Sepsis-Induced Coagulopathy: A Comprehensive Narrative Review of Pathophysiology, Clinical Presentation, Diagnosis, and Management Strategies

Anesthesia & Analgesia, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 7, 2024

Physiological hemostasis is a balance between pro- and anticoagulant pathways, in sepsis, this equilibrium disturbed, resulting systemic thrombin generation, impaired activity, suppression of fibrinolysis, condition termed sepsis-induced coagulopathy (SIC). SIC common complication, being present 24% patients with sepsis 66% septic shock, often associated poor clinical outcomes high mortality. 1 , 2 Recent preclinical studies have generated new insights into the molecular pathogenesis SIC. In article, we analyze complex pathophysiology focus on role procoagulant innate immune signaling hemostatic activation--tissue factor production, endotheliopathy, antithrombotic functions. We also review presentations SIC, diagnostic scoring system laboratory tests, current standard care, trials evaluating efficacies therapies.

Language: Английский

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The tRNA ^Val half: A strong endogenous Toll-like receptor 7 ligand with a 5′-terminal universal sequence signature

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(19)

Published: April 29, 2024

Toll-like receptors (TLRs) are crucial components of the innate immune system. Endosomal TLR7 recognizes single-stranded RNAs, yet its endogenous ssRNA ligands not fully understood. We previously showed that extracellular (ex-) 5′-half molecules tRNA HisGUG (the 5′-tRNA half) in vesicles (EVs) human macrophages activate when delivered into endosomes recipient macrophages. Here, we explored immunostimulatory ex-5′-tRNA half and identified ValCAC/AAC half, most abundant tRNA-derived RNA macrophage EVs, as another molecule with strong activation capacity. Levels were highly up-regulated EVs upon exposure to lipopolysaccharide plasma patients infected Mycobacterium tuberculosis . The half-mediated effectively eradicated bacteria Mutation analyses terminal GUUU sequence a determinant for activation. confirmed is optimal ratio guanosine uridine activation; microRNAs or other RNAs motif can indeed stimulate TLR7, establishing universal signature These results advance our understanding offer insights diverse TLR7-involved pathologies their therapeutic strategies.

Language: Английский

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Training vs. Tolerance: The Yin/Yang of the Innate Immune System

Biomedicines, Journal Year: 2023, Volume and Issue: 11(3), P. 766 - 766

Published: March 2, 2023

For almost nearly a century, memory functions have been attributed only to acquired immune cells. Lately, this paradigm has challenged by an increasing number of studies revealing that innate cells are capable exhibiting memory-like features resulting in increased responsiveness subsequent challenges, process known as trained immunity (known also memory). In contrast, the refractory state endotoxin tolerance defined immunosuppressive myeloid portrayed significant reduction inflammatory capacity. Both training well adaptive reported be accompanied epigenetic and metabolic alterations occurring While conveys proper protection against secondary infections, induction promotes repairing mechanisms Consequently, inappropriate these cues may trigger maladaptive effects, promoting susceptibility infections—tolerance, or contribute progression disorder—trained immunity. This review aims at discussion opposing manners non-immune cells, describing molecular, involved interpreting clinical implications various pathologies.

Language: Английский

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Immunostimulatory short non-coding RNAs in the circulation of patients with tuberculosis infection

Molecular Therapy — Nucleic Acids, Journal Year: 2024, Volume and Issue: 35(1), P. 102156 - 102156

Published: Feb. 22, 2024

Mycobacterium tuberculosis (Mtb) infection is among the world's deadliest infectious diseases. Developing effective treatments and biomarkers for requires a deeper understanding of its pathobiology host responses. Here, we report comprehensive characterization circulating short non-coding RNAs (sncRNAs) in plasma samples from Mtb-infected patients. We achieved this by pre-treating with T4 polynucleotide kinase to convert all RNA ends those compatible sncRNA sequencing. discovered global drastic upregulation sncRNAs patients, tRNA-derived representing most dramatically elevated class. Most these originated limited subset tRNAs, specifically three tRNA isoacceptors, exhibited skewed patterns 5′-derived fragments, such as 5′ halves, fragments (tRFs), internal tRFs (i-tRFs) regions. Further, patients displayed markedly upregulated distinct profiles both rRNA- mRNA-derived sncRNAs. Some sncRNAs, which are abundant specific robustly activated human macrophages via Toll-like receptor 7 induced cytokine production. This accumulation circulating, immunostimulatory offers insights into sncRNA-driven aspects immune response against diseases suggests pool potential therapeutic targets biomarkers.

Language: Английский

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TLR7 Mediates Acute Respiratory Distress Syndrome in Sepsis by Sensing Extracellular miR-146a

American Journal of Respiratory Cell and Molecular Biology, Journal Year: 2022, Volume and Issue: 67(3), P. 375 - 388

Published: June 9, 2022

TLR7 (Toll-like receptor 7), the sensor for single-stranded RNA, contributes to systemic inflammation and mortality in murine polymicrobial sepsis. Recent studies show that extracellular miR-146a-5p serves as a ligand plays an important role regulating host innate immunity. However, of signaling pulmonary inflammation, endothelial activation, sepsis-associated acute respiratory distress syndrome remains unclear. Here, we intratracheal administration exogenous mice evokes lung activates endothelium, increases permeability via TLR7-dependent mechanisms. deficiency attenuates barrier dysfunction reduces inflammatory response sepsis model. Moreover, impact miR-146a-5p-TLR7 on activation appears be secondary effect because is undetectable human artery microvascular cells (ECs), which no direct treatment

