Materiały źródłowe

• #1 The Pathogenesis of Sepsis and Potential Therapeutic Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6862039/

  Sepsis is defined as a life-threatening organ dysfunction caused by a hosts dysfunctional response to infection. […] The present state of research on targeted therapeutic drugs is also elaborated upon to provide information for the treatment of sepsis. […] Sepsis is not only a process of systemic inflammatory response or immune disorder, it rather involves changes in the function of multiple organs in the body. […] The pathogenesis of sepsis is extremely complex, including imbalance in inflammatory response, immune dysfunction, mitochondrial damage, coagulopathy, neuroendocrine immune network abnormalities, endoplasmic reticulum stress, autophagy, and other pathophysiological processes, and ultimately leads to organ dysfunction. […] Inflammatory imbalance represents the most critical basis of sepsis pathogenesis and occurs throughout the whole process of sepsis, and the pathogens eliciting the response include organisms such as bacteria, fungi, parasites, and viruses.

• #2 Pathogenesis of Sepsis | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-319-73506-1_3

  Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. Both hyperinflammation and immune suppression ensue, to an extent that is harmful to the host. The inflammatory balance is disturbed, and this is associated with a failure to return to homeostasis. […] In sepsis, the normally careful inflammatory balance is disturbed, and hyperinflammation together with immune suppression ensue. This dysregulated immune response to infection is associated with a failure to return to homeostasis and harms the host, resulting in the life-threatening condition called sepsis. […] Sepsis is defined as a dysregulated host response to infection, leading to life-threatening organ dysfunction. The normally careful inflammatory balance is disturbed, and this dysregulation is associated with a failure to return to homeostasis. Hyperinflammation and immune suppression ensue, to an extent that is detrimental to the host.

• #3 The Pathogenesis of Sepsis and Potential Therapeutic Targets

  https://www.mdpi.com/1422-0067/20/21/5376

  Sepsis is defined as “a life-threatening organ dysfunction caused by a host’s dysfunctional response to infection”. […] The present state of research on targeted therapeutic drugs is also elaborated upon to provide information for the treatment of sepsis. […] Sepsis is not only a process of systemic inflammatory response or immune disorder, it rather involves changes in the function of multiple organs in the body. […] The pathogenesis of sepsis is extremely complex, including imbalance in inflammatory response, immune dysfunction, mitochondrial damage, coagulopathy, neuroendocrine immune network abnormalities, endoplasmic reticulum stress, autophagy, and other pathophysiological processes, and ultimately leads to organ dysfunction. […] Inflammatory imbalance represents the most critical basis of sepsis pathogenesis and occurs throughout the whole process of sepsis, and the pathogens eliciting the response include organisms such as bacteria, fungi, parasites, and viruses.

• #4 The Pathogenesis of Sepsis and Potential Therapeutic Targets

  https://www.mdpi.com/1422-0067/20/21/5376

  The host’s initial acute response to invasive pathogens typically causes macrophages to engulf the pathogens and produce a range of pro-inflammatory cytokines, and this can trigger cytokine storms and activate the innate immune system. […] The pathogenesis of sepsis includes a decrease in HLA-DR, lymphocyte replication, programmed cell death/apoptosis induction, anti-inflammatory molecules expression increasing, and cell-associated co-suppressor receptors and ligands upregulation. […] Sepsis-induced mitochondrial damage or dysfunction can result in cellular metabolic disorders, insufficient energy production, and oxidative stress, which give rise to the apoptosis of organ cells and immune cells, thus ultimately generate immune disorders, multiple organ failure, and even death. […] The interaction between inflammation and coagulation is widely considered to be a key point in the pathogenesis of sepsis.

• #5 Septic Shock: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/168402-overview

  These response mechanisms occur during septic shock, but on a systemic scale, leading to diffuse endothelial disruption, vascular permeability, vasodilation, and thrombosis of end-organ capillaries. Endothelial damage itself can further activate inflammatory and coagulation cascades, creating, in effect, a positive feedback loop and leading to further endothelial and end-organ damage. […] The evidence that sepsis results from an exaggerated systemic inflammatory response induced by infecting organisms is compelling. Inflammatory mediators are the key players in the pathogenesis of sepsis. […] The following three families of pattern recognition receptors are involved in the initiation of the sepsis response: Toll-like receptors (TLRs), Nucleotide-oligomerization domain leucine-rich repeat proteins, Cytoplasmic caspase activation and recruiting domain helicases.

