scholarly journals A systems approach to inflammation identifies therapeutic targets in SARS-CoV-2 infection

2020 ◽  
Author(s):  
Frank L. van de Veerdonk ◽  
Nico A.F. Janssen ◽  
Inge Grondman ◽  
Aline H. de Nooijer ◽  
Valerie A.C.M. Koeken ◽  
...  
Keyword(s):  
Systems Approach ◽  
Plasma Concentrations ◽  
Severe Pneumonia ◽  
Targeted Proteomics ◽  
Complement Components ◽  
Icu Patients ◽  
Terminal Complement Complex ◽  
Multicenter Observational Study ◽  
Tnf Α ◽  
Terminal Complement

AbstractBackgroundInfection with SARS-CoV-2 manifests itself as a mild respiratory tract infection in the majority of individuals, which progresses to a severe pneumonia and acute respiratory distress syndrome (ARDS) in 10-15% of patients. Inflammation plays a crucial role in the pathogenesis of ARDS, with immune dysregulation in severe COVID-19 leading to a hyperinflammatory response. A comprehensive understanding of the inflammatory process in COVID-19 is lacking.MethodsIn this prospective, multicenter observational study, patients with PCR-proven or clinically presumed COVID-19 admitted to the intensive care unit (ICU) or clinical wards were included. Demographic and clinical data were obtained and plasma was serially collected. Concentrations of IL-6, TNF-α, complement components C3a, C3c and the terminal complement complex (TCC) were determined in plasma by ELISA. Additionally, 269 circulating biomarkers were assessed using targeted proteomics. Results were compared between ICU and non ICU patients.FindingsA total of 119 (38 ICU and 91 non ICU) patients were included. IL-6 plasma concentrations were elevated in COVID-19 (ICU vs. non ICU, median 174.5 pg/ml [IQR 94.5-376.3] vs. 40.0 pg/ml [16.5-81.0]), whereas TNF-α concentrations were relatively low and not different between ICU and non ICU patients (median 24.0 pg/ml [IQR 16.5-33.5] and 21.5 pg/ml [IQR 16.0-33.5], respectively). C3a and terminal complement complex (TCC) concentrations were significantly higher in ICU vs. non ICU patients (median 556.0 ng/ml [IQR 333.3-712.5]) vs. 266.5 ng/ml [IQR 191.5-384.0] for C3a and 4506 mAU/ml [IQR 3661-6595] vs. 3582 mAU/ml [IQR 2947-4300] for TCC) on the first day of blood sampling. Targeted proteomics demonstrated that IL-6 (logFC 2.2), several chemokines and hepatocyte growth factor (logFC 1.4) were significantly upregulated in ICU vs. non ICU patients. In contrast, stem cell factor was significantly downregulated (logFC −1.3) in ICU vs. non ICU patients, as were DPP4 (logFC −0.4) and protein C inhibitor (log FC −1.0), the latter two factors also being involved in the regulation of the kinin-kallikrein pathway. Unsupervised clustering pointed towards a homogeneous pathogenetic mechanism in the majority of patients infected with SARS-CoV-2, with patient clustering mainly based on disease severity.InterpretationWe identified important pathways involved in dysregulation of inflammation in patients with severe COVID-19, including the IL-6, complement system and kinin-kallikrein pathways. Our findings may aid the development of new approaches to host-directed therapy.FundingVidi grant (F.L.v.d.V.) and Spinoza grant (M.G.N.) from the Netherlands Organization for Scientific Research, and ERC Advanced Grant (#833247 to M.G.N.).

Hydrocortisone vs Tocilizumab Effects on Cytokine Storm in Critically Ill Patients with COVID-19.

2020 ◽  
Author(s):  
Maria Vargas ◽  
Pasquale Buonanno ◽  
Carmine Iacovazzo ◽  
Gaetano Di Spigna ◽  
Daniela Spalletti ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Statistical Significance ◽  
Plasma Concentrations ◽  
Severe Pneumonia ◽  
Cytokine Storm ◽  
Tnf Α ◽  
Speed Up ◽  
The Impact ◽  
Late Stages

