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Neutrophil extracellular trap inhibition improves survival in neonatal mouse infectious peritonitis.Pediatric Research Mar 2023Treatment of neonatal peritonitis and sepsis is challenging. Following infection, neutrophils elaborate neutrophil extracellular traps (NETs)-extracellular lattices of...
BACKGROUND
Treatment of neonatal peritonitis and sepsis is challenging. Following infection, neutrophils elaborate neutrophil extracellular traps (NETs)-extracellular lattices of decondensed chromatin decorated with antimicrobial proteins. NETs, however, can augment pathogenic inflammation causing collateral damage. We hypothesized that NET inhibition would improve survival in experimental neonatal infectious peritonitis.
METHODS
We induced peritonitis in 7 to 10-day-old mice by intraperitoneal injection with cecal slurry. We targeted NETs by treating mice with neonatal NET-Inhibitory Factor (nNIF), an endogenous NET-inhibitor; Cl-amidine, a PAD4 inhibitor; DNase I, a NET degrading enzyme, or meropenem (an antibiotic). We determined peritoneal NET and cytokine levels and circulating platelet-neutrophil aggregates. Survival from peritonitis was followed for 6 days.
RESULTS
nNIF, Cl-amidine, and DNase I decreased peritoneal NET formation and inflammatory cytokine levels at 24 h compared to controls. nNIF, Cl-amidine, and DNase I decreased circulating platelet-neutrophil aggregates, and NET-targeting treatments significantly increased survival from infectious peritonitis compared to controls. Finally, nNIF administration significantly improved survival in mice treated with sub-optimal doses of meropenem even when treatment was delayed until 2 h after peritonitis induction.
CONCLUSIONS
NET inhibition improves survival in experimental neonatal infectious peritonitis, suggesting that NETs participate pathogenically in neonatal peritonitis and sepsis.
IMPACT
1. Neutrophil extracellular trap formation participates pathogenically in experimental neonatal infectious peritonitis. 2. NET-targeting strategies improve outcomes in a translational model of neonatal infectious peritonitis. 3. NET inhibition represents a potential target for drug development in neonatal sepsis and infectious peritonitis.
Topics: Animals; Mice; Extracellular Traps; Animals, Newborn; Meropenem; Neutrophils; Peritonitis; Deoxyribonuclease I; Sepsis; Cytokines; Mice, Inbred C57BL
PubMed: 35902703
DOI: 10.1038/s41390-022-02219-0 -
Journal of Nephrology Sep 2023Peritoneal dialysis- (PD) related infections continue to be a major cause of morbidity and mortality in patients on renal replacement therapy via PD. However, despite... (Review)
Review
Peritoneal dialysis- (PD) related infections continue to be a major cause of morbidity and mortality in patients on renal replacement therapy via PD. However, despite the great efforts in the prevention of PD-related infectious episodes, approximately one third of technical failures are still caused by peritonitis. Recent studies support the theory that ascribes to exit-site and tunnel infections a direct role in causing peritonitis. Hence, prompt exit site infection/tunnel infection diagnosis would allow the timely start of the most appropriate treatment, thereby decreasing the potential complications and enhancing technique survival. Ultrasound examination is a simple, rapid, non-invasive and widely available procedure for tunnel evaluation in PD catheter-related infections. In case of an exit site infection, ultrasound examination has greater sensitivity in diagnosing simultaneous tunnel infection compared to the physical exam alone. This allows distinguishing the exit site infection, which will likely respond to antibiotic therapy, from infections that are likely to be refractory to medical therapy. In case of a tunnel infection, the ultrasound allows localizing the catheter portion involved in the infectious process, thus providing significant prognostic information. In addition, ultrasound performed after two weeks of antibiotic administration allows monitoring patient response to therapy. However, there is no evidence of the usefulness of ultrasound examination as a screening tool for the early diagnosis of tunnel infections in asymptomatic PD patients.