• #6 Septic Shock: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/168402-overview

  Gram-positive and gram-negative bacteria induce a variety of proinflammatory mediators, including the cytokines mentioned above, which play a pivotal role in initiating sepsis and shock. Various bacterial cell-wall components are known to release the cytokines, including lipopolysaccharide (LPS; gram-negative bacteria), peptidoglycan (gram-positive and gram-negative bacteria), and lipoteichoic acid (gram-positive bacteria). […] The predominant hemodynamic feature of septic shock is arterial vasodilation. The mechanisms implicated in this pathologic vasodilation are multifactorial, but the primary factors are thought to be (1) activation of adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle cells and (2) activation of NO synthase. […] The basic pathophysiologic problem seems to be a disparity between oxygen uptake and oxygen demand in the tissues, which may be more pronounced in some areas than in others.

• #7 Pathophysiology of sepsis – UpToDate

  https://www.uptodate.com/contents/pathophysiology-of-sepsis

  The pathophysiology of sepsis and mechanisms of multiple organ system dysfunction are reviewed here. […] Sepsis results when the response to infection becomes generalized and involves normal tissues remote from the site of injury or infection. […] The host response to an infection is initiated when innate immune cells, particularly macrophages, recognize and bind to microbial components. […] Causative pathogen replicates and releases microbial components such as endotoxins, exotoxins, and DNA that are designated pathogen-associated molecular patterns (PAMPs). […] PRRs can also recognize endogenous danger signals, so-called alarmins or danger-associated molecular patterns (DAMPs) that are released during the inflammatory insult.

• #8 Sepsis – Wikipedia

  https://en.wikipedia.org/wiki/Sepsis

  Sepsis caused by gram-positive bacteria may result from an immunological response to cell wall lipoteichoic acid. […] Bacterial exotoxins that act as superantigens also may cause sepsis. […] An invading pathogen is recognized by its pathogen-associated molecular patterns (PAMPs). […] These PAMPs are recognized by the pattern recognition receptors (PRRs) of the innate immune system, which may be membrane-bound or cytosolic. […] The association of a PAMP and a PRR will cause a series of intracellular signalling cascades. […] Cytokines such as tumor necrosis factor, interleukin 1, and interleukin 6 may activate procoagulation factors in the cells lining blood vessels, leading to endothelial damage. […] The damaged endothelial surface inhibits anticoagulant properties as well as increases antifibrinolysis, which may lead to intravascular clotting, the formation of blood clots in small blood vessels, and multiple organ failure.

• #9 The Pathogenesis of Sepsis and Potential Therapeutic Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6862039/

  The pathogenesis of sepsis includes a decrease in HLA-DR, lymphocyte replication, programmed cell death/apoptosis induction, anti-inflammatory molecules expression increasing, and cell-associated co-suppressor receptors and ligands upregulation. […] Sepsis-induced mitochondrial damage or dysfunction can result in cellular metabolic disorders, insufficient energy production, and oxidative stress, which give rise to the apoptosis of organ cells and immune cells, thus ultimately generate immune disorders, multiple organ failure, and even death. […] The interaction between inflammation and coagulation is widely considered to be a key point in the pathogenesis of sepsis. […] The homeostasis that depends on the interaction of the neuroendocrineimmune system is also considered to be a crucial part of the host response during septic shock.

• #10 4. Pathophysiology of Sepsis | ATrain Education

  https://www.atrainceu.com/content/4-pathophysiology-sepsis

  Sepsis has been shown to develop when the innate immune response becomes amplified and dysfunctional, leading to an imbalance between pro-inflammatory and anti-inflammatory responses. It is the innate immune response that plays a major role in sepsis pathophysiology. […] Cytokines regulate a variety of inflammatory responses, including the migration of immune cells to the infection, which is a crucial step in containing a localized infection and preventing it from becoming systemic. […] An inflammation-induced disruption of the coagulation system, for instance, significantly worsens the effects of sepsis and can result in lethal disseminated intravascular coagulation (DIC) (Schulte et al., 2013). […] Traditionally, sepsis was viewed as an excessive systemic pro-inflammatory reaction to an infection. More recently it has been proposed that the early phase of hyper-inflammation is followed or overlapped by a prolonged state of immunosuppression, referred to as sepsis-induced immunoparalysis. This immunoparalytic state is characterized by impaired innate and adaptive immune responses and may play a central role in tissue damage, multiple organ failure, and death induced by sepsis (Schulte et al., 2013).

• #11 Pathogenesis of Sepsis | SpringerLink

  https://link.springer.com/chapter/10.1007/978-3-319-73506-1_3

  Sepsis is associated with a strong activation of the immune system, by stimulation of PRRs by PAMPs and DAMPs, leading to the activation of target genes coding for proinflammatory cytokines such as tumor necrosis factor (TNF), IL-1, IL-12, and IL-18. […] If the delicate balance between activation and inhibition of the inflammatory response is disturbed, the pleiotropic hyperinflammatory response in sepsis ensues. […] Sepsis-associated immune suppression involves several cell types. During sepsis massive apoptosis leads to depletion of immune cells, especially CD4+ and CD8+ T cells and B cells. […] Sepsis is further characterized by profound changes in the function of antigen presenting cells. Monocytes and macrophages demonstrate a strongly decreased capacity to release proinflammatory cytokines upon stimulation with bacterial agonists (a feature commonly referred to as endotoxin tolerance) and reduced HLA-DR expression. […] The immune suppressive effects of sepsis can remain for months, perhaps even longer. It is hypothesized that epigenetic imprints occur both on mature immune cells in the periphery and progenitor cells in the bone marrow, thereby contributing to this long-lasting immune suppression.