Abstract Introduction: Patients with severe pneumonia due COVID-19 are reported to have substantially lower lymphocyte counts and higher plasma concentrations of a number of inflammatory cytokines. In the late stages of COVID-19, cytokine storms are the mainly cause of disease progression and death. We performed a prospective observational study to evaluate the impact of tocilizumab and hydrocortisone on cytokine storm in critically ill patients with COVID-19.Methods: We included all adult patients with laboratory-confirmed COVID-19 infection and severe respiratory failure admitted to our ICU from March 10 to April 30. As therapeutic options, patients received tocilizumab od hydrocortisone. The primary end point was the evaluation of cytokine storm in terms of variation of the IL-6 and IL-6R, sgp130 and TNF-α concentrations during time to different treatment.Results: Eight patients received tocilizumab while 15 patients received hydrocortisone. IL-6 levels were lower in the hydrocortisone group with statistical significance was found at the days 2, 3, 8 and 9. The levels of IL-6R were lower during the days in the hydrocortisone group with statistical significance at days 1, 2, 3, 4, 5, 6, 8 and 10. Hydrocortisone group had higher levels of TNF-α at days 2, 3 and 4. The levels of sgo130 between tocilizumab and hydrocortisone groups were not statistically different during the days.Conclusions: In critically ill patients with severe COVID-19, the use of hydrocortisone allowed a better control of the cytokine storms, was further associated to less days of curarization, pronation and length of stay in ICU, and speed up the time to get negative RT-PCR swab.

Influence of Carbohydrate Supplementation on Plasma Cytokine and Neutrophil Degranulation Responses to High Intensity Intermittent Exercise

2002 ◽  
Vol 12 (2) ◽  
pp. 145-156 ◽  
Author(s):  
Nicolette C. Bishop ◽  
Michael Gleeson ◽  
Ceri W. Nicholas ◽  
Ajmol Ali
Keyword(s):  
High Intensity ◽  
Intermittent Exercise ◽  
Plasma Concentrations ◽  
Neutrophil Function ◽  
Moderate Intensity ◽  
Post Exercise ◽  
Carbohydrate Supplementation ◽  
Tnf Α ◽  
Neutrophil Degranulation ◽  
Factor Α

Ingesting carbohydrate (CHO) beverages during prolonged, continuous heavy exercise results in smaller changes in the plasma concentrations of several cytokines and attenuates a decline in neutrophil function. In contrast, ingesting CHO during prolonged intermittent exercise appears to have negligible influence on these responses, probably due to the overall moderate intensity of these intermittent exercise protocols. Therefore, we examined the effect of CHO ingestion on plasma interIeukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and lipopolysaccharide (LPS)-stimuIated neutrophil degranulation responses to high-intensity intermittent running. Six trained male soccer players performed 2 exercise trials, 7 days apart, in a randomized, counterbalanced design. On each occasion, they completed six 15-min periods of intermittent running consisting of maximal sprinting interspersed with less intense periods of running and walking. Subjects consumed either CHO or artificially sweetened placebo(PLA) beverages immediately before and at 15-min intervals during the exercise. At 30 min post-exercise, CHO versus PLA was associated with a higher plasma glucose concentration (p< .01), a lower plasma cortisol and IL-6 concentration (p < .02), and fewer numbers of circulating neutrophils (p < .05). Following the exercise, LPS-stimulated elastase release per neutrophil fell 31 % below baseline values on the PLA trial (p = .06) compared with 11% on the CHO trial (p = .30). Plasma TNF-α concentration increased following the exercise (main effect of time, p < .001) but was not affected by CHO. These data indicate that CHO ingestion attenuates changes in plasma IL-6 concentration, neutrophil trafficking, and LPS-stimulated neutrophil degranulation in response to intermittent exercise that involves bouts of very high intensity exercise.

scholarly journals O-Antigen-Deficient Francisella tularensis Live Vaccine Strain Mutants Are Ingested via an Aberrant Form of Looping Phagocytosis and Show Altered Kinetics of Intracellular Trafficking in Human Macrophages

2011 ◽  
Vol 80 (3) ◽  
pp. 952-967 ◽  
Author(s):  
Daniel L. Clemens ◽  
Bai-Yu Lee ◽  
Marcus A. Horwitz
Keyword(s):  
Vaccine Strain ◽  
Intracellular Trafficking ◽  
Live Vaccine ◽  
Live Vaccine Strain ◽  
Complement Components ◽  
Content Type ◽  
Human Macrophages ◽  
O Antigen ◽  
Kinetics Of ◽  
Terminal Complement

