Iron overload in paediatrics undergoing cardiopulmonary bypass

AbstractPathological changes in iron status are known to occur during bypass and will be superimposed upon physiological abnormalities in iron distribution, characteristic of the neonatal period. We have sought to define the severity of iron overload in these patients. Plasma samples from 65 paediatric patients undergoing cardiopulmonary bypass (CPB) were analysed for non-haem iron, total iron binding capacity, transferrin and bleomycin-detectable iron. Patients were divided into four age groups for analysis. Within each age group, patients who were in iron overload at any time point were statistically compared to those who were not. The most significant changes in iron chemistry were seen in the plasma of neonates, with 25% in a state of plasma iron overload. 18.5% of infants and 14.3% of children at 1–5 years were also in iron overload at some time point during CPB. No children over 5 years, however, went into iron overload. Increased iron saturation of transferrin eliminates its ability to bind reactive forms of iron and to act as an antioxidant. When transferrin is fully saturated with iron, reactive forms of iron are present in the plasma which can stimulate iron-driven oxidative reactions. Our data suggest that paediatric patients are at greater risk of iron overload during CPB, and that some form of iron chelation therapy may be advantageous to decrease oxidative stress

Decreased serum levels of angiotensin converting enzyme (ACE)2 and enhanced cytokine levels with severity of COVID-19: normalisation upon disease recovery

Background:SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). Circulating soluble angiotensin-converting enzyme (sACE2), the main receptor for SARS-CoV-2, together with components of the renin-angiotensin system promote infection and disease severity. Objective: In this pilot study we followed the time-course of sACE2 levels in relation to systemic cytokines in severe and moderate COVID-19 patients treated with remdesivir/dexamethasone in combination. Methods: Peripheral blood was obtained upon admission from 30 patients (12 with moderate disease and 18 with severe disease) and 14 patients with PCR-confirmed mild COVID-19. Severe and moderate patients were treated with remdesivir (200mg/first day and 100mg/day for the remaining days ) and dexamethasone (100mg/day ). 6 healthy control subjects (HC) were also enrolled. Serum interleukin (IL)-6 and IL-8 and sACE2 levels were measured by ELISA at baseline and during treatment in severe and moderate patients and at baseline in mild and HCs. Results: Baseline sACE2 levels were lower in severe (p=0.0005) and moderate (p=0.0022) patients than in patients with mild COVID-19 and in HC (p=0.0023 and p=0.0012 respectively). Serum sACE2 levels increased in patients with severe disease recovered over time compared with moderate (p=0.0021) and severe (p=0.0411) COVID-19 subjects at baseline. Systemic IL-6 and IL-8 levels were higher in all patient groups compared with HC and were not significantly affected over time or by remdesivir/dexamethasone treatment for 5 days. Conclusion: Serum sACE2 levels increase in severe COVID-19 patients as they recover over time whilst circulating cytokines are unaffected. Future studies should link these results to clinical outcomes. Funding: IMA is financially supported by the Welcome Trust (093080/Z/10/Z), the EPSRC (EP/T003189/1), and the Community Jameel Imperial College COVID-19 Excellence Fund (G26290) and by the UK MRC (MR/T010371/1). SM is supported by EU project 853850. Declaration of Interests: The authors declare that there is no conflict of interest to this article. Ethics Approval Statement: The study was approved by the institutional ethics board of the Masih Daneshvari Hospital (Ethics number SBMU.NRITLD.REC.1399.226)

Update on Neutrophil Function in Severe Inflammation

Neutrophils are main players in the effector phase of the host defense against micro-organisms and have a major role in the innate immune response. Neutrophils show phenotypic heterogeneity and functional flexibility, which highlight their importance in regulation of immune function. However, neutrophils can play a dual role and besides their antimicrobial function, deregulation of neutrophils and their hyperactivity can lead to tissue damage in severe inflammation or trauma. Neutrophils also have an important role in the modulation of the immune system in response to severe injury and trauma. In this review we will provide an overview of the current understanding of neutrophil subpopulations and their function during and post-infection and discuss the possible mechanisms of immune modulation by neutrophils in severe inflammation

Metabolomic profiling of amines in sepsis predicts changes in NOS canonical pathways

Rationale Nitric oxide synthase (NOS) is a biomarker/target in sepsis. NOS activity is driven by amino acids, which cycle to regulate the substrate L-arginine in parallel with cycles which regulate the endogenous inhibitors ADMA and L-NMMA. The relationship between amines and the consequence of plasma changes on iNOS activity in early sepsis is not known. Objective Our objective was to apply a metabolomics approach to determine the influence of sepsis on a full array of amines and what consequence these changes may have on predicted iNOS activity. Methods and measurements 34 amino acids were measured using ultra purification mass spectrometry in the plasma of septic patients (n = 38) taken at the time of diagnosis and 24–72 hours post diagnosis and of healthy volunteers (n = 21). L-arginine and methylarginines were measured using liquid-chromatography mass spectrometry and ELISA. A top down approach was also taken to examine the most changed metabolic pathways by Ingenuity Pathway Analysis. The iNOS supporting capacity of plasma was determined using a mouse macrophage cell-based bioassay. Main results Of all the amines measured 22, including L-arginine and ADMA, displayed significant differences in samples from patients with sepsis. The functional consequence of increased ADMA and decreased L-arginine in context of all cumulative metabolic changes in plasma resulted in reduced iNOS supporting activity associated with sepsis. Conclusions In early sepsis profound changes in amine levels were defined by dominant changes in the iNOS canonical pathway resulting in functionally meaningful changes in the ability of plasma to regulate iNOS activity ex vivo