• #12 Multiple Organ Dysfunction Syndrome in Sepsis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/169640-overview

  The precise mechanisms of cell injury and resulting organ dysfunction in sepsis are not fully understood. MODS is associated with widespread endothelial and parenchymal cell injury, some of which can be explained by the following 4 proposed mechanisms. […] The septic circulatory lesion disrupts tissue oxygenation, alters the metabolic regulation of tissue oxygen delivery, and contributes to organ dysfunction. […] Endotoxin, TNF-, and NO may cause damage to mitochondrial electron transport, leading to disordered energy metabolism. […] Apoptosis (programmed cell death) is the principal mechanism by which dysfunctional cells are normally eliminated. […] The interaction between proinflammatory and anti-inflammatory mediators may lead to an imbalance between them.

• #13 Sepsis‑induced cardiac dysfunction and pathogenetic mechanisms (Review)

  https://www.spandidos-publications.com/10.3892/mmr.2023.13114

  The mechanism of mitochondrial dysfunction and adaptive response to mitochondrial dysfunction is shown in Fig. 1. […] Mitochondrial dysfunction is a key component of sepsis. […] The critical causative factors responsible for mitochondrial dysfunction include inducible NOS (iNOS) synthase and mtNOS. […] In summary, one of the major causes of mitochondrial dysfunction involves ROS and NO, which may be key mechanisms of action in sepsis. […] The aforementioned studies suggest that ketone bodies may represent a pathogenic mechanism in sepsis. […] The present study summarized the primary factors that contribute to the pathogenesis of SC, such as mitochondrial dysfunction, metabolic changes, cell death and signaling pathways. […] Mitochondrial dysfunction, primarily due to increased ROS and no steady-state concentrations inside mitochondria, increases various reversible and irreversible toxic modifications on biomolecules, such as protein carbonylation and lipid peroxidation. […] In addition, ferroptosis and pyroptosis contribute to pathogenesis of SC.

• #14 Sepsis and Septic Shock – Critical Care Medicine – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/critical-care-medicine/sepsis-and-septic-shock/sepsis-and-septic-shock

  Septic shock occurs more often in neonates, older adults, and pregnant people. Predisposing factors include […] The pathogenesis of septic shock is not completely understood. An inflammatory stimulus (eg, a bacterial toxin) triggers production of pro-inflammatory mediators, including tumor necrosis factor (TNF) and interleukin (IL)-1. These cytokines cause neutrophil-endothelial cell adhesion, activate the clotting mechanism, and generate microthrombi. They also release numerous other mediators, including leukotrienes, lipoxygenase, histamine, bradykinin, serotonin, and IL-2. They are opposed by anti-inflammatory mediators, such as IL-4 and IL-10, resulting in a negative feedback mechanism. […] Even in the stage of increased cardiac output, vasoactive mediators cause blood flow to bypass capillary exchange vessels (a distributive defect). Poor capillary flow resulting from this shunting, along with capillary obstruction by microthrombi, decreases delivery of oxygen and impairs removal of carbon dioxide and waste products. Decreased perfusion causes dysfunction and sometimes failure of 1 organs, including the kidneys, lungs, liver, brain, and heart. […] Coagulopathy may develop because of intravascular coagulation with consumption of major clotting factors, excessive fibrinolysis in reaction thereto, and more often a combination of both.

• #15 The Pathogenesis of Sepsis and Potential Therapeutic Targets

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6862039/

  The unfolded or misfolded proteins are accumulated in the ER during sepsis, altering its homeostasis, and leading to oxidative stress and severe calcium disorders that result in ER stress. […] Autophagy is a critical defense mechanism used by the host to resist external pathogens and dangerous signals, and plays a critical role in the induction and regulation of natural immune-cell inflammatory response, and is a key factor affecting sepsis development.

• #16 The Pathogenesis of Sepsis and Potential Therapeutic Targets

  https://www.mdpi.com/1422-0067/20/21/5376

  The homeostasis that depends on the interaction of the neuroendocrine–immune system is also considered to be a crucial part of the host response during septic shock. […] The endoplasmic reticulum (ER) is an intracellular organelle that is involved in protein translocation, folding, posttranslational modification, and further transport to the Golgi apparatus. […] Autophagy is a critical defense mechanism used by the host to resist external pathogens and dangerous signals, and plays a critical role in the induction and regulation of natural immune-cell inflammatory response, and is a key factor affecting sepsis development.