Topics: Humans; Catheter-Related Infections; Catheters, Indwelling; Peritoneal Dialysis; Anti-Bacterial Agents; Peritonitis
PubMed: 36939999
DOI: 10.1007/s40620-023-01589-w -
Frontiers in Cellular and Infection... 2023Bacterial infections and the concurrent inflammation have been associated with increased long-term cardiovascular (CV) risk. In patients receiving peritoneal dialysis...
Bacterial infections and the concurrent inflammation have been associated with increased long-term cardiovascular (CV) risk. In patients receiving peritoneal dialysis (PD), bacterial peritonitis is a common occurrence, and each episode further increases late CV mortality risk. However, the underlying mechanism(s) remains to be elucidated before safe and efficient anti-inflammatory interventions can be developed. Damage-Associated Molecular Patterns (DAMPs) have been shown to contribute to the acute inflammatory response to infections, but a potential role for DAMPs in mediating long-term vascular inflammation and CV risk following infection resolution in PD, has not been investigated. We found that bacterial peritonitis in mice that resolved within 24h led to CV disease-promoting systemic and vascular immune-mediated inflammatory responses that were maintained up to 28 days. These included higher blood proportions of inflammatory leukocytes displaying increased adhesion molecule expression, higher plasma cytokines levels, and increased aortic inflammatory and atherosclerosis-associated gene expression. These effects were also observed in infected nephropathic mice and amplified in mice routinely exposed to PD fluids. A peritonitis episode resulted in elevated plasma levels of the DAMP Calprotectin, both in PD patients and mice, here the increase was maintained up to 28 days. , the ability of culture supernatants from infected cells to promote key inflammatory and atherosclerosis-associated cellular responses, such as monocyte chemotaxis, and foam cell formation, was Calprotectin-dependent. , Calprotectin blockade robustly inhibited the short and long-term peripheral and vascular consequences of peritonitis, thereby demonstrating that targeting of the DAMP Calprotectin is a promising therapeutic strategy to reduce the long-lasting vascular inflammatory aftermath of an infection, notably PD-associated peritonitis, ultimately lowering CV risk.
Topics: Humans; Mice; Animals; Peritoneal Dialysis; Peritonitis; Inflammation; Bacterial Infections; Atherosclerosis
PubMed: 38094743
DOI: 10.3389/fcimb.2023.1285193 -
Methods in Molecular Biology (Clifton,... 2021Studying the pathophysiology of sepsis still requires animal models, and the mouse remains the most commonly used species. Here we discuss the "cecal slurry" (CS) model...
Studying the pathophysiology of sepsis still requires animal models, and the mouse remains the most commonly used species. Here we discuss the "cecal slurry" (CS) model of polymicrobial, peritoneal sepsis and compare and contrast it to other commonly used methods. Among the different murine models of sepsis, cecal ligation and puncture (CLP), and not the CS, is often considered the "gold standard" to induce polymicrobial sepsis in laboratory animals. CLP is a well-described model involving a simple surgical procedure that closely mimics the clinical course of intra-abdominal sepsis. However, CLP may not be an option for experiments involving newborn pups, where the cecum is indistinguishable from small bowel, where differences in microbiome content may affect the experiment, or where surgical procedures/anesthesia exposure needs to be limited. An important alternative method is the CS model, involving the intraperitoneal injection of cecal contents from a donor animal into the peritoneal cavity of a recipient animal to induce polymicrobial sepsis. Furthermore, CS is an effective alternative model of intraperitoneal polymicrobial sepsis in adult mice and can now be considered the "gold standard" for experiments in neonatal mice.
Topics: Abdomen; Animals; Animals, Newborn; Cecum; Disease Models, Animal; Female; Ligation; Mice; Peritonitis; Punctures; Sepsis
PubMed: 34048005
DOI: 10.1007/978-1-0716-1488-4_4 -
International Journal of Clinical... 2022This study aimed to explore follow-up mode changes for peritoneal dialysis (PD) patients and their effects on PD quality during the COVID-19 pandemic.
OBJECTIVE
This study aimed to explore follow-up mode changes for peritoneal dialysis (PD) patients and their effects on PD quality during the COVID-19 pandemic.
