Morphological and Molecular Biological Characteristics of Experimental Rat Glioblastoma Tissue Strains Induced by Different Carcinogenic Chemicals.

Glioblastoma (GBM) is a highly aggressive human neoplasm with poor prognosis due to its malignancy and therapy resistance. To evaluate the efficacy of antitumor therapy, cell models are used most widely, but they are not as relevant to human GBMs as tissue models of gliomas, closely corresponding to human GBMs in cell heterogeneity. In this work, we compared three different tissue strains of rat GBM 101.8 (induced by DMBA), GBM 11-9-2, and GBM 14-4-5 (induced by ENU). MATERIALS AND METHODS: We estimated different gene expressions by qPCR-RT and conducted Western blotting and histological and morphometric analysis of three different tissue strains of rat GBM. RESULTS: GBM 101.8 was characterized by the shortest period of tumor growth and the greatest number of necroses and mitoses; overexpression of Abcb1, Sox2, Cdkn2a, Cyclin D, and Trp53; and downregulated expression of Vegfa, Pdgfra, and Pten; as well as a high level of HIF-1α protein content. GBM 11-9-2 and GBM 14-4-5 were relevant to low-grade gliomas and characterized by downregulated Mgmt expression; furthermore, a low content of CD133 protein was found in GBM 11-9-2. CONCLUSIONS: GBM 101.8 is a reliable model for further investigation due to its similarity to high-grade human GBMs, while GBM 11-9-2 and GBM 14-4-5 correspond to Grade 2-3 gliomas.

Immune Cells in the Tumor Microenvironment of Soft Tissue Sarcomas.

Soft tissue sarcomas (STSs) are a rare heterogeneous group of malignant neoplasms characterized by their aggressive course and poor response to treatment. This determines the relevance of research aimed at studying the pathogenesis of STSs. By now, it is known that STSs is characterized by complex relationships between the tumor cells and immune cells of the microenvironment. Dynamic interactions between tumor cells and components of the microenvironment enhance adaptation to changing environmental conditions, which provides the high aggressive potential of STSs and resistance to antitumor therapy. Today, active research is being conducted to find effective antitumor drugs and to evaluate the possibility of using therapy with immune cells of STS. The difficulty in assessing the efficacy of new antitumor options is primarily due to the high heterogeneity of this group of malignant neoplasms. Studying the role of immune cells in the microenvironment in the progression STSs and resistance to antitumor therapies will provide the discovery of new biomarkers of the disease and the prediction of response to immunotherapy. In addition, it will help to initially divide patients into subgroups of good and poor response to immunotherapy, thus avoiding wasting precious time in selecting the appropriate antitumor agent.

Role of Microenvironmental Components in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell cancer (HNSCC) is one of the ten most common malignant neoplasms, characterized by an aggressive course, high recurrence rate, poor response to treatment, and low survival rate. This creates the need for a deeper understanding of the mechanisms of the pathogenesis of this cancer. The tumor microenvironment (TME) of HNSCC consists of stromal and immune cells, blood and lymphatic vessels, and extracellular matrix. It is known that HNSCC is characterized by complex relationships between cancer cells and TME components. TME components and their dynamic interactions with cancer cells enhance tumor adaptation to the environment, which provides the highly aggressive potential of HNSCC and resistance to antitumor therapy. Basic research aimed at studying the role of TME components in HNSCC carcinogenesis may serve as a key to the discovery of both new biomarkers-predictors of prognosis and targets for new antitumor drugs. This review article focuses on the role and interaction with cancer of TME components such as newly formed vessels, cancer-associated fibroblasts, and extracellular matrix.

Molecular and phenotypic distinctions of macrophages in tolerant and susceptible to hypoxia rats.