• #17 Sepsis – Wikipedia

  https://en.wikipedia.org/wiki/Sepsis

  The low blood pressure seen in those with sepsis is the result of various processes, including excessive production of chemicals that dilate blood vessels such as nitric oxide, a deficiency of chemicals that constrict blood vessels such as vasopressin, and activation of ATP-sensitive potassium channels. […] In those with severe sepsis and septic shock, this sequence of events leads to a type of circulatory shock known as distributive shock.

• #18

  https://journals.lww.com/cjasn/fulltext/2022/07000/the_pathophysiology_of_sepsis_associated_aki.17.aspx

  The NLRP3 inflammasome activates caspase-1 facilitating the maturation of IL-1 and IL-18, which exacerbates inflammation. […] The NLRP3 inflammasome is central to the inflammatory cascade in sepsis-activated innate immunity and should be considered as an important target for therapeutic intervention in sepsis-associated AKI. […] Emerging evidence suggests that microRNAs (miRNAs), small noncoding RNAs composed of about 22 nucleotides, are critical for the pathophysiology of both sepsis and AKI. […] Autophagy is activated during sepsis and AKI and plays a protective role in sepsis-associated AKI. […] Metabolic reprogramming during sepsis-associated AKI can have a major effect on outcomes, but this process remains incompletely understood. […] Dysfunctional mitochondria are normally removed by selective mitochondrial autophagy.

• #19

  https://journals.lww.com/co-gastroenterology/fulltext/2021/11000/gut_microbiota_and_sepsis__from_pathogenesis_to.7.aspx

  This review summarizes recent progress in our understanding of the role of the gut microbiota in sepsis pathogenesis and outlines the potential role of microbiota-targeted therapies. […] The composition of the gut microbiome is profoundly distorted during sepsis, with a loss of commensal bacteria and an overgrowth of potential pathogenic micro-organisms. […] Disruptions of these intestinal communities are associated with both an increased susceptibility to develop sepsis, as well as a higher risk of adverse outcomes. […] Emerging evidence display an important role of gut micro-organisms (including bacteria, fungi, eukaryotic viruses, and bacteriophages) and their derived metabolites in both the susceptibility to, as well as outcomes of sepsis. […] Altered gut microbiota influence inflammatory responses and increase gut barrier permeability, which could enable the translocation of pathobionts to the systemic circulation and distant organs.

• #20

  https://journals.lww.com/co-gastroenterology/fulltext/2021/11000/gut_microbiota_and_sepsis__from_pathogenesis_to.7.aspx

  Despite of the findings linking altered compositions of the microbiome to sepsis outcomes, the exact mechanisms underlying the protective effects of gut microbes in sepsis have not yet been fully identified. […] The host immune response is not only affected by such gut microbiota-derived metabolites, but commensal bacteria can also reciprocally respond to immune activation and change their metabolic output. […] Although these findings shed new light on possible mechanisms involved in the role of gut microbiota in sepsis, murine research does not fully replicate conditions present during sepsis in humans and translating these findings to humans is urgently needed to further boost the development of novel microbiome-based therapeutics. […] In summary, disruption of intestinal inhabitants during critical illness extends beyond bacteria, yet the clinical consequences of these disturbances still have to be elucidated.

• #21 Sepsis: mechanisms of bacterial injury to the patient | Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine | Full Text

  https://sjtrem.biomedcentral.com/articles/10.1186/s13049-019-0596-4

  In bacteremia the majority of bacterial species are killed by oxidation on the surface of erythrocytes and digested by local phagocytes in the liver and the spleen. […] Sepsis-causing bacteria overcome this mechanism of human innate immunity by versatile respiration, production of antioxidant enzymes, hemolysins, exo- and endotoxins, exopolymers and other factors that suppress host defense and provide bacterial survival. […] The pathogenesis of the sepsis syndrome is dependent on activation of the innate immune response. Innate immunity plays a direct role in the development of sepsis and is also crucial for the activation and modulation of later antigen-specific adaptive immune responses. […] Once activated by microbial products, macrophages acquire microbicidal competence that usually leads to effective immunity. However, several bacterial pathogens, first of all, sepsis-causing bacteria, have evolved mechanisms of inhibiting macrophages and host immune response.