We examined the uptake and intracellular trafficking ofF. tularensisLive Vaccine Strain (LVS) and LVS with disruptions ofwbtDEFandwbtIgenes essential for synthesis of the O antigen of lipopolysaccharide. Unlike parental bacteria, O-antigen-deficient LVS is efficiently killed by serum with intact complement but not by serum lacking terminal complement components. Opsonization of O-antigen-deficient LVS in serum lacking terminal complement components allows efficient uptake of these live bacteria by macrophages. In the presence of complement, whereas parentalF. tularensisLVS is internalized within spacious pseudopod loops, mutant LVS is internalized within tightly juxtaposed multiple onion-like layers of pseudopodia. Without complement, both parental and mutant LVSs are internalized within spacious pseudopod loops. Thus, molecules other than O antigen are important in triggering dramatic pseudopod extensions and uptake by spacious pseudopod loops. Following uptake, both parental and mutant LVSs enter compartments that show limited staining for the lysosomal membrane glycoprotein CD63 and little fusion with secondary lysosomes. Subsequently, both parental and mutant LVSs lose their CD63 staining. Whereas the majority of parental LVS escapes into the cytosol by 6 h after uptake, mutant LVS shows a marked lag but does escape by 1 day after uptake. Despite the altered kinetics of phagosome escape, both mutant and parental strains grow to high levels within human macrophages. Thus, the O antigen plays a role in the morphology of uptake in the presence of complement and the kinetics of intracellular growth but is not essential for escape, survival, altered membrane trafficking, or intramacrophage growth.

Exercise elevates plasma levels but not gene expression of IL-1β, IL-6, and TNF-α in blood mononuclear cells

2000 ◽  
Vol 89 (4) ◽  
pp. 1499-1504 ◽  
Author(s):  
Andrei I. Moldoveanu ◽  
Roy J. Shephard ◽  
Pang N. Shek
Keyword(s):  
Gene Expression ◽  
Oxygen Uptake ◽  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Peak Oxygen Uptake ◽  
Cytokine Gene Expression ◽  
Mrna Accumulation ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Blood Mononuclear Cells

Physical activity induces a subclinical inflammatory response, mediated in part by leukocytes, and manifested by elevated concentrations of circulating proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). However, the source of the cytokines that appear during exercise remains unknown. In this study, we examined exercise-induced changes in plasma cytokine concentrations and their corresponding mRNA expression in peripheral blood mononuclear cells. Ten healthy [peak oxygen uptake = 48.8 ± 6.5 (SD) ml · kg−1 · min−1] but untrained men [age = 25 ± 5 (SD) yr] undertook 3 h of exercise (cycling and inclined walking) at 60–65% peak oxygen uptake. Circulating leukocyte subset counts were elevated during and 2 h postexercise but returned to normal within 24 h. Plasma concentrations of IL-1β, IL-6, and TNF-α peaked at the end of exercise and remained elevated at 2 h (IL-6) and up to 24 h (IL-1β and TNF-α) postexercise. Cytokine gene expression in circulating mononuclear cells was measured by using the reverse transcriptase-polymerase chain reaction; mRNA accumulation did not change with exercise. In conclusion, mRNA accumulation of IL-1β, IL-6, and TNF-α in circulating mononuclear cells is not affected by 3 h of moderate endurance exercise and does not seem to account for the observed increases in plasma cytokines.

scholarly journals Compared the Microbiota Profiles between Samples from Bronchoalveolar Lavage and Endotracheal Aspirates in Severe Pneumonia: A Real-World Experience

2022 ◽  
Vol 11 (2) ◽  
pp. 327
Author(s):  
Yeong-Nan Cheng ◽  
Wei-Chih Huang ◽  
Chen-Yu Wang ◽  
Pin-Kuei Fu
Keyword(s):  
Microbial Community ◽  
Bronchoalveolar Lavage ◽  
Microbial Community Composition ◽  
Severe Pneumonia ◽  
Metagenomic Sequencing ◽  
Microbial Composition ◽  
Icu Patients ◽  
Mechanically Ventilated ◽  
The Difference ◽  
New Onset

Lower respiratory tract sampling from endotracheal aspirate (EA) and bronchoalveolar lavage (BAL) are both common methods to identify pathogens in severe pneumonia. However, the difference between these two methods in microbiota profiles remains unclear. We compared the microbiota profiles of pairwise EA and BAL samples in ICU patients with respiratory failure due to severe pneumonia. We prospectively enrolled 50 ICU patients with new onset of pneumonia requiring mechanical ventilation. EA and BAL were performed on the first ICU day, and samples were analyzed for microbial community composition via 16S rRNA metagenomic sequencing. Pathogens were identified in culture medium from BAL samples in 21 (42%) out of 50 patients. No difference was observed in the antibiotic prescription pattern, ICU mortality, or hospital mortality between BAL-positive and BAL-negative patients. The microbiota profiles in the EA and BAL samples are similar with respect to diversity, microbial composition, and microbial community correlations. The antibiotic treatment regimen was rarely changed based on the BAL findings. The samples from BAL did not provide more information than EA in the microbiota profiles. We suggest that EA is more useful than BAL for microbiome identification in mechanically ventilated patients.