Individual hypoxia tolerance is a major influence on the course and outcome of infectious and inflammatory diseases. Macrophages, which play central roles in systemic inflammatory response and other immunity reactions, are subject to functional activation orchestrated by several transcription factors including hypoxia inducible factors (HIFs). HIF-1 expression levels and the lipopolysaccharide (LPS)-induced systemic inflammatory response severity have been shown to correlate with hypoxia tolerance. Molecular and functional features of macrophages, depending on the organisms resistance to hypoxia, can determine the severity of the course of infectious and inflammatory diseases, including the systemic inflammatory response. The purpose is the comparative molecular and functional characterization of non-activated and LPS-activated bone marrow-derived macrophages under normoxia in rats with different tolerance to oxygen deprivation. Hypoxia resistance was assessed by gasping time measurement in an 11,500 m altitude-equivalent hypobaric decompression chamber. Based on the outcome, the animals were assigned to three groups termed 'tolerant to hypoxia' (n = 12), 'normal', and 'susceptible to hypoxia' (n = 13). The 'normal' group was excluded from subsequent experiments. One month after hypoxia resistance test, the blood was collected from the tail vein to isolate monocytes. Non-activated and LPS-activated macrophage cultures were investigated by PCR, flow cytometry and Western blot methods. Gene expression patterns of non-activated cultured macrophages from tolerant and susceptible to hypoxia animals differed. We observed higher expression of VEGF and CD11b and lower expression of Tnfa, Il1b and Epas1 in non-activated cultures obtained from tolerant to hypoxia animals, whereas HIF-1α mRNA and protein expression levels were similar. LPS-activated macrophage cultures derived from susceptible to hypoxia animals expressed higher levels of Hif1a and CCR7 than the tolerant group; in addition, the activation was associated with increased content of HIF-1α in cell culture medium. The observed differences indicate a specific propensity toward pro-inflammatory macrophage polarization in susceptible to hypoxia rats.

Morphofunctional Changes in Brain and Peripheral Blood in Adult and Aged Wistar Rats with AlCl3-Induced Neurodegeneration.

BACKGROUND: the general lifespan has been prolonged greatly during the past century, and the incidence of age-associated diseases, including neurodegenerative ones, has increased as well. However, modelling of age-related pathologies is mostly conducted on adult rodents. We studied morphofunctional changes in the brain and peripheral blood of adult Wistar rats in comparison with old Wistar rats to determine age-related physiological changes and differences in adaptive reactions to AlCl3 exposure. METHODS: the work was performed on adult and old male Wistar rats. The animals consumed a 100 mg/kg solution of AlCl3 each day for 60 days. Morphological changes of neurons and microglia, mRNA expression levels of pro-inflammatory and anti-inflammatory cytokines, microglia activation markers, amyloid-related proteins, and hallmarks of cellular senescence, monocyte, and lymphocyte subpopulations in the peripheral blood were examined. RESULTS: old rats showed increasing hyperchromic neurons in the hippocampus; activation of microglia; upregulation of pro-inflammatory cytokines and cellular senescence markers; downregulation of anti-inflammatory cytokines; and Hif-1a and a decrease in B-cells and monocyte in peripheral blood. CONCLUSION: compared to young animals, aged rats respond to aluminum exposure with a severe decline of most cells' function and irreversible neuronal loss. Regarding all reported data, neurodegeneration modelling and investigating of factors capable of accelerating or preventing it should be performed in experimental work on aged animals.

Immune Cells in Head-and-Neck Tumor Microenvironments.

Head-and-neck cancers constitute a heterogeneous group of aggressive tumors with high incidence and low survival rates, collectively being the sixth most prevalent cancer type globally. About 90% of head-and-neck cancers are classified as squamous cell carcinomas (HNSCC). The innate and adaptive immune systems, indispensable for anti-cancer immune surveillance, largely define the rates of HNSCC emergence and progression. HNSCC microenvironments harbor multiple cell types that infiltrate the tumors and interact both with tumor cells and among themselves. Gradually, tumor cells learn to manipulate the immune system, either by adapting their own immunogenicity or through the release of immunosuppressive molecules. These interactions continuously evolve and shape the tumor microenvironment, both structurally and functionally, facilitating angiogenesis, proliferation and metastasis. Our understanding of this evolution is directly related to success in the development of advanced therapies. This review focuses on the key mechanisms that rule HNSCC infiltration, featuring particular immune cell types and their roles in the pathogenesis. A close focus on the tumor-immunity interactions will help identify new immunotherapeutic targets in patients with HNSCC.

Alzheimer's Disease and Inflammaging.

Alzheimer's disease is one of the most common age-related neurodegenerative disorders. The main theory of Alzheimer's disease progress is the amyloid-ß cascade hypothesis. However, the initial mechanisms of insoluble forms of amyloid-ß formation and hyperphosphorylated tau protein in neurons remain unclear. One of the factors, which might play a key role in senile plaques and tau fibrils generation due to Alzheimer's disease, is inflammaging, i.e., systemic chronic low-grade age-related inflammation. The activation of the proinflammatory cell phenotype is observed during aging, which might be one of the pivotal mechanisms for the development of chronic inflammatory diseases, e.g., atherosclerosis, metabolic syndrome, type 2 diabetes mellitus, and Alzheimer's disease. This review discusses the role of the inflammatory processes in developing neurodegeneration, activated during physiological aging and due to various diseases such as atherosclerosis, obesity, type 2 diabetes mellitus, and depressive disorders.

