The Pathogenesis of Sepsis and Potential Therapeutic Targets

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(21), P. 5376 - 5376

Published: Oct. 29, 2019

Sepsis is defined as "a life-threatening organ dysfunction caused by a host's dysfunctional response to infection". Although the treatment of sepsis has developed rapidly in past few years, incidence and mortality clinical still climbing. Moreover, because diverse manifestations sepsis, clinicians continue face severe challenges diagnosis, treatment, management patients with sepsis. Here, we review recent development our understanding regarding cellular pathogenesis target diagnosis goal enhancing current The present state research on targeted therapeutic drugs also elaborated upon provide information for

Language: Английский

---

Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options

Military Medical Research, Journal Year: 2022, Volume and Issue: 9(1)

Published: Oct. 9, 2022

Sepsis is a common complication of combat injuries and trauma, defined as life-threatening organ dysfunction caused by dysregulated host response to infection. It also one the significant causes death increased health care costs in modern intensive units. The use antibiotics, fluid resuscitation, support therapy have limited prognostic impact patients with sepsis. Although its pathophysiology remains elusive, immunosuppression now recognized major septic death. Sepsis-induced resulted from disruption immune homeostasis. characterized release anti-inflammatory cytokines, abnormal effector cells, hyperproliferation suppressor expression checkpoints. By targeting immunosuppression, especially checkpoint inhibitors, preclinical studies demonstrated reversal immunocyte dysfunctions established resistance. Here, we comprehensively discuss recent findings on mechanisms, regulation biomarkers sepsis-induced highlight their implications for developing effective strategies treat shock.

Language: Английский

---

Neutrophils in cancer carcinogenesis and metastasis

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: Oct. 21, 2021

Abstract In recent years, neutrophils have attracted increasing attention because of their cancer-promoting effects. An elevated neutrophil-to-lymphocyte ratio is considered a prognostic indicator for patients with cancer. Neutrophils are no longer regarded as innate immune cells single function, let alone bystanders in the pathological process Their diversity and plasticity being increasingly recognized. This review summarizes previous studies assessing roles mechanisms cancer initiation, progression, metastasis relapse. Although findings controversial, fact that play dual role promoting suppressing undeniable. The allows them to adapt different microenvironments exert effects on Given from our own research, we propose reasonable hypothesis may be reprogrammed into state microenvironment. new perspective indicates neutrophil reprogramming course treatment problem worthy attention. Preventing or reversing potential strategy adjuvant therapy.

Language: Английский

---

Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19

Critical Care, Journal Year: 2020, Volume and Issue: 24(1)

Published: Dec. 1, 2020

Abstract Background COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in samples but also blood, stool urine. Severe characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or load plasma associated severe response. Methods A total of 250 patients were recruited (50 outpatients, 100 hospitalized ward critically ill). Viral detection quantification was performed using droplet digital PCR, targeting the N1 N2 regions nucleoprotein gene. The association between severity evaluated multivariate logistic regression. Correlations biomarkers evidencing dysregulation calculating Spearman correlation coefficients. Results frequency higher ill (78%) compared (27%) outpatients (2%) ( p < 0.001). Critical had loads than non-critically patients, non-survivors showing highest values. When compared, did not show significant associations analysis. In contrast, when ICU both critical illness (OR [CI 95%], ): (3.92 [1.183–12.968], 0.025), (N1) (1.962 [1.244–3.096], 0.004); (N2) (2.229 [1.382–3.595], correlated levels chemokines (CXCL10, CCL2), indicative systemic inflammatory (IL-6, CRP, ferritin), activation NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation (D-Dimer INR), tissue damage (LDH, GPT), neutrophil (neutrophils counts, myeloperoxidase, GM-CSF) immunodepression (PD-L1, IL-10, lymphopenia monocytopenia). Conclusions are COVID-19. correlates key signatures responses, suggesting major role uncontrolled replication pathogenesis

Language: Английский

---

Sepsis-Induced Immunosuppression

Annual Review of Physiology, Journal Year: 2021, Volume and Issue: 84(1), P. 157 - 181

Published: Oct. 27, 2021

Sepsis is expected to have a substantial impact on public health and cost as its prevalence increases. Factors contributing increased include progressively aging population, advances in the use of immunomodulatory agents treat rising number diseases, immune-suppressing therapies organ transplant recipients cancer patients. It now recognized that sepsis associated with profound sustained immunosuppression, which has been implicated predisposing factor susceptibility patients secondary infections mortality. In this review, we discuss mechanisms sepsis-induced immunosuppression biomarkers identify state impaired immunity. We also highlight immune-enhancing strategies evaluated sepsis, well therapeutics under current investigation. Finally, describe future challenges need for new treatment paradigm, integrating predictive enrichment patient factors may guide selection tailored immunotherapy.

