Yulia A. Zhuravleva

Inflammation underlies the pathogenesis of most infectious and non-infectious diseases. The versatility of inflammatory mechanisms makes it possible to assess the systemic inflammatory response (SIR) using unified indicators. Various complex indices, derived from molecular or cellular blood parameters, can serve as such indicators. The aim: to analyze the possibility of assessing the systemic inflammatory response in tuberculosis and type 2 diabetes mellitus using composite inflammatory indices. The study included patients with infiltrative lung tuberculosis (n = 42) and type 2 diabetes mellitus (T2DM, n = 26). The control group included healthy volunteers (n = 22). Composite indices were calculated based on the general blood test results: Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Systemic Immune-Inflammation Index (SII). The reactivity coefficient (RC) was calculated based on the serum concentrations of C-reactive protein (CRP), IL-6, IL-8, IL-10, and tumor necrosis factor α (TNFα) using the original method. The results of the study showed that the medians of the analyzed hematological indices (NLR, PLR, SII) were comparable in patients with tuberculosis and Т2DM, as well as in control values. The frequency of exceeding reference values did not differ in all three groups. At the same time, the CR calculated taking into account molecular inflammatory markers was statistically significantly higher in patients with tuberculosis and Т2DM compared to the control group, both in absolute values and in the frequency of exceeding reference values. According to the ROC-analysis, the integral CR index also had the highest diagnostic significance in terms of the “sick-healthy” classification, while the accuracy of the model was low for the other indices. Composite indices based on the cellular composition of blood (NLR, PLR, SII) are nonspecific and do not reflect specific pathogenetic links of SIR, so other indicators with greater diagnostic significance are required to assess the SIR in patients, which take into account the specific features of the production of molecular inflammatory factors. [2] The integral RC, which takes into account the levels of C-reactive protein, IL-6, IL-8, IL-10, and TNFα, has a high diagnostic value for SIR.

Currently, there is no doubt that insulin resistance (IR) in prediabetes and type 2 diabetes mellitus (T2DM) is associated with chronic systemic metabolic inflammation (SMI). SMI is typically considered a form of low-grade systemic inflammation (LGSI). At the same time, one cannot rule out the possibility of the transformation of LGSI into more pronounced forms of chronic systemic inflammation (ChSI), typical of systemic autoimmune diseases and characterized by a high severity of systemic inflammatory response (SIR). The aim of this research is to assess the pathogenetic role of SMI as a general pathological process in the pathogenesis of prediabetes and T2DM, as well as differentiating SMI into LGSI and ChSI. The study included two main groups—T2DM (n = 65) and prediabetes (n = 24)—as well as three control groups of healthy individuals of different ages (n = 50, n = 89, and n = 22). In the patients of the main groups, metabolic syndrome (MetS) was diagnosed in accordance with the American Heart Association criteria, and metabolic indices (HOMA-IR, HOMA-islet, and TyG) were calculated. The levels of C-reactive protein (CRP) and cytokines (TNFα, IL-6, IL-8, and IL-10) were determined in blood plasma as SIR parameters, and the levels of cortisol (690 nmol/L or 250 and >500 ng/mL), and troponin I (>0.2 ng/mL) were used as additional SMI criteria. Based on molecular inflammatory markers, the ChSI and LGSI scales were calculated using the authors’ original method. SMI in T2DM and prediabetes manifested itself as both LGSI (in 57% of cases in T2DM and 46% in prediabetes) and ChSI (in 18.5% of cases in T2DM and 8.3% in prediabetes). The verification of SMI based on the frequently used criterion of CRP levels above 3 mg/L turned out to be ineffective in our study (this criterion was detected in the control groups in 24–45%). Therefore, we used CRP > 10 mg/L in combination with cytokines as the SIR criterion. Additionally, we identified the SMI criteria: D-dimer > 250 ng/mL in 27.7% of T2DM and 0% in the control groups and prediabetes; cortisol 15.4% in T2DM and 8.3% in prediabetes; and troponin I 7.7% in T2DM and 4.2% in prediabetes. SMI (LGSI and ChSI) develops in the majority of patients with prediabetes (54.1%) and T2DM (75.4%). To assess SMI, it is advisable to use the integral SIR criteria in combination with the markers of chronic stress, tissue damage, and coagulopathy.