Harmful effects of the microplastic pollution on animal health: a literature review.

Background: The environmental pollution by microplastics is a global problem arising from the extensive production and use of plastics. Small particles of different plastics, measured less than 5 mm in diameter, are found in water, air, soil, and various living organisms around the globe. Humans constantly inhale and ingest these particles. The associated health risks raise major concerns and require dedicated evaluation. Objectives: In this review we systematize and summarize the effects of microplastics on the health of different animals. The article would be of interest to ecologists, experimental biologists, environmental physicians, and all those concerned with anthropogenic environmental changes. Methodology: We searched PubMed and Scopus from the period of 01/2010 to 09/2021 for peer-reviewed scientific publications focused on (1) environmental pollution with microplastics; (2) uptake of microplastics by humans; and (3) the impact of microplastics on animal health. Results: The number of published studies considering the effects of microplastic particles on aquatic organisms is considerable. In aquatic invertebrates, microplastics cause a decline in feeding behavior and fertility, slow down larval growth and development, increase oxygen consumption, and stimulate the production of reactive oxygen species. In fish, the microplastics may cause structural damage to the intestine, liver, gills, and brain, while affecting metabolic balance, behavior, and fertility; the degree of these harmful effects depends on the particle sizes and doses, as well as the exposure parameters. The corresponding data for terrestrial mammals are less abundant: only 30 papers found in PubMed and Scopus deal with the effects of microplastics in laboratory mice and rats; remarkably, about half of these papers were published in 2021, indicating the growing interest of the scientific community in this issue. The studies demonstrate that in mice and rats microplastics may also cause biochemical and structural damage with noticeable dysfunctions of the intestine, liver, and excretory and reproductive systems. Conclusions: Microplastics pollute the seas and negatively affect the health of aquatic organisms. The data obtained in laboratory mice and rats suggest a profound negative influence of microplastics on human health. However, given significant variation in plastic types, particle sizes, doses, models, and modes of administration, the available experimental data are still fragmentary and controversial.

About 4-day rhythm of proliferative activity of fibroblast-like cell cultures isn't endogenous and don't depend from the variations of Earth's magnetic field.

A study of the 4-day rhythm of the proliferative activity of the embryonic fibroblast-like cells in the logarithmic growth phase was carried out. It was shown that in cell cultures obtained on different days from embryos of different ages, the phase of the 4-day rhythm coincides. In vitro the maxima of the proliferative activity were consistent with the minima of the motor activity of mice. Freezing the culture for 2 or 6 days does not cause a shift in the phase of the 4-day rhythm of cell proliferative activity compare with the unfreezing culture. That indicates the existence of an external synchronizer, which determines the 4-day infradian rhythm of the proliferative activity of embryonic cells. Then we daily thawed samples of single L929 culture of mice fibroblast-like cells for 22 and 17 days and researched the dynamics of its proliferative activity. We also showed 4-day rhythm of the simultaneous increase in the number of cells for all thawed samples. Taking into account that deep freezing of a culture leads to the cessation of all life processes, the fact we obtained indicates an exogenous mechanism of the formation of about a 4-day rhythm of the proliferative activity of cell culture. Variations of the Earth's magnetic field could be one of the external synchronizers of the infradian rhythm. We studied the increase in number of L929 cell in conditions of a magnetic permalloy screen and showed that the magnetic shielding no affect the parameters of the infradian rhythm of L929 cell proliferative activity. So further searches of the external synchronizers are need.

Age-related differences in hypoxia-associated genes and cytokine profile in male Wistar rats.