Language: Английский

---

Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19

Cell, Journal Year: 2021, Volume and Issue: 184(7), P. 1836 - 1857.e22

Published: Feb. 10, 2021

Language: Английский

---

Rationalizing antimicrobial therapy in the ICU: a narrative review

Intensive Care Medicine, Journal Year: 2019, Volume and Issue: 45(2), P. 172 - 189

Published: Jan. 18, 2019

Language: Английский

---

Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 Antibody (BMS-936559)*

Critical Care Medicine, Journal Year: 2019, Volume and Issue: 47(5), P. 632 - 642

Published: Feb. 12, 2019

Objectives: To assess for the first time safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) its effect on biomarkers in participants with sepsis-associated immunosuppression. Design: Randomized, placebo-controlled, dose-escalation. Setting: Seven U.S. hospital ICUs. Study Population: Twenty-four sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or renal injury), absolute lymphocyte count less than or equal to 1,100 cells/μL. Interventions: Participants received single-dose BMS-936559 (10–900 mg; n = 20) placebo ( 4) infusions. Primary endpoints were death adverse events; key secondary included receptor occupancy monocyte human leukocyte antigen-DR levels. Measurements Main Results: The treated group was older (median 62 yr pooled vs 46 placebo), a greater percentage had more 2 dysfunctions (55% 25% placebo); other baseline characteristics comparable. Overall mortality (10 mg dose: 2/4; 30 mg: 100 1/4; 300 900 0/4; placebo: 0/4). All events (75% grade 1–2). Seventeen percent serious event (3/20 pooled, 1/4 none deemed drug-related. Adverse that potentially immune-related occurred 54% participants; most 1–2, required corticosteroids, No significant changes cytokine levels observed. Full achieved 28 days after (900 mg). At two highest doses, apparent increase expression (> 5,000 monoclonal antibodies/cell) observed persisted beyond days. Conclusions: In this clinical evaluation programmed protein-1/programmed pathway inhibition well tolerated, no evidence drug-induced hypercytokinemia storm, at higher some indication restored status over Further randomized trials are needed evaluate efficacy patients sepsis.

Language: Английский

---

Myeloid-Derived Suppressor Cells in Sepsis

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Feb. 26, 2019

Myeloid-derived suppressor cells (MDSCs) are immature myeloid characterized by their immunosuppressive functions. MDSCs expand during chronic and acute inflammatory conditions, the best described being cancer. Recent studies uncovered an important role of in pathogenesis infectious diseases along with sepsis. Here we discuss mechanisms underlying expansion functions MDSCs, results preclinical clinical linking to sepsis pathogenesis. Strikingly, all date suggest that high proportions blood associated worsening, incidence nosocomial infections and/or mortality. Hence, attractive biomarkers therapeutic targets for sepsis, especially because these barely detectable healthy subjects. Blocking MDSC-mediated immunosuppression trafficking or depleting might improve outcome. While some key aspects biology need depth investigations, exploring avenues may participate pave way towards implementation personalized medicine precision immunotherapy patients suffering from

Language: Английский

---

Chemically and Biologically Engineered Bacteria‐Based Delivery Systems for Emerging Diagnosis and Advanced Therapy

Advanced Materials, Journal Year: 2021, Volume and Issue: 33(38)

Published: Aug. 4, 2021

Abstract Bacteria are one of the main groups organisms, which dynamically and closely participate in human health disease development. With integration chemical biotechnology, bacteria have been utilized as an emerging delivery system for various biomedical applications. Given unique features such their intrinsic biocompatibility motility, bacteria‐based systems drawn wide interest diagnosis treatment diseases, including cancer, infectious kidney failure, hyperammonemia. Notably, at interface biotechnology bacteria, many research opportunities initiated, opening a promising frontier application. Herein, current synergy design principles systems, microbial modulation, clinical translation reviewed, with special focus on advances therapy.

Language: Английский

---