Currently, there is no doubt that type 2 diabetes mellitus (T2DM) is associated with local and systemic manifestations of meta-inflammation, which is considered as one of the variants of low-grade inflammation. Aim of the study was to develop and test a scale for assessing chronic systemic meta-inflammation in patients with prediabetes and T2DM based on a comparative analysis of inflammation biomarker levels. Material and methods . Two groups of patients were studied: prediabetes (n = 26, fasting serum glucose level of 6.1–6.9 mmol/L and/or postprandial glycemia 7.8–11.0 mmol/L, and glycated hemoglobin content Results and discussion . Systemic meta-inflammation developed in 57.7 % of patients with prediabetes and in 74.6 % patients with T2DM, but was not detected in the control group. At the same time, in 7.7 and 19 % cases with prediabetes and T2DM, respectively, meta-inflammation in intensity can be characterized as systemic hyperinflammation, when the levels of individual proinflammatory cytokines increased by ten folds relative to the upper normal limit. Conclusions . Systemic meta-inflammation develops in most, but not all patients with prediabetes and T2DM. In some patients, however, its intensity goes beyond low-grade inflammation and is rather characterized as systemic hyperinflammation, with its characteristic “cytokine storm” phenomenon.

Insulin resistance (IR) is a central driver of cardiometabolic disease and an increasingly recognized modifier of inflammatory and vascular pathology. Beyond impaired glucose homeostasis, IR emerges from chronic, metabolically induced inflammation (“meta-inflammation”) and convergent cellular stress programs that propagate across tissues and organ systems, ultimately shaping endothelial dysfunction, atherogenesis, and cardiometabolic complications. Here, we synthesize multilevel links between insulin receptor signaling, intracellular stress modules (oxidative, endoplasmic reticulum, inflammatory, and fibrotic pathways), tissue-level dysfunction, and systemic inflammatory amplification. This work is a conceptual narrative review informed by targeted database searches and citation tracking, with explicit separation of mechanistic/experimental evidence from human observational and interventional data; causal inferences are framed primarily on mechanistic and interventional findings, whereas associative statements are reserved for observational evidence. We propose an integrative framework in which stress-response pathways are context-dependent and become maladaptive when chronically activated under nutrient excess and persistent inflammatory cues, generating self-reinforcing loops between IR and inflammation that accelerate vascular injury. This framework highlights points of convergence that can guide mechanistic prioritization and translational hypothesis testing.

The paper presents an analysis of systemic inflammatory markers (SIM) in patients with insulin resistance classified into various compensation degrees of chronic metabolic disorders (decompensated and compensated type 2 diabetes mellitus – DM2, prediabetes). Our aim was to analyse the features of chronic SIM marker production in patients with different stages of insulin resistance, i.e., prediabetes, compensated DM2 and decompensated DM2. Materials and Methods: The study included patients with hyperglycemia, who were divided into 3 groups according to blood glucose and glycated hemoglobin levels (26 patients with prediabetes, 34 cases with compensated DM2 and 29 persons with decompensated DM2). The control group included healthy blood donors (n = 89). Serum concentrations of C-reactive protein (CRP), interleukins IL- 6, IL- 8, IL- 10, tumor necrosis factor alpha (TNFα), D-dimer, troponin I, myoglobin, cortisol, and procalcitonin were determined by enzyme immunoassay. The results of the study showed that most markers of systemic inflammation in all three groups of patients with pathological insulin resistance exceeded those in the control group. The most intense variations were observed with markers of systemic inflammatory response (CRP, IL- 6, IL-8 and TNFα) and microthrombosis (D-dimer). Their production elevated as soon as at the pre-diabetes stage and increased as glycemic disturbances progressed. The increased serum procalcitonin concentration in DM2 is presumably may be caused by translocation of bacterial antigens from the intestine as a result of enterocyte damage. Cortisol levels in most patients remained within reference values and did not differ significantly depending on the stage of insulin resistance. The same trend was observed for systemic alteration markers – myoglobin and troponin I, which may be considered as a good prognostic sign. In response to metabolic changes, there is a systemic activation of proinflammatory mechanisms since early stages of hyperglycemia, This disorder proceeds with increasing signs of insulin resistance. Indices of systemic inflammatory response and microthrombosis showed the most significant changes.

