Neutrophils-A key component of ischemia-reperfusion injury

Ischemia-reperfusion injury (IRI) is a common occurrence following myocardial infarction, transplantation, stroke, and trauma that can lead to multiple organ failure, which remains the foremost cause of death in critically ill patients. Current therapeutic strategies for IRI are mainly palliative, and there is an urgent requirement for a therapeutic that could prevent or reverse tissue damage caused by IRI. Neutrophils are the primary responders following ischemia and reperfusion and represent important components in the protracted inflammatory response and severity associated with IRI. Experimental studies demonstrate neutrophil infiltration at the site of ischemia and show that inducing neutropenia can protect organs from IRI. In this review, we highlight the mechanisms involved in neutrophil recruitment, activation, and adherence and how this contributes to disease severity in IRI. Inhibiting neutrophil mobilization, tissue recruitment, and ultimately neutrophil-associated activation of local and systemic inflammatory responses may have therapeutic potential in the amelioration of local and remote tissue damage following IRI. Copyrigh

Long-term immunogenicity and safety of the hepatitis B vaccine HepB-CpG (HEPLISAV-B) compared with HepB-Eng (Engerix-B) in adults with chronic kidney disease

Background: Hepatitis B virus (HBV) infection remains a significant global burden, especially for patients with chronic kidney disease (CKD) receiving hemodialysis. Three doses of HepB–CpG (HEPLISAV-B® vaccine) induced a superior immune response compared with 4 double doses of HepB–Eng (Engerix-B®) in a phase 3 trial (HBV-17) in adults with CKD. Here we report the long-term immunogenicity and safety of HepB-CpG and HepB–Eng in eligible participants of HBV-17 who enrolled in this optional 34-month follow-up trial (HBV-19). Methods: HBV-19 is a multicenter, open-label, phase 3b trial of adults with CKD who previously received a complete series of HepB-CpG or HepB-Eng in the HBV-17 trial. Participants were assigned to seroprotection categories at enrollment on the basis of their antibody response to hepatitis B surface antigen (anti-HBs) in HBV-17. The objective was to evaluate the durability of seroprotection (defined as an anti-HBs concentration ≥ 10 mIU/mL) induced by HepB-CpG and HepB-Eng. Participants whose anti-HBs concentration was below 10 mIU/mL received additional HepB-CpG or HepB-Eng doses. Results: 147 participants were enrolled; 66.7 % were men, median age was 65.0 years, and 83.7 % were white. The durability of seroprotection in participants with CKD was similar in those who received HepB-CpG and those who received HepB-Eng. Antibody concentrations ≥ 100 mIU/mL persisted for longer in HepB-CpG than HepB-Eng recipients, among those with anti-HBs ≥ 100 mIU/mL post vaccination. The geometric mean anti-HBs concentration in the HepB-CpG group was significantly higher than in the HepB-Eng group over time (P ≤ 0.0001). The safety profiles were similar between the vaccine groups. Conclusions: Due to the higher antibody levels induced by HepB-CpG in participants with CKD, seroprotection against HBV may be expected to persist longer than that induced by HepB-Eng. ClinicalTrials.gov: NCT01282762

Deguelin Attenuates Reperfusion Injury and Improves Outcome after Orthotopic Lung Transplantation in the Rat

The main goal of adequate organ preservation is to avoid further cellular metabolism during the phase of ischemia. However, modern preservation solutions do rarely achieve this target. In donor organs hypoxia and ischemia induce a broad spectrum of pathologic molecular mechanisms favoring primary graft dysfunction (PGD) after transplantation. Increased hypoxia-induced transcriptional activity leads to increased vascular permeability which in turn is the soil of a reperfusion edema and the enhancement of a pro-inflammatory response in the graft after reperfusion. We hypothesize that inhibition of the respiration chain in mitochondria and thus inhibition of the hypoxia induced mechanisms might reduce reperfusion edema and consecutively improve survival in vivo. In this study we demonstrate that the rotenoid Deguelin reduces the expression of hypoxia induced target genes, and especially VEGF-A, dose-dependently in hypoxic human lung derived cells. Furthermore, Deguelin significantly suppresses the mRNA expression of the HIF target genes VEGF-A, the pro-inflammatory CXCR4 and ICAM-1 in ischemic lungs vs. control lungs. After lung transplantation, the VEGF-A induced reperfusion-edema is significantly lower in Deguelin-treated animals than in controls. Deguelin-treated rats exhibit a significantly increased survival-rate after transplantation. Additionally, a downregulation of the pro-inflammatory molecules ICAM-1 and CXCR4 and an increase in the recruitment of immunomodulatory monocytes (CD163+ and CD68+) to the transplanted organ involving the IL4 pathway was observed. Therefore, we conclude that ischemic periods preceding reperfusion are mainly responsible for the increased vascular permeability via upregulation of VEGF. Together with this, the resulting endothelial dysfunction also enhances inflammation and consequently lung dysfunction. Deguelin significantly decreases a VEGF-A induced reperfusion edema, induces the recruitment of immunomodulatory monocytes and thus improves organ function and survival after lung transplantation by interfering with hypoxia induced signaling

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Acute Liver Injury Is Independent of B Cells or Immunoglobulin M

Acute liver injury is a clinically important pathology and results in the release of Danger Associated Molecular Patterns, which initiate an immune response. Withdrawal of the injurious agent and curtailing any pathogenic secondary immune response may allow spontaneous resolution of injury. The role B cells and Immunoglobulin M (IgM) play in acute liver injury is largely unknown and it was proposed that B cells and/or IgM would play a significant role in its pathogenesis.Tissue from 3 models of experimental liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury) and patients transplanted following paracetamol overdose were stained for evidence of IgM deposition. Mice deficient in B cells (and IgM) were used to dissect out the role B cells and/or IgM played in the development or resolution of injury. Serum transfer into mice lacking IgM was used to establish the role IgM plays in injury.Significant deposition of IgM was seen in the explanted livers of patients transplanted following paracetamol overdose as well as in 3 experimental models of acute liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury). Serum transfer into IgM-deficient mice failed to reconstitute injury (p = 0.66), despite successful engraftment of IgM. Mice deficient in both T and B cells (RAG1-/-) mice (p<0.001), but not B cell deficient (μMT) mice (p = 0.93), were significantly protected from injury. Further interrogation with T cell deficient (CD3εKO) mice confirmed that the T cell component is a key mediator of sterile liver injury. Mice deficient in B cells and IgM mice did not have a significant delay in resolution following acute liver injury.IgM deposition appears to be common feature of both human and murine sterile liver injury. However, neither IgM nor B cells, play a significant role in the development of or resolution from acute liver injury. T cells appear to be key mediators of injury. In conclusion, the therapeutic targeting of IgM or B cells (e.g. with Rituximab) would have limited benefit in protecting patients from acute liver injury