Platelets are the smallest blood cells, and yet their total volume and surface area exceed those of all types of leukocytes combined. Platelets are produced by the bone marrow megakaryocytes and megakaryocytes in the lung microvessels. Approximately 50% of all platelets are produced in the lungs, which makes it possible to characterize them as the main site for the production of platelets. In small circuit of blood circulation, there are approximately 30% more platelets than in large circuit. This “excess” of platelets is necessary for the stabilization of the endothelial barrier of the lung vessels regulated by the platelet mediator sphingosine-1-phosphate, a regulator of tight junctions of endothelial cells. The circulating platelets have an amazing ability to “bud” new pro- and pre-platelets, giving rise to new platelets. The removal of platelets from circulation proceeds via their phagocytosis by spleen macrophages (if platelets are covered with IgG or are bound to immune complexes), or Kupffer liver cells and hepatocytes (if platelets have incomplete glycans or desialated proteins). In homeostatic conditions, most of the platelets are removed in liver. Platelet clearance in bacterial infections and sepsis is accelerated because of the activity of bacterial sialidases. Recognition of desialized platelet structures is carried out by the liver cells through the Asgr receptor. Despite DNA absence, the platelets are able to synthesize proteins at mRNAs that are present in majority of platelets. Activation of platelets leads to aggregation and exocytosis of the granule contents, and production of immunomodulating molecules. However, activation of platelets may be incomplete and has various consequences. In a non-classical activation model, platelets can release microparticles that contain about 600 different proteins. About 75% of microparticles in the blood of healthy donors are derived from platelets. Like as immune system cells, platelets are activated by numerous endogenous ligands (alarms), including ADP and ATP, which bind to purinergic receptors P2Y1, P2Y12 andP2X1. Platelets accumulate and retain 99% of the serotonin stored in the body. The platelets contribute to induction of inflammation by releasing proinflammatory cytokines, chemokines, and lipid mediators. In addition, platelets are the source of enzymes that accomplish the capacities of neutrophils and endothelium for production of anti-inflammatory lipid mediators that contribute to tissue repair following acute phase of inflammation.
Резюме Abstract In recent years, a critical mass of information has accumulated, which has made it possible to equate platelets to the cells of innate immunity, which ensures the initiation of inflammation and the reactions of innate immunity. In the presented review platelets were examined from the point of view of antibacterial immune reactions. Mechanisms that allow platelets to recognize bacteria and their soluble products as characteristic of immune cells (via TLR2, TLR4, TLR7 and TLR9, FcγRIIa and receptors for complement components), as well as the mechanisms involved in the hemostasis process (GPIb, GPIIb-IIIa)
Thrombocytes keep a leading role in conjugating thrombosis, inflammation and congenital immune responses. The platelets provide stable adhesion and interaction with immune cells. Activated platelets express CD40L (CD154), a membrane glycoprotein of tumor necrosis factor (TNF) family. Hence, the platelets are the main source of sCD40L in blood plasma. Platelet CD154 may interact with CD40 receptor on endothelial cells, causing an inflammatory response, and enhancing production of immunoglobulins by B-lymphocytes. Membrane and soluble CD154 of platelets combined with other signals can induce maturation and activation of dendritic cells (DC). The platelets possess functional receptors, e.g., TLR2, TLR4, TLR7 and TLR9 they also bear Fc-receptors, including FcγRIIA, FcεRI and FcαRIA. FcγRIIA on platelets mediate protection against bacteria. Cross-linking of FcαRI on platelets results in production of prothrombotic and pro-inflammatory mediators such as tissue factor and IL-1β. Activation of platelets via FcεR1 causes release of chemokine RANTES and serotonin, which contribute to the pro-inflammatory response of other immune cells. Platelets possess receptors for activated complement components and its fragments (CR2, CR3, CR4, C1q, C1 inhibitor and factors D and H). Activated platelets trigger the complement system through the release of protein kinases and ATP, and also by phosphorylation of C3 and C3b. α-granules of platelets contain chemokines which represent the most numerous group of antimicrobial proteins of platelets (kinocidins), and there is an antimicrobial protein of the defensin family – hBD-1 in the cytoplasm of platelets. Ligand and receptor of the TNF superfamily (TRAIL and LIGHT), the SDF-1 chemokine (CXCL12), the IL-1βinterleukins, IL-8 and the soluble IL-6 receptor (sRIL-6) are recognized as platelet products belonging to the family of cytokines and their receptors. The HMGB-1 protein classified as an inflammatory cytokine, is expressed by activated platelets and causes formation of the extracellular traps by neutrophils. Platelets produce numerous growth factors, including EGF-α and EGF-β1, EGF-β2, TGF-α and TGF-β1, TGF-β2, PDGF, HGF, FGF-β, IGF, pro- and antiangiogenic factors, e.g., VEGF-F and angiopoietins Ang-1 and Ang-2. Fulfillment of immune functions by the platelets is carried out by their interaction with leukocytes, which are attracted to the site of infection and inflammation and retained during the development of an “immune thrombus” under conditions of high shear stress. Platelets can not only maintain and guide the immune response, but also initiate these events. They are able to present the antigen in the context of MHC class I molecules, and activate naїve CD8+T lymphocytes. Potential consequences of platelet interaction with neutrophils, monocytes, dendritic cells and lymphocytes are discussed in the review article.