METHODS
A retrospective single-center study was conducted. All patients who received PD treatment at the Second Affiliated Hospital of Soochow University between January 2018 and March 2020 were enrolled in this study. Patient data during the first quarter of 2018 (Q1-2018), the first quarter of 2019 (Q1-2019), and the first quarter of 2020 (Q1-2020) were collected.
RESULTS
No significant differences were observed for any serum examinations in different follow-up periods ( > 0.05). A significantly reduced outpatient follow-up rate was observed in Q1-2020 compared with Q1-2018 and Q1-2019 (71.6% Vs 78.9% Vs 84.7%, < 0.001), accompanied by a significantly increased remote follow-up rate (28.4% Vs 21.1% Vs 15.3%, < 0.001). Compared with Q1-2018 and Q1-2019, the hospitalization rate (27.7% Vs 30.9% Vs 15.7%, < 0.001) and the incidence of peritonitis (0.162 Vs 0.186 Vs 0.08 per patient-year, < 0.001) decreased significantly in Q1-2020. PD patients had a significant decline in the drop-out rate for Q1-2020 compared with Q1-2019 (4.4% Vs 7.3% Vs 2.2%, < 0.001). No differences in the incidence of catheter-related infections were observed. No significant differences were observed for any peritoneal dialysis key performance indicators (KPIs) between outpatient follow-up and remote follow-up patients.
CONCLUSION
During the COVID-19 pandemic (Q1-2020), our center practiced more remote follow-up procedures in PD patients. The hospitalization rate and peritonitis incidence were significantly decreased compared with the same time in previous years. No statistical differences were observed in other KPIs for peritoneal dialysis. This study shows that telehealth methods are a reasonable alternative to in-person care in the care/management of PD patients.
Topics: COVID-19; Humans; Kidney Failure, Chronic; Pandemics; Peritoneal Dialysis; Peritonitis; Retrospective Studies; Telemedicine
PubMed: 35685587
DOI: 10.1155/2022/6524717 -
Frontiers in Immunology 2024Peritoneal dialysis is a widely used method for treating kidney failure. However, over time, the peritoneal structure and function can deteriorate, leading to the... (Review)
Review
Peritoneal dialysis is a widely used method for treating kidney failure. However, over time, the peritoneal structure and function can deteriorate, leading to the failure of this therapy. This deterioration is primarily caused by infectious and sterile inflammation. Sterile inflammation, which is inflammation without infection, is particularly concerning as it can be subtle and often goes unnoticed. The onset of sterile inflammation involves various pathological processes. Peritoneal cells detect signals that promote inflammation and release substances that attract immune cells from the bloodstream. These immune cells contribute to the initiation and escalation of the inflammatory response. The existing literature extensively covers the involvement of different cell types in the sterile inflammation, including mesothelial cells, fibroblasts, endothelial cells, and adipocytes, as well as immune cells such as macrophages, lymphocytes, and mast cells. These cells work together to promote the occurrence and progression of sterile inflammation, although the exact mechanisms are not fully understood. This review aims to provide a comprehensive overview of the signals from both stromal cells and components of immune system, as well as the reciprocal interactions between cellular components, during the initiation of sterile inflammation. By understanding the cellular and molecular mechanisms underlying sterile inflammation, we may potentially develop therapeutic interventions to counteract peritoneal membrane damage and restore normal function.
Topics: Humans; Peritoneal Dialysis; Peritoneum; Animals; Stromal Cells; Cell Communication; Inflammation; Peritonitis
PubMed: 38779674
DOI: 10.3389/fimmu.2024.1387292 -
Microbiology Spectrum Dec 2021Peritoneal catheter-associated biofilm infection is reported to be the main cause of refractory peritonitis in peritoneal dialysis patients. The application of...