The relationship between the processes of coagulation and inflammation protects the organism from potentially dangerous biological agents. However, hyperinflammation leads to an increase in the procoagulation potential, and activation of hemostasis factors maintains the inflammatory process. This phenomenon is called “immunothrombosis” or “ thromboinflammation”. The study of thromboinflammatory mechanisms is an actual problem of modern medicine, because in the future it will help to improve the therapy of diseases, in the pathogenesis of which thromboinflammation plays a significant role. The aim: to carry out a comparative analysis of the severity of the systemic inflammatory response in patients with immuno- inflammatory rheumatic diseases depending on the manifestations of hypercoagulation.To achieve the aim, a comparative analysis of proinflammatory markers (IL-6, IL-8, IL-10, TNFα, sIL-2R, CRP, ECP, β2-microglobulin) in the blood of patients with immune-inflammatory rheumatic diseases (systemic lupus erythematosus, rheumatoid arthritis, reactive arthritis, ankylosing spondylitis, psoriatic arthritis, rheumatic heart disease) was performed. Based on these inflammatory markers according to the authors' original methodology, the integral index of systemic inflammatory response (SIR) — Reactivity Level (RL) — was calculated. The cohort was divided into 2 groups: with the presence of signs of hypercoagulation and without signs of hypercoagulation according to the presence of elevated D-dimer level (> 500 ng/mL). Control group — healthy blood donors.The results of the study showed that SIR develops in patients with immuno-inflammatory rheumatic diseases regardless of the blood hemostatic potential. Patients with signs of hypercoagulation were characterized by higher values of most proinflammatory molecular markers, as well as increased integral level of SIR, which indicates a strong relationship between coagulation processes and inflammation at the systemic level. In addition, the probability of hypercoagulation increases with increasing severity of SIR (assessed by means of the integral index — RL). Thus, there is a transition of quantitatively more pronounced signs to a new qualitative level of pathological process development.The pathogenesis of immuno-inflammatory rheumatic diseases is characterized by the development of SIR (hypercytokinemia, acute phase response, intravascular leukocyte activation), the severity of which is closely related to intravascular microthrombosis.

Currently, there is rationale for separating the systemic manifestations of classical inflammation from systemic inflammation (SI) itself as an independent form of the general pathological process underlying the pathogenesis of the most severe acute and chronic diseases. With this aim in view, we used integral scales of acute and chronic SI (ChSI), including the following blood plasma parameters: interleukins 6, 8, 10; tumor necrosis factor alpha; C-reactive protein; D-dimer; cortisol; troponin I; myoglobin. The presence of multiple organ dysfunction according to the SOFA score was also taken into account. The effectiveness of the scales was tested in groups of intensive care patients during different periods of acute trauma, sepsis, and septic shock. The ChSI scale was applicable under systemic autoimmune diseases, chronic purulent infections, chronic limb threatening ischemia, and end-stage renal disease of various genesis. The number of examined patients was 764 in total. The scales allowed us to verify specific phases of acute SI and identify pathogenetic risk factors of lethal outcomes, as well as the most severe variants of the chronic pathologies course. These scales are open adaptable systems (in terms of the nomenclature and choice of indicators). They are primarily intended for scientific research. However, the SI verification methodology presented in this paper may be useful for developing advanced criteria for assessing both the typical links in the pathogenesis of many diseases and the severity of the overall condition of patients for clinical practice.