Hypoxia tolerance of the organism depends on many factors, including age. High newborn organisms tolerance and high level of oxidative stress throughout aging were demonstrated by many studies. However, there is lack of investigations reflecting the expression of key hypoxia-inducible factor HIF in different age organisms in correlation to levels of pro-inflammatory and anti-inflammatory cytokines. Liver is a sensitive to hypoxia organ, and is an important organ in providing an acute reaction to infections - it synthesizes acute inflammation phase proteins, in particular, C-reactive protein. The aim of study was to determine relationship between age-related tolerance to hypoxia and HIF-1 and PHD2 (prolyl hydroxylase domain protein) expression levels in the liver and the production of cytokines in the spleen in newborn, prepubertal and adult Wistar rats. Newborn rats are characterized by high mRNA Hif-1α expression level in the liver, accompanied by a low content of HIF-1 protein and high level of PHD2. The growth in HIF-1α protein level throughout age is accompanied by the growth of pro-inflammatory cytokines level. Prepubertal animals are the least hypoxia resistant and their HIF-1α mRNA expression level was higher than in adult animals. The PHD2 activity in prepubertal animals was significantly reduced in comparison to newborn rats, and the HIF-1α protein level did not change. Further studies require the identification of additional mechanisms, determining the regulation of the HIF-1α level in prepubertal animals.

Level of Murine DDX3 RNA Helicase Determines Phenotype Changes of Hepatocytes In Vitro and In Vivo.

DDX3 RNA helicase is intensively studied as a therapeutic target due to participation in the replication of some viruses and involvement in cancer progression. Here we used transcriptome analysis to estimate the primary response of hepatocytes to different levels of RNAi-mediated knockdown of DDX3 RNA helicase both in vitro and in vivo. We found that a strong reduction of DDX3 protein (>85%) led to similar changes in vitro and in vivo-deregulation of the cell cycle and Wnt and cadherin pathways. Also, we observed the appearance of dead hepatocytes in the healthy liver and a decrease of cell viability in vitro after prolonged treatment. However, more modest downregulation of the DDX3 protein (60-65%) showed discordant results in vitro and in vivo-similar changes in vitro as in the case of strong knockdown and a different phenotype in vivo. These results demonstrate that the level of DDX3 protein can dramatically influence the cell phenotype in vivo and the decrease of DDX3, for more than 85% leads to cell death in normal tissues, which should be taken into account during the drug development of DDX3 inhibitors.

The Role of Macrophages in the Pathogenesis of SARS-CoV-2-Associated Acute Respiratory Distress Syndrome.

Macrophages are cells that mediate both innate and adaptive immunity reactions, playing a major role in both physiological and pathological processes. Systemic SARS-CoV-2-associated complications include acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation syndrome, edema, and pneumonia. These are predominantly effects of massive macrophage activation that collectively can be defined as macrophage activation syndrome. In this review we focus on the role of macrophages in COVID-19, as pathogenesis of the new coronavirus infection, especially in cases complicated by ARDS, largely depends on macrophage phenotypes and functionalities. We describe participation of monocytes, monocyte-derived and resident lung macrophages in SARS-CoV-2-associated ARDS and discuss possible utility of cell therapies for its treatment, notably the use of reprogrammed macrophages with stable pro- or anti-inflammatory phenotypes.

The Dynamics of ß-Amyloid Proteoforms Accumulation in the Brain of a 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia among the elderly. Neuropathologically, AD is characterized by the deposition of a 39- to 42-amino acid long ß-amyloid (Aß) peptide in the form of senile plaques. Several post-translational modifications (PTMs) in the N-terminal domain have been shown to increase the aggregation and cytotoxicity of Aß, and specific Aß proteoforms (e.g., Aß with isomerized D7 (isoD7-Aß)) are abundant in the senile plaques of AD patients. Animal models are indispensable tools for the study of disease pathogenesis, as well as preclinical testing. In the presented work, the accumulation dynamics of Aß proteoforms in the brain of one of the most widely used amyloid-based mouse models (the 5xFAD line) was monitored. Mass spectrometry (MS) approaches, based on ion mobility separation and the characteristic fragment ion formation, were applied. The results indicated a gradual increase in the Aß fraction of isoD7-Aß, starting from approximately 8% at 7 months to approximately 30% by 23 months of age. Other specific PTMs, in particular, pyroglutamylation, deamidation, and oxidation, as well as phosphorylation, were also monitored. The results for mice of different ages demonstrated that the accumulation of Aß proteoforms correlate with the formation of Aß deposits. Although the mouse model cannot be a complete analogue of the processes occurring in the human brain in AD, and several of the observed parameters differ significantly from human values supposedly due to the limited lifespan of the model animals, this dynamic study provides evidence on at least one of the possible mechanisms that can trigger amyloidosis in AD, i.e., the hypothesis on the relationship between the accumulation of isoD7-Aß and the progression of AD-like pathology.

