The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. ...Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1β secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1β secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.
Essentials
Role of platelets in immunological transfusion‐related acute lung injury (TRALI) is debated.
Immunological TRALI was tested in mice exhibiting severe thrombocytopenia or platelet ...dysfunction.
Platelets are required to prevent lung hemorrhage but not edema formation and respiratory distress.
Platelets are dispensable for the initiation and development of TRALI.
Summary
Background
Transfusion‐related acute lung injury (TRALI) is a serious transfusion‐related complication. Previous conflicting studies have indicated that platelets are either crucial or dispensable for TRALI.
Objectives
To evaluate the role of platelets in major histocompatibility complex (MHC) I‐induced‐TRALI.
Methods
Antibody‐mediated TRALI was experimentally induced in mice by lipopolysaccharide priming followed by the administration of an anti‐MHC I mAb.
Results
TRALI was tested in the context of severe thrombocytopenia provoked by the administration of diphtheria toxin (DT) in transgenic iDTR mice selectively expressing DT receptor in megakaryocytes. The pathologic responses occurring within the first 10 min following the injection of the anti‐MHC I mAb, i.e. the severity of lung edema and the drop in aortic blood oxygenation, were similar in severely thrombocytopenic DT‐iDTR and control mice. At later times, mortality was nevertheless increased in DT‐iDTR mice, owing to lung hemorrhages. When less severe thrombocytopenia was induced with an antiplatelet mAb, TRALI started and developed similarly as in control mice, but hemorrhages were absent. Furthermore, when platelet functions were defective because of administration of aspirin or clopidogrel, or because of glycoprotein (GP)IIbIIIa deficiency, TRALI still developed but no lung hemorrhages were observed. In contrast, when GPVI was immunodepleted, TRALI still occurred, but was occasionally accompanied by hemorrhages.
Conclusions
Platelets are dispensable for the initiation and development of MHC I‐induced TRALI. Although they do not protect against the disruption of the vascular endothelial cell barrier and the subsequent plasma leakage and edema formation, platelets are essential to prevent more serious damage resulting in hemorrhages in alveoli.
Exacerbation triggered by respiratory infection is an important cause of morbidity and mortality in chronic obstructive pulmonary disease (COPD) patients. Strategies aiming to preventing infection ...may have significant public health impact. Our previous study demonstrated decreased immunological response to seasonal flu vaccination in COPD patients, questioning the efficiency of other vaccines in this group of patients. We performed a prospective, monocenter, longitudinal study that evaluated the humoral and cellular responses upon pertussis vaccination. We included 13 patients with stable COPD and 8 healthy volunteers. No difference in circulating B and T cell subsets at baseline was noted. Both groups presented similar levels of TFH, plasmablasts and pertussis specific antibodies induction after vaccination. Moreover, monitoring T cell immunity after ex-vivo peptide stimulation revealed equivalent induction of functional and specific CD4+ T cells (IFNγ, TNFα and IL-2-expressing T cells) in both groups. Our results highlight the immunological efficiency of pertussis vaccination in this particularly vulnerable population and challenge the concept that COPD patients are less responsive to all immunization strategies. Healthcare providers should stress the necessity of decennial Tdap booster vaccination in COPD patients.
The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine ...lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.
Abstract In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt ...to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.
To describe the clinical and economic burden of severe asthma in France over 12 months.
Data were retrieved from the observational, prospective “Cohorte Obstruction Bronchique et Asthme” (COBRA) ...cohort, which has enrolled nearly 1000 asthma patients since 2007 from throughout France. Patients undergoing treatment with GINA step-4 or 5 medications uninterruptedly for 12 months (thus defining “severe asthma”) were identified and their clinical data used to describe the clinical burden of asthma (exacerbations, symptoms outside exacerbations, and level of asthma control). Patients’ utilization of healthcare resources was described and used to estimate the direct medical costs incurred to treat severe asthma.
155 patients were included in the present study. Over the 12-month period of interest, 128 (83%) patients experienced at least one asthma exacerbation, 22 (14%) patients were hospitalized for asthma, 133 (86%) patients experienced continuous symptoms outside exacerbations, and 77 (50%) patients experienced important limitations in daily life activities. The median number of asthma-related drugs used was 4. The mean estimated annual asthma-related cost was 8,222 euros (standard deviation, SD = 11,886), including 7,229 euros (SD = 11,703) for controller medications.
Symptoms outside exacerbation periods are highly prevalent in severe asthma patients, for whom the main driver of medical costs is controller medication.
•In severe asthma, asthma symptoms occurring outside exacerbation periods are as frequent in patients with exacerbations than in patients without exacerbations.•The main driver of direct medical cost is asthma controller medication.