Peritoneal catheter-associated biofilm infection is reported to be the main cause of refractory peritonitis in peritoneal dialysis patients. The application of antimicrobial lock therapy, based on results on central venous catheters, may be a promising option for treatment of biofilm-harboring peritoneal catheters. This study investigated the effects of two lock solutions, EDTA and taurolidine, on an model of Pseudomonas aeruginosa biofilm-related peritoneal catheter infection. Silicone peritoneal catheters were incubated for 24 h with a bioluminescent strain of P. aeruginosa. Then, serial dilutions of taurolidine and/or EDTA were applied (for 24 h) once or twice onto the contaminated catheters, and P. aeruginosa viability/persistence were evaluated in real time up to 120 h using a Fluoroskan reader. On selected supernatants, high-performance liquid chromatography mass spectrometry (HPLC-MS) analysis was performed to measure the production of autoinducers (AI), phenazines, and pyocyianines. Taurolidine alone or in combination with EDTA caused a significant decrease of bacterial load and biofilm persistence on the contaminated catheters. The treatment did not lead to the sterilization of the devices, yet it resulted in a substantial destructuration of the catheter-associated P. aeruginosa biofilm. HPLC-MS analysis showed that the treatment of biofilm-harboring catheters with taurolidine and EDTA also affected the secretory activity of the pathogen. EDTA and taurolidine affect P. aeruginosa biofilm produced on peritoneal catheters and profoundly compromise the microbial secretory profile. Future studies are needed to establish whether such lock solutions can be used to render peritoneal catheter-related infections more susceptible to antibiotic treatment. An model allows studies on the mechanisms by which the lock solutions exert their antimicrobial effects on catheter-associated biofilm, thus providing a better understanding of the management of devise-associated infections.
Topics: Anti-Bacterial Agents; Bacterial Load; Biofilms; Catheter-Related Infections; Catheters, Indwelling; Drug Therapy, Combination; Edetic Acid; Humans; Peritoneal Dialysis; Peritonitis; Pseudomonas Infections; Pseudomonas aeruginosa; Taurine; Thiadiazines; Virulence
PubMed: 34787464
DOI: 10.1128/Spectrum.01047-21 -
The Pan African Medical Journal 2022Pseudotumoral peritoneal tuberculosis is uncommon, but its incidence is high in endemic areas. Given the great radioclinical similarity between pseudotumoral peritoneal...
Pseudotumoral peritoneal tuberculosis is uncommon, but its incidence is high in endemic areas. Given the great radioclinical similarity between pseudotumoral peritoneal tuberculosis and ovarian cancer, we conducted a retrospective study in the Department of Obstetrics and Gynaecology of the Military Hospital of Instruction Mohammed V in Rabat, involving 14 cases (n= 14) of pseudotumoral peritoneal tuberculosis in order to illustrate the problem of differential diagnosis. All other extra-pelvic locations were excluded, the average age of our patients was 33.4 years with a maximum of cases in the 16-40 years group: 71% (n=10/14). Common clinical symptoms of this particular form of peritoneal tuberculosis were abdominal pain: 100% (n=14/14) associated with abdominopelvic mass: 71% (n=10/14) and ascites: 64% (n=09/14) mimicking peritoneal carcinosis of ovarian origin, especially since both pathologies progressed in a context of impaired general condition. Diagnosis was based on invasive laparoscopic examinations: 35% (n=05/14) or laparotomy: 57% (n=08/14) with biopsies. Indeed, only histological examination can help to establish definitive Corriger diagnosis, in the majority of cases. Therapeutic management of our patients was based on medical treatment, according to the national tuberculosis control program, and surgical treatment. The use of invasive explorations is often unavoidable before initiating any anti-bacillary treatment. Patients´ outcome under specific treatment is favorable, the prognosis of fertility is engaged in young women.
Topics: Humans; Female; Adult; Retrospective Studies; Peritonitis, Tuberculous; Peritoneum; Ascites; Laparoscopy; Diagnosis, Differential
PubMed: 36762164
DOI: 10.11604/pamj.2022.43.130.35899 -
Renal Failure Nov 2020Peritoneal dialysis (PD) is an important renal replacement therapy for end-stage renal disease (ESRD) patients. However, its complications, such as peritoneal fibrosis...