Sex differences of inflammatory and immune response in pups of Wistar rats with SIRS.

It is a common fact, that the content of sex hormones in humans and animals varies in different age periods. The functional state of the immune system also changes with age. However, sex differences studies of inflammatory and immune responses during puberty prevail in literature. Investigation of immune responses to LPS peculiarities in prepubertal females and males may contribute to the development of more effective immunotherapy and minimize side effects of children vaccination. Therefore, the aim of this work was to investigate the LPS-induced SIRS sex differences in prepubertal Wistar rats. Despite the absence of sex differences in estradiol and testosterone levels, LPS-induced inflammatory changes in liver and lungs are more pronounced among males. Males demonstrate the increasing neopterin, corticosterone levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Not less important is that in females, demonstrating less morphological changes in liver and lungs, endotoxin level is tenfold higher, and corticosterone level decreases. Thus, endotoxin cannot be used as a marker of the severity of multiple organ failure in prepubertal period. The LPS-induced immune reactions in females and males are similar and are characterized by immunosuppression. Both females and males have decreased production of cytokines (IL-2, IL-4, TNF-α, TGF-ß) and the absolute number of CD3 + and CD3 + CD8 + lymphocytes in blood. The acute atrophy of thymus and apoptosis of thymic cells are revealed in animals of both sexes. However, the number of CD3 + CD4 + T-helpers and CD4 + CD25 + Foxp3 + T-cells decreases only in females with SIRS, and in males there was a decrease of CD45R + B-cells. The least expressed sex differences in immune responses in the prepubertal period can be determined by the low levels of sex steroids and the absence of their immunomodulatory effect. Further studies require the identification of mechanisms, determining the sex differences in the inflammatory and immune responses in prepubertal animals.

Ultradian and Infradian Rhythms in the Dynamic of Testosterone Concentration in the Serum of the White-Breasted Hedgehog Erinaceus roumanicus.

The aim of the study was to identify ultradian (intraday) and infradian (multi-day) rhythms in the dynamics of testosterone concentration in the blood serum of white-breasted hedgehogs. Blood sampling was performed from the femoral veins of 12 male hedgehogs. We found ultradian rhythms of testosterone on both sampling dates-March 7-8 (a day length of 11 hours and 15 minutes) and May 10-11 (a day length of 16 hours). An 8-hour rhythm of testosterone concentration has been established. The acrophases were at the same times in both photoperiods and thus independent of sunset times. The study of the infradian rhythms of testosterone was daily carried out on May 22-June 3, at 07:40 to 08:50 and from June 27 to July 7, at 16:15-16:50. It revealed an infradian rhythm of the testosterone concentration with a period of 4-days in both the morning and the evening sampling. According to our previous investigation, the infradian rhythms of testosterone among individual hedgehogs, rodents and primates have the same period. That indicates the common mechanisms for their formation. In case of experimental studies, the phase of ultradian and infradian biorhythms will need to be taken into account because the testosterone concentration in acrophase is 2-4 times higher than in bathyphase.

Morphological Characteristics of the Thymus and Spleen and the Subpopulation Composition of Lymphocytes in Peripheral Blood during Systemic Inflammatory Response in Male Rats with Different Resistance to Hypoxia.

On the model of the systemic inflammatory response (SIRS), induced by lipopolysaccharide (LPS), the morphological and functional changes in the thymus and spleen and the subpopulation composition of peripheral blood lymphocytes of rats differing in resistance to hypoxia were studied. It was demonstrated that the level of endotoxin in blood serum after 3 hours of LPS administration in susceptible-to-hypoxia rats was 64 times higher than in the control group, while in tolerant-to-hypoxia animals it was only 8 times higher in 6 hours. After 24 hours of LPS injection, only in susceptible-to-hypoxia rats did the level of C-reactive protein in blood serum increase. There is a difference in the dynamics of morphological changes of lymphoid organs after LPS injection in tolerant- and susceptible-to-hypoxia animals. After 3 hours of LPS administration, the tolerant-to-hypoxia rats showed no changes in the thymus, spleen, and subpopulation composition of lymphocytes in peripheral blood. After 6 hours there was only a decrease in B-lymphocytes and increase in cytotoxic T-lymphocytes and NK cells. After 1 day of LPS injection, the tolerant-to-hypoxia rats had devastation in PALS of the spleen. After 3 hours of LPS injection the susceptible-to-hypoxia animals had reactive changes in the lymphoid organs: decrease of the thymus cortex, narrowing of the marginal zones of spleen lymphoid follicles, widening of their germinal centers, and a decrease in the absolute number of cytotoxic T-lymphocytes, NK cells, and B-lymphocytes. After 24 hours of LPS injection the tolerant-to-hypoxia animals had a greater absolute number of T-lymphocytes and NK cells in comparison with the susceptible rats. Thus, in animals with different resistance to hypoxia the LPS-induced SIRS is characterized by different dynamics of morphological and functional changes of the thymus and spleen. The obtained data will serve as a basis for the development of new individual approaches to the prevention and treatment of infectious and inflammatory diseases.