Changes in PD-1- and CTLA-4-bearing blood lymphocytes in ICU COVID-19 patients treated with Favipiravir/Kaletra or Dexamethasone/Remdesivir: a pilot study

COVID-19, caused by SARS-CoV-2, requires new approaches to control the disease. Programmed cell death protein (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) play important roles in T-cell exhaustion in severe COVID-19. This study evaluated the frequency of whole blood lymphocytes expressing PD-1 and CTLA-4 in COVID-19 patients upon admission to the intensive care unit (ICU) (i.e., severe) or infection ward (i.e., moderate) and after 7 days of antiviral therapy. COVID-19 patients were treated with either favipiravir or Kaletra (FK group, 11 severe and 11 moderate) or dexamethasone plus remdesivir (DR group, 7 severe and 10 moderate) for 7 days in a pilot study. Eight healthy control subjects were also enrolled. The frequency of PD-1+ and CTLA-4+ lymphocytes in whole blood was evaluated by flow cytometry. Patients on DR therapy had shorter hospital stays than those on FK therapy. The frequency of PD-1+ lymphocytes in the FK group at baseline differed between COVID-19 patients and healthy controls, while the frequency of both PD-1+ and CTLA-4+ cells increased significantly 7 days of FK therapy. The response was similar in both moderate and severe patients. In contrast, the frequency of PD-1+ and CTLA-4+ lymphocytes varied significantly between patients and healthy controls before DR treatment. DR therapy enhanced PD-1+ but not the CTLA-4+ frequency of these cells after 7 days. We show that the frequency of PD-1 and CTAL-4-bearing lymphocytes during hospitalization was increased in Iranian ICU COVID-19 patients who received FK treatment, but that the frequency of CTLA-4+ cells was higher at baseline and did not increase in patients who received DR. The effectiveness of DR treatment may reflect differences in T-cell activation or exhaustion status, particularly in CTLA-4-expressing cells

Autoimmunity and COPD: clinical implications.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Long term cigarette smoking is the cause of more than 90% of COPD in Westernized countries. However, only a fraction of chronic heavy smokers develop symptomatic COPD by the age of 80 years. COPD is characterized by an abnormal immune response in the lower airways and its progression is associated with infiltration of the lung by innate and adaptive inflammatory immune cells that form lymphoid follicles. There is growing evidence that both cellular- and antibody-mediated autoimmunity has a fundamental role in the pathogenesis of stable COPD. In particular, carbonyl-modified proteins may help to drive autoimmunity in COPD and to cause the characteristic small airways abnormalities and even contribute to the pathogenesis of pulmonary emphysema. Although direct, indirect, and circumstantial evidence of a role for autoimmunity in stable COPD patients has been identified, no cause-and-effect relationship between autoimmunity and the mechanisms of COPD has been firmly established in man. As such the potential contribution of an autoimmune response to the pathogenesis of COPD exacerbation is still being investigated and represents an area of active research. Many drugs targeting autoimmune responses are already available and the results of controlled clinical trials are awaited with great interest. The potential for measuring specific serum autoantibodies as biomarkers to predict clinical phenotypes or progression of stable COPD is promising

Proinflammatory effects of free haemoglobin on alveolar epithelial cells

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Recent evidence from omic analysis for redox signalling and mitochondrial oxidative stress in COPD

Abstract COPD is driven by exogenous and endogenous oxidative stress derived from inhaled cigarette smoke, air pollution and reactive oxygen species from dysregulated mitochondria in activated inflammatory cells within the airway and lung. This is compounded by the loss in antioxidant defences including FOXO and NRF2 and other antioxidant transcription factors together with various key enzymes that attenuate oxidant effects. Oxidative stress enhances inflammation; airway remodelling including fibrosis and emphysema; post-translational protein modifications leading to autoantibody generation; DNA damage and cellular senescence. Recent studies using various omics technologies in the airways, lungs and blood of COPD patients has emphasised the importance of oxidative stress, particularly that derived from dysfunctional mitochondria in COPD and its role in immunity, inflammation, mucosal barrier function and infection. Therapeutic interventions targeting oxidative stress should overcome the deleterious pathologic effects of COPD if targeted to the lung. We require novel, more efficacious antioxidant COPD treatments among which mitochondria-targeted antioxidants and Nrf2 activators are promising

Transcription Factors

Transcription factors are regulatory proteins that can increase or decrease the transcription of a particular gene from deoxyribonucleic acid into the corresponding ribonucleic acid. They play a key role in embryonic development, the creation and maintenance of cell type- and tissue-specific patterns of protein synthesis and the response to cellular signaling pathways. Transcription factors are involved in a large number of human diseases such as congenital malformations, hereditary syndromes and a myriad of benignant and malignant neoplasms. Some transcription factors in addition to their regulation of homeostatic genes control the expression of many inflammatory genes and may, therefore, play a key role in the pathogenesis of a rapidly growing number of inflammatory/autoimmune diseases contributing to determine disease severity and response to treatment