scholarly journals Broncho-alveolar inflammation in COVID-19 patients: a correlation with clinical outcome

2020 ◽  
Author(s):  
laura pandolfi ◽  
Fossali Tommaso ◽  
Frangipane Vanessa ◽  
Bozzini Sara ◽  
Morosini Monica ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Mononuclear Cells ◽  
Severe Pneumonia ◽  
Nasopharyngeal Swab ◽  
Icu Patients ◽  
Transmission Microscopy ◽  
Inflammatory Status ◽  
Viral Particles ◽  
A Prospective Study ◽  
Electron Transmission Microscopy

Abstract Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19. Methods: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n=28) and to the Intermediate Medicine Ward (IMW) (n=5). We analyze the differential cell count, ultrastructure of cells and Interleukin(IL)6, 8 and 10 levels.Results: ICU patients showed a marked increase in neutrophils (1.24 x 105 ml-1 , 0.85-2.07), lower lymphocyte (0.97 x 105 ml-1, 0.024-0.34) and macrophages fractions (0.43 x 105 ml-1, 0.34-1.62) compared to IMW patients (0.095 x 105 ml-1, 0.05-0.73; 0.47 x 105 ml-1, 0.28-1.01 and 2.14 x 105 ml-1, 1.17-3.01, respectively) (p<0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p<0.01, IL8 p<0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p<0.1) or antivirals (p<0.05). Conclusions: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.

A Possible Mechanism of Action of 17α-Hydroxyprogesterone Caproate: Enhanced IL-10 Production

2021 ◽  
Author(s):  
Christina J. Megli ◽  
Alisse Hauspurg ◽  
Raman Venkataramanan ◽  
Steve N. Caritis
Keyword(s):  
Mechanism Of Action ◽  
Cytokine Production ◽  
Plasma Concentrations ◽  
In Vitro Study ◽  
Vitro Study ◽  
Clinical Samples ◽  
Omega 3 ◽  
Tnf Α ◽  
Hydroxyprogesterone Caproate

Objective The rate of recurrent spontaneous preterm birth (PTB) was reduced by 33% in the Maternal-Fetal Medicine Unit (MFMU) Network trial of 17α-hydroxyprogesterone caproate (17-OHPC), but the mechanism of action, 17 years later, remains elusive. The robustness of the interleukin-10 (IL-10) response to lipopolysaccharide (LPS) stimulation of leukocytes in pregnant women with a prior PTB correlates with gestational age at delivery. This study sought to determine if there is a relationship between the concentration of 17-OHPC and response to LPS stimulation. Study Design We performed a secondary analysis of data from the Omega-3 MFMU trial which evaluated the effectiveness of omega-3 fatty acid supplementation in reducing recurrent PTB. We utilized previously characterized data from a subanalyses of the Omega-3 trial of IL-10 and tumor necrosis factor alpha (TNF-α) levels from peripheral blood mononuclear cells stimulated with LPS. Blood was obtained from enrolled women at 16 to 22 weeks' gestation (baseline) and 25 to 28 weeks' gestation (posttreatment). All women received 17-OHPC and plasma 17-OHPC concentrations were measured at 25 to 28 weeks' gestation. We analyzed these data to determine if there was a relationship between 17-OHPC concentration and cytokine production. We then performed an in vitro study to determine if 17-OHPC could directly alter cytokine production by THP-1-derived macrophages. Results In the clinical samples, we found that 17-OHPC plasma concentrations were correlated with the quantity of the LPS-stimulated production of IL-10. TNF-α production after LPS stimulation was unrelated to 17-OHPC concentration. In the in vitro study, we demonstrate a 17-OHPC concentration dependent increase in IL-10 production. Conclusion In women receiving 17-OHPC for PTB prevention, we demonstrate a relationship between plasma 17-OHPC and LPS-stimulated IL-10 production by circulating leukocytes. We also demonstrate that, in vitro, 17-OHPC treatment affects IL-10 production by LPS-stimulated macrophages. Collectively, these findings support an immunomodulatory mechanism of action of 17-OHPC in the prevention of recurrent PTB. Key Points

The Terminal Complement Complex C5b-9: A Possible Mediator of Acute and Chronic Glomerulonephritis

Nephrology ◽  
1991 ◽  
pp. 888-897 ◽  
Author(s):  
Gertrud Maria Hänsch ◽  
Matthias Schönermark ◽  
Christof Wagner ◽  
Gisela Schieren ◽  
Bernhard Jahn
Keyword(s):  
Chronic Glomerulonephritis ◽  
Terminal Complement Complex ◽  
Terminal Complement
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