Dependence of the severity of the systemic inflammatory response on resistance to hypoxia in male Wistar rats.

PURPOSE: The aim of the study was to characterize the severity of the systemic inflammatory response induced by lipopolysaccharide (LPS) in animals with different resistance levels to hypoxia. MATERIALS AND METHODS: Two to three months old male Wistar rats (220-240 g) were divided according to hypoxia tolerance in a hypobaric chamber. After a month, they were injected intraperitoneally with Escherichia coli LPS at a dose of 1.5 mg/kg. After 3, 6 and 24 hours of LPS injection, we studied the levels of IL-1ß, C-reactive protein (CRP) and TGF-ß in the serum, the expression of Hif-1α and Nf-kb in the liver, morphological disorders in the lung and ex vivo production of IL-10 by splenic cells activated by ConA. RESULTS: In the early periods after the injection of LPS, increase in Nf-kb expression in the liver was observed only in the rats susceptible to hypoxia. After 6 hours of LPS injection, the number of neutrophils in the interalveolar septa of the lungs of rats susceptible to hypoxia was higher than in tolerant rats. This points to the development of more pronounced LPS-induced inflammation in the rats susceptible to hypoxia and is accompanied by increased expression of Hif-1α in the liver after 6 hours of LPS administration, serum IL-1ß level after 3 hours and CRP level after 24 hours. The production of the anti-inflammatory cytokine IL-10 by the spleen was significantly decreased after 6 hours of LPS injection only in the animals tolerant to hypoxia. After 24 hours of LPS injection, a significant decrease in serum TGF-ß level occurred in the rats tolerant to hypoxia in comparison with the control group, which improved the survival rates of the animals. CONCLUSION: We have demonstrated the differences in the severity of the LPS-induced inflammatory response in male Wistar rats with different resistance levels to hypoxia. Rats susceptible to hypoxia are characterized by a more pronounced inflammatory response induced by LPS.

Sex differences of inflammation in target organs, induced by intraperitoneal injection of lipopolysaccharide, depend on its dose.

PURPOSE: The aim of our research was to study sex differences and the severity of inflammatory changes in target organs and the peculiarities of immunological disorders when low and high doses of lipopolysaccharide (LPS) were administered to rats. METHODS: Male and female 2- to 3-month-old Wistar rats (200-250 g) were injected intraperitoneally with Escherichia coli LPS in one of two doses: 1.5 or 15 mg/kg. In a day after the LPS injection, we studied endotoxin, corticosterone, sex steroids, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity levels in the serum; morphological disorders in the lung, liver, thymus, and spleen; ex vivo production of IL-2, IL-4, tumor necrosis factor (TNF), and interferon γ (IFNγ) by splenic cells activated by ConA; and relative amount of T- and B-lymphocytes in the peripheral blood. RESULTS: After the injection of low-dose LPS, the serum endotoxin level increased only in males and was combined with a more pronounced inflammatory response in the lungs and thymus and an increase in ALT and AST activity levels without any changes in corticosterone level. After the injection of high-dose LPS, the inflammatory and pathological changes in the target organs manifested as severe endotoxemia and sex differences of pathological changes in the lungs and liver were not revealed. The level of production of IL-2, IL-4, IFNγ, and TNF by splenic cells and the number of T-lymphocytes, including cytotoxic cells, in the peripheral blood, decreased in males, which is an evidence of a pronounced suppression of the immune response. CONCLUSION: We have shown that the morphofunctional changes in the organs of the immune system in females and males, as well as the intensity of the sex differences of inflammation, depend on the severity of systemic inflammatory response, induced by different doses of LPS.