In the emergency department (ED), pseudohyperkalemia from hemolysis may indirectly harm patients by exposing them to increased length of stay, cost, and repeat blood draws. The need to repeat ...hemolyzed potassium specimens in low-risk patients has not been well studied. Our objective was to determine the rate of true hyperkalemia among low-risk, adult ED patients with hemolyzed potassium specimens.
We conducted this prospective observational study at two large (129,000 annual visits) academic EDs in the mid-Atlantic. Data were collected from June 2017-November 2017 as baseline data for planned departmental quality improvement and again from June 2018-November 2018. Inclusion criteria were an initial basic metabolic panel in the ED with a hemolyzed potassium level > 5.1 milliequivalents per liter that was repeated within 12 hours, age (≥18, and bicarbonate (HCO
) > 20. Exclusion criteria were age > 65, glomerular filtration rate (GFR) < 60, creatine phosphokinase > 500, hematologic malignancy, taking potassium-sparing or angiotensin-acting agents, or treatment with potassium-lowering agents (albuterol, insulin, HCO
, sodium polystyrene sulfonate, or potassium-excreting diuretic) prior to the repeat lab draw.
Of 399 encounters with a hemolyzed, elevated potassium level in patients with GFR ≥ 60 and age > 18 that were repeated, we excluded 333 patients for age > 64, lab repeat > 12 hours, invalid identifiers, potassium-elevating or lowering medicines or hematologic malignancies.This left 66 encounters for review. There were no instances of hyperkalemia on the repeated, non-hemolyzed potassium levels, correlating to a true positive rate of 0% (95% confidence interval 0-6%). Median patient age was 46 (interquartile range IQR 34 - 56) years. Median hemolyzed potassium level was 5.8 (IQR 5.6 - 6.15) millimoles per liter (mmol/L), and median repeated potassium level was 3.9 (IQR 3.6 - 4.3) mmol/L. Median time between lab draws was 145 (IQR 87 - 262) minutes.
Of 66 patients who met our criteria, all had repeat non-hemolyzed potassiums within normal limits. The median of 145 minutes between lab draws suggests an opportunity to decrease the length of stay for these patients. Our results suggest that in adult patients < 65 with normal renal function, no hematologic malignancy, and not on a potassium-elevating medication, there is little to no risk of true hyperkalemia. Further studies should be done with a larger patient population and multicenter trials.
The French-language Respiratory Medicine Society (SPLF) proposes a guide for the follow-up of patients who have presented with SARS-CoV-2 pneumonia. The proposals are based on known data from ...previous epidemics, on acute lesions observed in SARS-CoV-2 patients and on expert opinion. This guide proposes a follow-up based on three categories of patients: (1) patients managed outside hospital for possible or proven SARS-CoV-2 infection, referred by their physician for persistent dyspnoea; (2) patients hospitalized for SARS-CoV-2 pneumonia in a medical unit; (3) patients hospitalized for SARS-CoV-2 pneumonia in an intensive care unit. The subsequent follow-up will have to be adapted to the initial assessment. This guide emphasises the possibility of others causes of dyspnoea (cardiac, thromboembolic, hyperventilation syndrome…). These proposals may evolve over time as more knowledge becomes available.
Purpose
Previous clinical trials suggested that inhaled nitric oxide (iNO) could have beneficial effects in sickle cell disease (SCD) patients with acute chest syndrome (ACS).
Methods
To determine ...whether iNO reduces treatment failure rate in adult patients with ACS, we conducted a prospective, double-blind, randomized, placebo-controlled clinical trial. iNO (80 ppm,
N
= 50) gas or inhaled nitrogen placebo (
N
= 50) was delivered for 3 days. The primary end point was the number of patients with treatment failure at day 3, defined as any one of the following: (1) death from any cause, (2) need for endotracheal intubation, (3) decrease of PaO
2
/FiO
2
≥ 15 mmHg between days 1 and 3, (4) augmented therapy defined as new transfusion or phlebotomy.
Results
The two groups did not differ in age, gender, genotype, or baseline characteristics and biological parameters. iNO was well tolerated, although a transient decrease in nitric oxide concentration was mandated in one patient. There was no significant difference in the primary end point between the iNO and placebo groups 23 (46 %) and 29 (58 %); odds ratio (OR), 0.8; 95 % CI, 0.54–1.16;
p
= 0.23. A post hoc analysis of the 45 patients with hypoxemia showed that those in the iNO group were less likely to experience treatment failure at day 3 7 (33.3 %) vs 18 (72 %); OR = 0.19; 95 % CI, 0.06–0.68;
p
= 0.009.
Conclusions
iNO did not reduce the rate of treatment failure in adult SCD patients with mild to moderate ACS. Future trials should target more severely ill ACS patients with hypoxemia.
Clinical trial registration
NCT00748423.
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