-traumatic stress disorder in an experiment. Russian Physiological Journal Named after I.M. Sechenov. 2018;104(7):817−826. (In Russ.)] doi: https://doi.org/10.7868/S0869813918070079Chen CC, Grimbaldeston MA, Tsai M, et al. Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci USA. 2005;102(32):11408–11413. doi: https://doi.org/10.1073/pnas.0504197102Atiakshin D, Buchwalow I, Samoilova V, Tiemann M. Tryptase as a polyfunctional component of mast cells. Histochem Cell Biol. 2018;149(5):461–477. doi: https://doi.org/10.1007/s00418-018-1659-8Akula S, Paivandy A, Fu Z, et al. Quantitative in-depth analysis of the mouse mast cell transcriptome reveals organ-specific mast cell heterogeneity. Cells. 2020;9(1). pii: E211. doi: https://doi.org/10.3390/cells9010211Бигильдеев А.Е., Петинати Н.А., Дризе Н.И. Как методы молекулярной биологии повлияли на понимание устройства кроветворной системы // Молекулярная биология. — 2019. — Т. 53. — № 5. — С. 711–724. [Bigildeev AE, Petinati NA, Drize NI. How molecular biology methods influenced understanding of the hematopoietic system. Molecular Biology. 2019;53(5):711−724. (In Russ.)] doi: https://doi.org/10.1134/S0026898419050021Li Z, Liu S, Xu J, et al. Adult connective tissue-resident mast cells originate from late erythro-myeloid progenitors. Immunity. 2018;49(4):640–653. doi: https://doi.org/10.1016/j.immuni.2018.09.023Dahlin JS, Hallgren J. Mast cell progenitors: Origin, development and migration to tissues. Mol Immunol. 2015;63(1):9–17. doi: https://doi.org/10.1016/j.molimm.2014.01.018Moon TC. Advances in mast cell biology: New understanding of heterogeneity and function. Mucosal Immunol. 2010;3(2):111–128. doi: https://doi.org/10.1038/mi.2009.136Moon TC, Befus AD, Kulka M. Mast cell mediators: their differential release and the secretory pathways involved. Front Immunol. 2014;5:569. doi: https://doi.org/10.3389/fimmu.2014.00569Da Silva E, Jamur M, Oliver C. Mast cell function: a new vision of an old cell. J. Histochem Cytochem. 2014;62(10):698–738. doi: https://doi.org/10.1369/0022155414545334Weiskirchen R, Meurer SK, Liedtke C, Huber M. Mast cells in liver fibrogenesis. Cells. 2019;8(11). pii: E1429. doi: https://doi.org/10.3390/cells8111429Xing W, Austen KF, Gurish MF, et al. Protease phenotype of constitutive connective tissue and of induced mucosal mast cells in mice is regulated by the tissue. Proc Nat. Acad Sci. USA. 2011;108(34):14210–14215. doi: https://doi.org/10.1073/pnas.1111048108Abonia JP, Blanchard C, Butz BB., et al. Involvement of mast cells in eosinophilic esophagitis. J Allergy Cli. Immunol. 2010;126(1):140–149. doi: https://doi.org/10.1016/j.jaci.2010.04.009Williams RM, Webb WW. Single granule pH cycling in antigen-induced mast cell secretion. J Cell Sci. 2000;113(Pt21):3839–3850.Chelombitko MA, Fedorov AV, Ilyinskaya OP, et al. Role of reactive oxygen species in mast cell degranulation. Biochemistry. 2016;81(12):1564–1577. doi: https://doi.org/10.1134/S000629791612018XWang B, Jia J, Zhang X, et al. Heparanase affects secretory granule homeostasis of murine mast cells through degrading heparin. J Allergy Clin Immunol. 2011;128(6):1310–1317. doi: https://doi.org/10.1016/j.jaci.2011.04.011Vukman KV, Försönits A, Oszvald Á, et al. Mast cell secretome: Soluble and vesicular components. Semin Cell Dev Biol. 2017;67:65–73. doi: https://doi.org/10.1016/j.semcdb.2017.02.002Taghon T, Yui MA, Rothenberg EV. Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3. Nat. Immunol. 2007;8(8):845–855. doi: https://doi.org/10.1038/ni1486Mittal A, Sagi V, Gupta M, et al. Mast cell neural interactions in health and disease. Front Cell Neurosci. 2019;13:110. doi: https://doi.org/10.3389/fncel.2019.00110Xu H, Bin NR, Sugita S. Diverse exocytic pathways for mast cell mediators. Biochem Soc Trans. 2018;46(2):235–247. doi: https://doi.org/10.1042/BST20170450Klein O, Sagi-Eisenberg R. Anaphylactic degranulation of mast cells: focus on compound exocytosis. J Immunol Res. 2019;2019:9542656. doi: https://doi.org/10.1155/2019/9542656Prieto-García A, Zheng D, Adachi R, et al. Mast cell restricted mouse and human tryptase·heparin complexes hinder thrombin-induced coagulation of plasma and the generation of fibrin by proteolytically destroying fibrinogen. J Biol Chem. 2012;287(11):7834–7844. doi: https://doi.org/10.1074/jbc.M111.325712Пальцев А.И., Торгашев М.Н., Попова О.С. Патология желудочно-кишечного тракта и абдоминальные боли у ветеранов боевых действий // Терапевтический архив. — 2013. — Т. 85. — № 2. — С. 36–42. [Paltsev AI, Torgashev MN, Popova OS. Gastrointestinal tract pathology and abdominal pain in war veterans. Therapeutic Archive. 2013;85(2):36−42. (In Russ.)]Gattinoni L, Coppola S, Cressoni M., et al. COVID-19 does not Lead to a “typical” acute respiratory distress syndrome. Am J Respir Crit Care Med. 2020;201:1299–1300. doi: https://doi.org/https://doi.org/10.1164/rccm.202003-0817LEBelen-Apak FB, Sarialioglu F. The old but new: Can unfractioned heparin and low molecular weight heparins inhibit proteolytic activation and cellular internalization of SARS-CoV-2 by inhibition of host cell proteases? Med Hypotheses. 2020;142:109743. doi: https://doi.org/10.1016/j.mehy.2020.109743Hippensteel JA, LaRiviere WB, Colbert JF, et al. Heparin as a therapy for COVID-19: current evidence and future possibilities. Am J Physiol Lung Cell Mol Physiol. 2020;319(2):L211–L217. doi: https://doi.org/10.1152/ajplung.00199.2020Shi C, Tingting W, Li JP, et al. Comprehensive Landscape of Heparin Therapy for COVID-19. Carbohydr Polym. 2021;254:117232. doi: https://doi.org/10.1016/j.carbpol.2020.117232Domínguez-Salas S, Gómez-Salgado J, Andrés-Villas M, et al. Psycho-Emotional Approach to the Psychological Distress Related to the COVID-19 Pandemic in Spain: A Cross-Sectional Observational Study. Healthcare (Basel). 2020;8(3):E190. doi: https://doi.org/10.3390/healthcare8030190Huang X, Wei F, Hu L, et al. The Post-Traumatic Stress Disorder Impact of the COVID-19 Pandemic. Psychiatr Danub. 2020;32(3–4):587–589. DOI: https://doi.org/10.15690/vramn1388.