The review aims to consolidate research findings on the molecular mechanisms and virulence and pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and their relevance to four typical stages in the development of acute viral infection. These four stages are invasion; primary blockade of antiviral innate immunity; engagement of the virus’s protection mechanisms against the factors of adaptive immunity; and acute, long-term complications of COVID-19. The invasion stage entails the recognition of the spike protein (S) of SARS-CoV-2 target cell receptors, namely, the main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, and potential alternative receptors. The presence of a diverse repertoire of receptors allows SARS-CoV-2 to infect various types of cells, including those not expressing ACE2. During the second stage, the majority of the polyfunctional structural, non-structural, and extra proteins SARS-CoV-2 synthesizes in infected cells are involved in the primary blockage of antiviral innate immunity. A high degree of redundancy and systemic action characterizing these pathogenic factors allows SARS-CoV-2 to overcome antiviral mechanisms at the initial stages of invasion. The third stage includes passive and active protection of the virus from factors of adaptive immunity, overcoming of the barrier function at the focus of inflammation, and generalization of SARS-CoV-2 in the body. The fourth stage is associated with the deployment of variants of acute and long-term complications of COVID-19. SARS-CoV-2’s ability to induce autoimmune and autoinflammatory pathways of tissue invasion and development of both immunosuppressive and hyperergic mechanisms of systemic inflammation is critical at this stage of infection.

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SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19

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 Pathogenesis of End-Stage Renal Disease from the Standpoint of the Theory of General Pathological Processes of Inflammation.

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects.

/pdf/theophylline-old-drug-in-a-new-light-application-in-covid-19-3bcocbo7.pdf

Theophylline: Old Drug in a New Light, Application in COVID-19 through Computational Studies

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.

/pdf/inflammation-a-new-look-at-an-old-problem-1vo5xr1n.pdf

Inflammation: A New Look at an Old Problem

Background: Coronavirus 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), has created a tremendous economic and medical burden. The prevalence and prognostic value of SARS-CoV-2-induced kidney impairment remain controversial. The current study aimed to provide additional evidence on the incidence of acute kidney injury (AKI) in COVID-19 patients and propose the use of urinalysis as a tool for screening kidney impairment. Methods: 178 patients with confirmed COVID-19 were enrolled in this retrospective cohort study. The laboratory examinations included routine blood tests, blood biochemical analyses (liver function, renal function, lipids, and glucose), blood coagulation index, lymphocyte subset and cytokine analysis, urine routine test, C-reactive protein, erythrocyte sedimentation, and serum ferritin. Results: No patient exhibited a rise in serum creatinine or Cystatin C and occurrence of AKI, and only 2.8% of patients were recorded with an elevated level of blood urea nitrogen among all cases. On the contrary, 54.2% of patients who underwent routine urine testing presented with an abnormal urinalysis as featured by proteinuria, hematuria, and leucocyturia. Conclusions: Kidney impairment is prevalent among COVID-19 patients, with an abnormal urinalysis as a clinical manifestation, implying that a routine urine test is a stronger indication of prospective kidney complication than a blood biochemistry test.

https://www.mdpi.com/2075-4418/12/3/602/pdf?version=1645963558

Urinalysis, but Not Blood Biochemistry, Detects the Early Renal Impairment in Patients with COVID-19

The COVID-19 pandemic examines not only the state of actual health care but also the state of fundamental medicine in various countries. Pro-inflammatory processes extend far beyond the classical concepts of inflammation. They manifest themselves in a variety of ways, beginning with extreme physiology, then allostasis at low-grade inflammation, and finally the shockogenic phenomenon of "inflammatory systemic microcirculation". The pathogenetic core of critical situations, including COVID-19, is this phenomenon. Microcirculatory abnormalities, on the other hand, lie at the heart of a specific type of general pathological process known as systemic inflammation (SI). Systemic inflammatory response, cytokine release, cytokine storm, and thrombo-inflammatory syndrome are all terms that refer to different aspects of SI. As a result, the metabolic syndrome model does not adequately reflect the pathophysiology of persistent low-grade systemic inflammation (ChSLGI). Diseases associated with ChSLGI, on the other hand, are risk factors for a severe COVID-19 course. The review examines the role of hypoxia, metabolic dysfunction, scavenger receptors, and pattern-recognition receptors, as well as the processes of the hemophagocytic syndrome, in the systemic alteration and development of SI in COVID-19.

Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes).

Evgenii Gusev

Papers

Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes).

The Pathogenesis of End-Stage Renal Disease from the Standpoint of the Theory of General Pathological Processes of Inflammation.