Language: Английский

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Expression of MicroRNAs in Sepsis-Related Organ Dysfunction: A Systematic Review

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(16), P. 9354 - 9354

Published: Aug. 19, 2022

Sepsis is a critical condition characterized by increased levels of pro-inflammatory cytokines and proliferating cells such as neutrophils macrophages in response to microbial pathogens. Such processes lead an abnormal inflammatory multi-organ failure. MicroRNAs (miRNA) are single-stranded non-coding RNAs with the function gene regulation. This means that miRNAs involved multiple intracellular pathways thus contribute or inhibit inflammation. As result, their variable expression different tissues organs may play key role regulating pathophysiological events sepsis. Thanks this property, serve potential diagnostic prognostic biomarkers life-threatening events. In narrative review, we collect results recent studies on heart, blood, lung, liver, brain, kidney during sepsis molecular which they involved. reviewing literature, find at least 122 signaling sepsis-related organ dysfunction. help clinicians detect, prevent, treat failures early, although further needed deepen knowledge contribution.

Language: Английский

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Sepsis‐associated encephalopathy: Autophagy and miRNAs regulate microglial activation

Physiological Reports, Journal Year: 2024, Volume and Issue: 12(5)

Published: March 1, 2024

Abstract Sepsis‐associated encephalopathy (SAE) describes diffuse or multifocal cerebral dysfunction caused by the systemic inflammatory response to sepsis. SAE is a common neurological complication in patients middle and late stages of sepsis intensive care unit. Microglia, resident macrophages central nervous system, phagocytose small numbers neuronal cells apoptotic cells, among other maintain dynamic balance brain's internal environment. The neuroinflammatory induced activated microglia plays role pathogenesis various system diseases. In this paper, we systematically describe functions phenotypes microglia, summarize how mediate neuroinflammation contribute occurrence development SAE, discuss recent progress autophagy‐ microRNA‐mediated regulation microglial activation provide theoretical basis for prevention treatment identify related therapeutic targets.

Language: Английский

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MicroRNA let-7b enhances spinal cord nociceptive synaptic transmission and induces acute and persistent pain through neuronal and microglial signaling

Pain, Journal Year: 2024, Volume and Issue: 165(8), P. 1824 - 1839

Published: March 6, 2024

Abstract Secreted microRNAs (miRNAs) have been detected in various body fluids including the cerebrospinal fluid, yet their direct role regulating synaptic transmission remains uncertain. We found that intrathecal injection of low dose let-7b (1 μg) induced short-term (<24 hours) mechanical allodynia and heat hyperalgesia, a response is compromised Tlr7 −/− or Trpa1 mice. Ex vivo calcium imaging GCaMP6-report mice revealed increased signal spinal cord afferent terminals doral root ganglion/dorsal ganglia neurons following perfusion intraplantar let-7b. Patch-clamp recordings also demonstrated enhanced excitatory (miniature postsynaptic currents [EPSCs]) nociceptive optogenetic activation axonal terminals. The elevation signaling EPSCs was dependent on presence toll-like receptor-7 (TLR7) transient receptor potential ion channel subtype A1 (TRPA1). In addition, endogenous enriched synaptosome, peripheral inflammation neurons, tissue, fluid. Notably, antagomir inhibited inflammatory pain inflammation-induced plasticity (EPSC increase), suggesting an transmission. Furthermore, let-7b, at higher (10 μg), persistent for >2 weeks, which abolished high microgliosis cord. Of interest, minocycline only let-7b–induced male but not female Our findings indicate secreted microRNA has capacity to provoke through both neuronal glial signaling, thereby establishing miRNA as emerging neuromodulator.

Language: Английский

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IL-1β, the first piece to the puzzle of sepsis-related cognitive impairment?

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: April 11, 2024

Sepsis is a leading cause of death resulting from an uncontrolled inflammatory response to infectious agent. Multiple organ injuries, including brain are common in sepsis. The underlying mechanism sepsis-associated encephalopathy (SAE), which associated with neuroinflammation, not yet fully understood. Recent studies suggest that the release interleukin-1β (IL-1β) following activation microglial cells plays crucial role development long-lasting neuroinflammation after initial sepsis episode. This review provides comprehensive analysis recent literature on molecular signaling pathways involved cell and release. It also explores physiological pathophysiological IL-1β cognitive function, particular focus its contribution findings this may assist healthcare providers developing novel interventions against SAE.

Language: Английский

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Toll-like receptor 7: A novel neuroimmune target to reduce excessive alcohol consumption

Neurobiology of Stress, Journal Year: 2024, Volume and Issue: 31, P. 100639 - 100639

Published: May 6, 2024

Toll-like receptors (TLRs) are a family of innate immune that recognize molecular patterns in foreign pathogens and intrinsic danger/damage signals from cells. TLR7 is nucleic acid sensing endosomal TLR activated by single-stranded RNAs microbes or small noncoding act as endogenous ligands. through the MyD88 adaptor protein activates transcription factor interferon regulatory 7 (IRF7). found throughout brain highly expressed microglia, main cells have also been implicated alcohol drinking mice. Upregulation

Language: Английский

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