• #22 Sepsis: mechanisms of bacterial injury to the patient | Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine | Full Text

  https://sjtrem.biomedcentral.com/articles/10.1186/s13049-019-0596-4

  Oxidation of bacteria on the surface of erythrocytes kills the majority of bacterial species, but sepsis-causing bacteria have evolved numerous mechanisms against oxidation that provide their survival in the bloodstream. […] The next line of host defense is intravascular coagulation that may cause disseminated intravascular coagulation. […] For survival, growth and proliferation bacteria have evolved different mechanisms of adaptation, particularly, production of a thick capsule, biofilm formation and switching into the L-form. […] Capsule considerably decreases the ability of antimicrobial agents to gain entry into the cell where the drug targets are located. […] Bacterial wall is an essential structure for viability: it protects the cell protoplast from mechanical damage and from osmotic rupture.

• #23 Sepsis: mechanisms of bacterial injury to the patient | Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine | Full Text

  https://sjtrem.biomedcentral.com/articles/10.1186/s13049-019-0596-4

  L-form bacteria (free and inside leukocytes) are resistant to wall-targeting antibiotics because of the absence of bacterial wall. […] The mechanisms by which bacteria cause sepsis and septic shock involve bacterial factors (cell wall, secreted products) and host factors (susceptibility, primary (immune) response, secondary (tissue) response, etc.). […] Bacterial toxins allow the pathogen to modulate host defenses. […] Sepsis-causing planktonic pathogens survive oxycytosis by producing antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) and versatile respiration adapted to high concentrations of reactive oxygen species. […] Production of hemolysins provides penetration of planktonic pathogens through erythrocyte membrane and forming a bacterial reservoir inside erythrocytes.

• #24 Sepsis: mechanisms of bacterial injury to the patient | Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine | Full Text

  https://sjtrem.biomedcentral.com/articles/10.1186/s13049-019-0596-4

  Inhibition of bacterial cell wall synthesis can stimulate bacteria to switch into a wall-deficient state called the L-form. […] The formation of biofilm is an adaptation of microbes to hostile environments. […] Bacterial biofilms are highly resistant to antibiotic treatment and immune responses. […] In sepsis the effectiveness of antibacterials in the bloodstream is limited by different factors. […] Planktonic bacteria cannot grow and multiply in the bloodstream because they become triboelectrically charged during move in the blood flow and friction with blood cells and vessel walls. […] Encapsulated bacteria and bacteria in biofilms are resistant to antibacterials, particularly, antibiotics because of low metabolism and polysaccharides that isolate bacteria from antibacterial agents.

• #25 Viral sepsis: diagnosis, clinical features, pathogenesis, and clinical considerations | Military Medical Research | Full Text

  https://mmrjournal.biomedcentral.com/articles/10.1186/s40779-024-00581-0

  Viruses exhibit distinct mechanisms for eliciting immune responses compared to bacteria and fungi. […] While bacteria and fungi utilize endotoxins, superantigens, and various toxins, viruses primarily exploit their nucleic acid genomes or protein structures. […] Viruses may infect non-immune host cells, resulting in cellular damage that amplifies both immune responses and tissue injury. […] Moreover, viruses often target immune cells (e.g., T and B cells) to stimulate the humoral immune response, leading to increased antibody production that may further exacerbate tissue damage. […] Additionally, viruses can modulate natural killer (NK) cells, crucial components of the immune defense, which may inadvertently harm uninfected tissues. […] Upon invading host cells, viruses engage traditional pattern recognition receptor (PRR) or retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) signaling pathways. […] They also enhance first-line antiviral defenses such as cyclic guanosine monophosphate adenosine monophosphate (GMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) and interferon signaling that lead to cellular stress, metabolic disruptions, and cell death, resulting in diverse clinical manifestations. […] These intricate pathophysiological processes contribute additional layers of complexity to virus-induced sepsis.

• #26 Septic Shock: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/168402-overview

  Maldistribution of blood flow, disturbances in the microcirculation, and, consequently, peripheral shunting of oxygen are responsible for diminished oxygen extraction and uptake, pathologic supply dependency of oxygen, and lactate acidemia in patients experiencing septic shock. […] Sepsis is described as an autodestructive process that permits the extension of the normal pathophysiologic response to infection (involving otherwise normal tissues), resulting in MODS. Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is immune to the consequences of the inflammatory excesses of sepsis.

• #27 Multiple Organ Dysfunction Syndrome in Sepsis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/169640-overview

  Inflammatory mediator release becomes a self-stimulating process, and release of other such mediators, including interleukin (IL)-1, platelet activating factor, IL-2, IL-6, IL-8, IL-10, and nitric oxide (NO), further increases cytokine levels. […] Sepsis is described as an autodestructive process that permits extension of the normal pathophysiologic response to infection to involve otherwise normal tissues and results in MODS. […] Although uncontrolled, once MODS develops systemic evidence of both proinflammatory and anti-inflammatory up-regulation are usually present, suggesting that failure of host defense homeostasis is the final pathway from sepsis to MODS, rather than simple hypotension-induced end-organ injury, as may occur with hemorrhagic shock. […] A novel hypothesis has emerged that survival from severe sepsis requires a generalized down-regulation of the body’s immune response, energetic functions, and associated organ performance.