Peritoneal dialysis (PD) is an important renal replacement therapy for end-stage renal disease (ESRD) patients. However, its complications, such as peritoneal fibrosis (PF) and angiogenesis can cause ultrafiltration failure and PD termination. Histone deacetylase 6 (HDAC6) has been demonstrated to be involved in PF. However, its underlying role in peritoneal angiogenesis is still unknown and clinical value needs to be explored. In this study, we analyzed the expression of HDAC6 in the peritoneum from patients with non-PD and PD-related peritonitis and dialysis effluent from stable PD patients. Our study revealed that HDAC6 expressed highly in the peritoneum with peritonitis and co-stained with α-smooth muscle actin (α-SMA), a biomarker of the myofibroblast. And the level of HDAC6 in the dialysate increased with time and positively correlated with transforming growth factor-β1 (TGF-β1), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), and negatively with cancer antigen 125 (CA125). , blockading HDAC6 with a selective inhibitor tubastatin A (TA) or silencing HDAC6 with a small interfering RNA (siRNA) prominently decreased IL-6-stimulated VEGF expression in cultured human peritoneal mesothelial cells (HPMCs), and inhibited proliferation and vasoformation of human umbilical vein endothelial cells (HUVECs). TA or HDAC6 siRNA also suppressed the expression of Wnt1, β-catenin, and the phosphorylation of STAT3 in IL-6-treated HPMCs. In summary, HDAC6 inhibition protects against PD-induced angiogenesis through suppression of IL-6/STAT3 and Wnt1/β-catenin signaling pathway, subsequently reducing the VEGF production and angiogenesis. It could become a new therapeutic target or forecast biomarker for PF, inflammation, and angiogenesis in the future.
Topics: Actins; Aged; Female; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Interleukin-6; Male; Middle Aged; Neovascularization, Pathologic; Peritoneal Dialysis; Peritoneal Fibrosis; Peritoneum; Peritonitis; RNA, Small Interfering; STAT3 Transcription Factor; Signal Transduction; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A; beta Catenin
PubMed: 32862739
DOI: 10.1080/0886022X.2020.1811119 -
Frontiers in Immunology 2021Platelets play a key role in the development, progression and resolution of the inflammatory response during sterile inflammation and infection, although the mechanism...
Platelets play a key role in the development, progression and resolution of the inflammatory response during sterile inflammation and infection, although the mechanism is not well understood. Here we show that platelet CLEC-2 reduces tissue inflammation by regulating inflammatory macrophage activation and trafficking from the inflamed tissues. The immune regulatory function of CLEC-2 depends on the expression of its ligand, podoplanin, upregulated on inflammatory macrophages and is independent of platelet activation and secretion. Mechanistically, platelet CLEC-2 and also recombinant CLEC-2-Fc accelerates actin rearrangement and macrophage migration by increasing the expression of podoplanin and CD44, and their interaction with the ERM proteins. During ongoing inflammation, induced by lipopolysaccharide, treatment with rCLEC-2-Fc induces the rapid emigration of peritoneal inflammatory macrophages to mesenteric lymph nodes, thus reducing the accumulation of inflammatory macrophages in the inflamed peritoneum. This is associated with a significant decrease in pro-inflammatory cytokine, TNF-α and an increase in levels of immunosuppressive, IL-10 in the peritoneum. Increased podoplanin expression and actin remodelling favour macrophage migration towards CCL21, a soluble ligand for podoplanin and chemoattractant secreted by lymph node lymphatic endothelial cells. Macrophage efflux to draining lymph nodes induces T cell priming. In conclusion, we show that platelet CLEC-2 reduces the inflammatory phenotype of macrophages and their accumulation, leading to diminished tissue inflammation. These immunomodulatory functions of CLEC-2 are a novel strategy to reduce tissue inflammation and could be therapeutically exploited through rCLEC-2-Fc, to limit the progression to chronic inflammation.
Topics: Animals; Blood Platelets; Cell Movement; Cytokines; Disease Models, Animal; Female; Inflammation Mediators; Lectins, C-Type; Lipopolysaccharides; Macrophage Activation; Macrophages, Peritoneal; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Peritonitis; Phagocytosis; Phenotype; RAW 264.7 Cells; Signal Transduction; T-Lymphocytes
PubMed: 34163489
DOI: 10.3389/fimmu.2021.693974