Актуальность. Учитывая важность пуриновой регуляции воспалительного процесса, раскрытие её участия в патогенезе хронической обструктивной болезни лёгких (ХОБЛ) может дать дополнительную информацию о патофизиологических механизмах воспаления и компенсации, приводящих к развитию ХОБЛ на фоне хронического воспаления, поддерживаемого туберкулёзной инфекцией. Цель настоящего исследования - выявить связь параметров аденозинового метаболизма с характеристиками окислительного взрыва, генерацией оксида азота и функциональными показателями внешнего дыхания у больных туберкулёзом лёгких в сочетании с ХОБЛ. Материалы и методы. В исследование включены мужчины активные курильщики с верифицированным диагнозом туберкулёз лёгких (ТЛ) и ТЛ в сочетании с ХОБЛ (ТЛ+ХОБЛ). Пуриновый метаболизм оценивали по активности аденозиндезаминазы (АДА-1 и АДА-2) в сыворотке крови (экто-АДА), мононуклеарах (мн) и нейтрофилах (нф), уровню экто-5’-нуклеотидазы (экто-5’-НК) в сыворотке крови, CD26 (дипептидилпептидазы-4, ДПП-4) в сыворотке и мононуклеарах. Окислительный взрыв фагоцитов оценивали по тесту восстановления нитросинего тетразолия (НСТ-тесту). Генерацию оксида азота - по концентрации метаболитов NO в сыворотке крови, мононуклеарах и нейтрофилах. Результаты. У больных ТЛ и ТЛ+ХОБЛ получены разнонаправленные изменения концентрации внеклеточного аденозина (рост активности экто-АДА-2, уровня экто-5’-НТ, снижение активности экто-АДА-1), в то время как внутриклеточные концентрации этого медиатора могут быть повышены (снижение активности АДА-1 и CD26 (ДПП-4) мононуклеаров). У больных ТЛ+ХОБЛ выявлено усиление респираторного взрыва мононуклеаров и нейтрофилов. У больных ТЛ регистрировали усиление продукции реактивных радикалов кислорода только в индуцированном НСТ-тесте нейтрофилов. В обеих группах отмечено значимое снижение продукции нитритов и нитратов как в моноцитах, так и нейтрофилах. У больных ТЛ параметры функции внешнего дыхания (ФВД) были связаны с активностью экто-5’-НТ и неспецифической пептидазы CD26 (ДПП-4), с продукцией нитритов нейтрофилами и моноцитами. В то время как у больных ТЛ+ХОБЛ показатели ФВД были ассоциированы с активностью экто-АДА-1 и АДА-1 в моноцитах, с сывороточной продукцией нитратов и продукцией нитритов нейтрофилами. Выводы. У больных ТЛ нарушение ФВД связано с избыточным образованием аденозина при чрезмерной активации формирующих его ферментов, а также с продукцией нитритов нейтрофилами и моноцитами, активных участников бактерицидных реакций, направленных против микобактерии туберкулеза (МБТ). Тогда как при ТЛ+ХОБЛ ведущим является нарушение деградации аденозина при снижении активности АДА-1, развитие эндотелиальной дисфункции и изменение функционального состояния нейтрофилов. Таким образом, разработка целенаправленных воздействий, приводящие к нормализации пуринергического обмена у больных ТЛ, в частности, к увеличению активности изоформы АДА-1, сможет обеспечить либо превенцию с ХОБЛ, либо, у лиц с уже развывшейся патологией, привести к стабилизации процесса. Background: Purine regulation plays an important role in inflammation. Therefore, disclosing the role of purine regulation in the pathogenesis of chronic obstructive pulmonary disease (COPD) may provide additional information about inflammation pathophysiology and compensation, which lead to COPD in chronic inflammation supported by tuberculosis infection. The aim of this study was to identify the relationship of adenosine metabolic indexes with characteristics of an oxidative burst, nitric oxide generation and functional parameters of external respiration (ER) in patients with pulmonary tuberculosis in combination with COPD. Materials and methods. The study included male active smokers with a verified diagnosis of pulmonary tuberculosis (PT) and PT in combination with COPD (PT+COPD). Purine metabolism was evaluated by adenosine deaminase (ADA-1 and ADA-2) activity in serum (ecto-ADA), mononuclear cells (mnc), and neutrophils (nph); serum concentration of ecto-5’-nucleotidase (ecto-5’-NT); and serum and mnc concentrations of CD26 (dipeptidyl peptidase-4, DPP-4). Oxidative burst in phagocytes was evaluated by the nitroblue tetrazolium conversion test (NBT-test). Nitric oxide generation - by concentrations of NO metabolites in blood serum, mnc, and nph. Results. Patients with PT and PT+COPD had multidirectional changes in extracellular adenosine concentration (increased activity of ecto-ADA-2, level of ecto-5’-NT, decreased activity of ecto-ADA-1). At the same time, intracellular adenosine concentrations could be increased (decreased mnc activities of ADA-1 and CD26 (DPP-4)). In patients with PT+COPD, the respiratory burst was observed only in mnc and nph. In patients with PT, increased production of reactive oxygen species was observed only in nph in the inductive NBT-test. In both groups, the nitrite and nitrate production significantly decreased both in monocytes and nph. In patients with PT, parameters of external respiration (ER) were linked to ecto-5’-NT and nonspecific peptidase CD26 (DPP-4) activities and to nitrite production by nph and monocytes. At the same time, in patients with PT+COPD, ER indexes were linked to monocyte activities of ecto-ADA-1 and ADA-1 and to serum nitrate and nph nitrite. Conclusion. In PT patients, impaired ER was associated with excessive formation of adenosine and excessive activation of adenosine-forming enzymes, as well as with nitrite production by nph and monocytes, which are active participants in bactericidal reactions directed against mycobacterium tuberculosis (MBT). However, in PT+COPD, the leading factor is impaired adenosine degradation with decreased ADA-1 activity, development of endothelial dysfunction, and changed nph functionality. Therefore, development of targeted means for normalizing the purinergic metabolism in patients with PT, specifically, by increasing the ADA-1 isoform activity, may provide either prevention in COPD or stabilization of the process in patients with already developed pathology.
Medical Immunology (Russia)/Meditsinskaya Immunologiya Медицинская Иммунология тотоксической и пролиферативной активности спленоцитов и соотношения количества пролиферирующих спленоцитов к числу клеток, вошедших в апоптоз. Таким образом, применение rIL-2 может скорректировать нарушение нейроэндокринных и иммунных дисфункций после ЧМТ и обеспечить снижение риска развития хронической неврологической патологии у больных ЧМТ.
Invasive aspergillosis (IA) is a serious disease, with mortality rate up to 80%. A. fumigatus is an angiovasive pathogen, fragments of its hyphae can detach and circulate in the bloodstream. Platelets are activated by surface structures, metabolites and soluble fungal complexes, resulting in adhesion to conidia and fungal hyphae. The melanin and hydrophobin contained in the conidia, as well as the galactosaminogalactan contained in the hyphae and the glyphotoxin secreted by the hyphae, suppress phagocytic cells, but activate the platelets. Activated platelets show direct antifungal activity by releasing microbicidal proteins and serotonin. In addition to direct antifungal effect, platelets form an interactive network with cellular components of the immune system and a complement system, increasing the response of neutrophils and monocytes. In the presence of platelets, the efficacy of antimycotics is greatly enhanced. The adverse effects of platelet activation in IA are associated with clinical conditions such as hemoptysis, pulmonary hemorrhage and infarctions of various organs. Another danger associated with IA is the development of thrombocytopenia. Thrombocytopenia is defined as an independent risk factor of mortality in IA in oncohematological patients after allogeneic transplantation of hematopoietic stem cells. Numerous evidences of the important role of platelets in protection from A. fumigatus suggest that the study of the number and functional state of platelets will provide a new data, which will help develop new methods for prediction and treatment of IA.
Necrotizing soft tissue infection (NSTI) is a severe surgical infection which can result in sepsis and septic shock when generalized.The aim of the study was to determine the frequency of thrombocytopenia in patients with generalized NSTI, the factors promoting its development, and its association with septic shock.Materials and Methods. We examined 129 patients with NSTI treated between 09.2015 and 12.2019 at St. George Hospital in St. Petersburg, Russia. Surgical treatment, hematological and biochemical examinations, and bacteriological analysis of blood and wound discharge were performed in each patient. The studied group included 22 patients with systemic inflammatory reaction syndrome, 63 patients with sepsis, and 44 patients with septic shock.Results. We found a decrease in platelet count in NSTI patients with septic shock as early as on the first day of the disease and its further decrease within the next 3 days, with the mean platelet volume (MPV) increasing during the same period and significantly exceeding that in patients with sepsis and systemic inflammatory response syndrome. In NSTI patients with thrombocytopenia on admission, we found a significant correlation between the platelet count and the percentage of segmented neutrophils (r=0.349; P<0.001; n=40). The maximum incidenсe of septic shock was observed in patients infected with Klebsiella pneumoniae (13 out of 19, 65%). These patients had the highest MPV but did not develop thrombocytopenia. Maximum frequency of thrombocytopenia and elevation of MPV and platelet distribution width (PDW) was found in patients with NSTI and underlying chronic viral hepatitis C. However, the relative frequency of septic shock in these patients was not increased.Conclusion. The development of septic shock in NSTI is associated with a specific platelet activation pattern
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