• #28 The Pathogenesis of Sepsis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3684427/

  Sepsis develops when the inflammatory response to infection rises to such a level that physiologic alterations within the host occur. […] The bacterial load may be of such magnitude (or the bacteria may be so virulent) that a strong inflammatory response appropriately matches the powerful bacterial stimulus, yet the collateral damage it simultaneously produces cannot be compensated for by the septic patient. […] Accelerated apoptosis, especially as it occurs in lymphocytes, may play a central role in the pathogenesis of sepsis. […] Apoptosis-induced loss of lymphocytes may be one of the key triggers of this state. […] Sepsis is a complex, dynamic disease in which aspects of the inflammatory response become dysregulated. […] Both apoptosis and necrosis occur during the septic response, and a portion of the dysregulated septic response occurs when the wrong cells die at the wrong time. […] CSMs are a key regulatory point in innate-adaptive interactions during sepsis and may provide a specific target for regulation of the adaptive response. […] Coagulopathy frequently accompanies sepsis and increases in severity as multiple organ failure and septic shock develop.

• #29 Sepsis Induced Myocardial Injury | JIR

  https://www.dovepress.com/research-progress-on-the-mechanism-of-sepsis-induced-myocardial-injury-peer-reviewed-fulltext-article-JIR

  The activation of PI3K/Akt pathway leads to the inhibition of apoptosis and mitigates SIMI. […] The real causes of cardiac dysfunction induced by sepsis are closely related to excessive inflammatory response. […] The explosive inflammatory response during sepsis is also driven by macrophage infiltration. […] Excessive inflammatory responses mediated by NF-Bp65 signaling have been reported extensively. […] Oxidative damage of cardiomyocytes with dysfunction has been documented in abundant literatures on the pathophysiology of sepsis. […] Pyroptosis is affected by oxidative stress, apoptosis and inflammation, and its controlled condition influences the progression of sepsis. […] The mechanism of pyroptosis on SIMI is mediated by ER/SIRT1/NLRP3/GSDMD signaling pathway, which is the most complete pathway discovered so far. […] There are still many signaling molecules lacking in the studied pathway, and also many signaling pathways related to sepsis are not reflected in the studies of SIMI; so it is imperative that we continue to explore and refine the existing mechanisms of SIMI.

• #30 Sepsis pathogenesis and outcome are shaped by the balance between the transcriptional states of systemic inflammation and antimicrobial response — Olink®

  https://olink.com/publication/sepsis-pathogenesis-and-outcome-are-shaped-by-the-balance-between-the-transcriptional-states-of-systemic-inflammation-and-antimicrobial-response

  Patients with sepsis differ in their clinical presentations and immune dysregulation in response to infection, but the fundamental processes that determine this heterogeneity remain elusive. […] Here, we aim to understand which types of immune dysregulation characterize patients with sepsis. […] We investigate sepsis pathogenesis in the context of two transcriptional states: one represents the immune response to eliminate pathogens (resistance, R) and the other is associated with systemic inflammation (SI). […] We find that patients with sepsis share a molecular fingerprint of a low R-to-SI balance i.e., a low R relative to the level of SI. […] Differences between patients with sepsis are explained by the wide diversity of R and SI states that fall under this fingerprint, such as patients with high SI, patients with low R, or both. […] We show how this R/SI framework can be used to guide patient stratification that is relevant to disease prognosis and management, outperforming existing classifications of sepsis.

• #31 Pathogenesis of sepsis: new concepts and implications for future treatment | The BMJ

  https://www.bmj.com/content/326/7383/262/related

  Peptidoglycan recognition proteins (PGRP) have been recently shown to be involved in the recognition of Gram positive (PGRP-SA) and Gram negative bacteria (PGRP-LC) by insects. […] Further work is needed to determine the exact role of PGRPs in the host defences against bacterial infections. […] TREM-1 is a recently identified receptor of the immunoglobulin superfamily expressed on neutrophils and monocytes. […] Modulation of TREM-1, and perhaps DAP12, activity might offer new treatment approaches for sepsis. […] Studies to understand the genetic basis of sepsis will be complicated be the fact that more than one gene is likely to be involved. […] Single nucleotide polymorphisms of the Tnf, IL-1 receptor antagonist, CD14, and plasminogen activator inhibitor-1 genes have been shown to be associated with increased susceptibility to severe sepsis and septic shock. […] Increased susceptibility to staphylococcal infections has been linked to a polymorphism of TLR2 (Arg753Gln).