Pro-inflammatory stress is inherent in any cells that are subject to damage or threat of damage. It is defined by a number of universal components, including oxidative stress, cellular response to DNA damage, unfolded protein response to mitochondrial and endoplasmic reticulum stress, changes in autophagy, inflammasome formation, non-coding RNA response, formation of an inducible network of signaling pathways, and epigenetic changes. The presence of an inducible receptor and secretory phenotype in many cells is the cause of tissue pro-inflammatory stress. The key phenomenon determining the occurrence of a classical inflammatory focus is the microvascular inflammatory response (exudation, leukocyte migration to the alteration zone). This same reaction at the systemic level leads to the development of life-critical systemic inflammation. From this standpoint, we can characterize the common mechanisms of pathologies that differ in their clinical appearance. The division of inflammation into alternative variants has deep evolutionary roots. Evolutionary aspects of inflammation are also described in the review. The aim of the review is to provide theoretical arguments for the need for an up-to-date theory of the relationship between key human pathological processes based on the integrative role of the molecular mechanisms of cellular and tissue pro-inflammatory stress.

Chronic kidney disease can progress to end-stage chronic renal disease (ESRD), which requires the use of replacement therapy (dialysis or kidney transplant) in life-threatening conditions. In ESRD, irreversible changes in the kidneys are associated with systemic changes of proinflammatory nature and dysfunctions of internal organs, skeletal muscles, and integumentary tissues. The common components of ESRD pathogenesis, regardless of the initial nosology, are (1) local (in the kidneys) and systemic chronic low-grade inflammation (ChLGI) as a risk factor for diabetic kidney disease and its progression to ESRD, (2) inflammation of the classical type characteristic of primary and secondary autoimmune glomerulonephritis and infectious recurrent pyelonephritis, as well as immune reactions in kidney allograft rejection, and (3) chronic systemic inflammation (ChSI), pathogenetically characterized by latent microcirculatory disorders and manifestations of paracoagulation. The development of ChSI is closely associated with programmed hemodialysis in ESRD, as well as with the systemic autoimmune process. Consideration of ESRD pathogenesis from the standpoint of the theory of general pathological processes opens up the scope not only for particular but also for universal approaches to conducting pathogenetic therapies and diagnosing and predicting systemic complications in severe nephropathies.

The scavenger receptors (SRs)) include > 30 different molecules structurally classified into 11 classes (A to L). They are expressed mostly on stromal macrophages, and their expression may be augmented in direct dependence with concentrations of their ligands. The SRs are heterogenous by their structure, however, being common in their functional potential. E.g., different SR classes may participate in absorption of modified low-density lipoproteins and glycated proteins, apoptotic and ageing cells, altered erythrocytes and platelets, like as a big variety of other endogenous ligands from metabolic and cellular “trash”. A common property of SRs is their participation in removal of small pathogen amounts from blood circulation, regulation of cell and tissue stress responses, ability to form complicated receptor complexes with other receptor types including integrins and toll-like receptors. Opposite to classic pattern-recognizing receptors, the SR involvement does not always elicit a pronounced cellular activation and development of pro-inflammatory cellular stress. The SR functional effects provide interactions between different physiological events and immune system, including the processes of neuroendocrine and metabolic regulation. These mechanisms provide both homeostatic stability and, likewise, act at the border of normal and pathological conditions, i.e., participating in pathogenesis of transitional processes, e.g., physiological ageing. Moreover, the SR-associated processes represent a key pathogenetic factor in different somatic diseases, e.g., those associated with low-intensity chronic inflammation, including obesity, type 2 diabetes, atherosclerosis, arterial hypertension, various neurodegenerative disorders. Similarly, the SRs are involved into the processes of cancer transformation and antitumor response, different processes of classical inflammation, from antigen presentation to the morphofunctional T cell and macrophage polarization in the inflammation foci and immunocompetent organs. SR are playing a controversial role in development of acute systemic inflammation, the main reason for lethal outcomes in the intensive care wards. Targeted effects upon the SRs represent a promising approach when treating a broad variety of diseases, whereas detection of membrane-bound and soluble SR forms could be performed by means of diagnostic and monitoring techniques in many human disorders.