• #32 Sepsis Induced Myocardial Injury | JIR

  https://www.dovepress.com/research-progress-on-the-mechanism-of-sepsis-induced-myocardial-injury-peer-reviewed-fulltext-article-JIR

  The identification, diagnosis, treatment, and prognosis of infectious cardiomyopathy, a common complication of sepsis, remain the huge challenge for physicians in ICU. […] Current studies on the mechanism of apoptosis following with SIMI mainly focus on MAPK and PI3K/AKT/mTOR signaling pathways and come up with those two inhibited ways can attenuate cardiac depression. […] Mitochondrial injury is a key link in the process from cellular injury to the initiation of sepsis. […] Mitochondrial dysfunction is the primary prerequisite for the pathophysiological process of SIMI, which consist of ATP production, Ca2+ homeostasis, mitochondrial permeability transition pore (MPTP) and over-produced oxygen-free radicals. […] In sepsis, UPRmt activation precedes mitochondrial autophagy, with UPRmt repairing mitochondrial proteins and mitochondrial autophagy repairing mitochondrial numbers.

• #33 Take a look at the Recent articles

  http://oatext.com/Different-therapeutic-strategies-chosen-according-to-different-mechanism-of-sepsis.php

  The conventional view of sepsis is an anti-inflammatory response to the pathogen, some researchers has described sepsis as the immune system gone haywire. […] Recent researches have elucidated important function of cytokines including tumor necrosis factor (TNF), intercleukin-1, intercleukin-6, intercleukin-8 in the course of sepsis, and tried to figure out their applied value in clinic. […] After invading into body, the cellular components released by pathogen, especially the lipopolysaccharide (LPS), a kind of bacterial endotoxin, can induce phagocytosis of macrophages and neutrophil granulocyte, the secretion functions of immune cells and endothelial cells. […] Activation of the cell results in two kinds of immune response, namely relative immunosuppression led by IL-4, IL-10 and relative immune enhancement led by IL-1, IL-2, TNF, the form will evolve into compensatory anti-inflammatory response syndrome (CARS), and the latter will be systemic inflammatory response syndrome (SIRS).

• #34 Sepsis: mechanisms of bacterial injury to the patient | Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine | Full Text

  https://sjtrem.biomedcentral.com/articles/10.1186/s13049-019-0596-4

  Inhibition of bacterial hemolysins may prevent pathogen penetration into erythrocytes. […] Antioxidant enzymes of sepsis-causing bacteria provide bacterial survival during phagocytosis in the tissues and oxycytosis (oxidation on the surface and inside erythrocytes) in the bloodstream. […] Sepsis therapy should include the use of antibacterial medications, modulation of bacterial respiration, inhibition of bacterial antioxidant enzymes and hemolysins, neutralization of exo- and endotoxins, dispersion of bacterial capsule and biofilm, increasing of host tolerance to bacterial products, facilitation of host bactericidal mechanisms, support of host vital functions and restore of homeostasis.

• #35 Mechanisms and treatment of organ failure in sepsis | Nature Reviews Nephrology

  https://www.nature.com/articles/s41581-018-0005-7

  The first goal in the prevention of organ dysfunction in sepsis is to restore and maintain adequate oxygen delivery to cells. […] Current treatment for sepsis aims to limit the development of organ dysfunction by providing rapid control of infection, haemodynamic stabilization and organ support when possible to ensure recovery of organ function.

• #36 Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs)

  https://www.mdpi.com/1422-0067/23/16/9274

  The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. […] In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. […] Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. […] Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. […] However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear.

• #37 Take a look at the Recent articles

  http://oatext.com/Different-therapeutic-strategies-chosen-according-to-different-mechanism-of-sepsis.php

  Researches focused on neutrophil activation have elucidated that this process which results from the action of cytokines is believed to be an important factor in the pathogenic mechanism of sepsis. […] When the inflammation response becomes systematic, the comprehensive activation of neutrophils tend to form aggregates and become more adherent to endothelial cells, finally cause endothelial cell dysfunction and damage. […] Increased levels of nitric oxide and its products can be also found in patients with sepsis, these substances will make hypotension occurred. […] So multiple organ failure syndromes including the failure of the kidney, cardiovascular system and so on may be the result of the interweaving of all these alteration in vivo. […] Because of the pathogenic complexity of sepsis, it is increasingly clear that the combined-modality treatment has stronger and faster medications than single therapy.

• #38 Take a look at the Recent articles

  http://oatext.com/Different-therapeutic-strategies-chosen-according-to-different-mechanism-of-sepsis.php

  The integration of inflammation and coagulation is so close that cytokines participating entirely in development process of sepsis stimulate thrombin activation and also play an important role in the development of the intravascular coagulation. […] The complex interaction between the inflammation and coagulation are future complicated by complement system during sepsis which can recognize infectious changes in the organism. […] The role of the digestive tract in sepsis is being much more accounted of. […] The gut is an important focus of infection in sepsis. […] Maintaining the integrity of the intestinal mucosal barrier as well as keeping a normal bacterial flora can help to reduce the possibility of bacterial translocation and the risk of sepsis. […] It is now believe that total enteral nutrition is an important factor to reserve normal gastrointestinal function.

• #39 Confronted with sepsis, key immune mechanism breaks, Indiana University scientists find

  https://medicine.iu.edu/news/2016/07/carlesso-stemcells-sepsis-1

  When the body encounters an infection, a molecular signaling system ramps up the bodys infection-fighting system to produce more white blood cells to attack invading bacteria. […] Now researchers have discovered that when facing a massive bacterial infection resulting in sepsis, that same signaling system malfunctions, damaging the bodys ability to fight the invaders. […] In this research we determined that in cases of severe infection and sepsis, a key mechanism in the bodys response to infection is broken. […] The IU researchers focused on a set of proteins called toll-like receptors, which function as sentinels on the surfaces of cells. […] The IU researchers looked at toll receptor 4 (TLR4), which activates two signaling pathways that stimulate the production of more neutrophils during common infections, but suppress it during severe infections.

• #40 Confronted with sepsis, key immune mechanism breaks, Indiana University scientists find

  https://medicine.iu.edu/news/2016/07/carlesso-stemcells-sepsis-1

  In a laboratory model of sepsis using mice, the researchers found that two abnormal effects activated by toll receptor 4 during severe infection the suppression of neutrophil production and the damage to the bone marrows blood-producing stem cells are mediated by two different molecules downstream of TLR4.

• #41 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20200327/Scientists-uncover-key-molecular-mechanism-underlying-different-aspects-of-sepsis.aspx

  Sepsis is a life-threatening condition that kills millions annually; it is poorly understood and has no specific treatment. […] Now, researchers from Tata Memorial Centre, India, led by Prof. Dr Indraneel Mittra, have uncovered an important molecular mechanism underlying different aspects of sepsis chromatin released by dying host cells after infection or injury. […] In the latest study, the scientists made a hypothesis that sepsis could possibly be caused by cfCh integrating into and disrupting the DNA of healthy cells; which, according to Prof Mittra, then causes them to die and release more cfCh, thereby sparking off a terrifying cascade of sorts that leads to more host cell death, thus leading to sepsis-related pathologies. […] All these findings validated their hypothesis: one of the ways in which sepsis is caused is indeed the integration of cfCh into healthy host cell DNA and subsequent DNA damage, apoptosis, and inflammation, which triggers a vicious cycle and a chain reaction of further apoptosis and inflammation.

• #42 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20200327/Scientists-uncover-key-molecular-mechanism-underlying-different-aspects-of-sepsis.aspx

  Our previous studies have shown that inflammation is caused by cfCh integration and its associated DNA damage. […] Our new findings suggest that previous clinical trials for drugs to treat sepsis might have failed because the drugs attempted to treat the symptoms of inflammation rather than attacking the root cause, which is integration of cfCh into DNA of healthy cells and disruption of DNA.

• #43 Pathogenesis of sepsis: new concepts and implications for future treatment | The BMJ

  https://www.bmj.com/content/326/7383/262

  Severe sepsis and septic shock are important causes of death in intensive care units. […] Although our understanding of the pathogenesis of inflammation and sepsis has improved, until recently this has not translated into clinical benefit. […] Several new treatment approaches have given encouraging results. Evidence suggests that the way forward is to develop pathogen specific regimens rather than assume that one treatment fits all. […] Bacterial cell walls, endotoxins, and exotoxins are powerful activators of innate and acquired immune responses. […] Molecules expressed by pathogens interact with Toll-like receptors on immune cells, activating the immune response. […] Cytokines are important in the pathogenesis of sepsis. […] Susceptibility to sepsis may be due to inherited or acquired mutations of innate immune genes. […] Severe sepsis and septic shock are clinical manifestations of a dysregulated immune response to invasive pathogens. […] Pathogen recognition receptors (such as Toll-like receptors) and mediators of sepsis (such as macrophage migration inhibitory factor) might be novel targets for treatment.

• #44 The immunopathogenesis of sepsis | Nature

  https://www.nature.com/articles/nature01326

  Sepsis is a condition that results from a harmful or damaging host response to infection. […] Many of the components of the innate immune response that are normally concerned with host defences against infection can, under some circumstances, cause cell and tissue damage and hence multiple organ failure, the clinical hallmark of sepsis. […] Because of the high mortality of sepsis in the face of standard treatment, many efforts have been made to improve understanding of the dysregulation of the host response in sepsis. […] As a result, much has been learnt of the basic principles governing bacterial-host interactions, and new opportunities for therapeutic intervention have been revealed.

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