COVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. Data regarding the host response within the lung are sparse. ...The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs. non-COVID-19).
Bronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-COVID-19 ARDS, and 14 COVID-19 ARDS patients. Clinical data, plasma, and epithelial lining fluid (ELF) concentrations of 45 inflammatory mediators and cell-free mitochondrial DNA were measured and compared.
COVID-19 ARDS patients required mechanical ventilation (MV) for significantly longer, even after adjustment for potential confounders. There was a trend toward higher concentrations of plasma CCL5, CXCL2, CXCL10, CD40 ligand, IL-10, and GM-CSF, and ELF concentrations of CXCL1, CXCL10, granzyme B, TRAIL, and EGF in the COVID-19 ARDS group compared with the non-COVID-19 ARDS group. Plasma and ELF CXCL10 concentrations were independently associated with the number of ventilator-free days, without correlation between ELF CXCL-10 and viral load. Mitochondrial DNA plasma and ELF concentrations were elevated in all ARDS patients, with no differences between the two groups. ELF concentrations of mitochondrial DNA were correlated with alveolar cell counts, as well as IL-8 and IL-1β concentrations.
CXCL10 could be one key mediator involved in the dysregulated immune response. It should be evaluated as a candidate biomarker that may predict the duration of MV in COVID-19 ARDS patients. Targeting the CXCL10-CXCR3 axis could also be considered as a new therapeutic approach.
ClinicalTrials.gov, NCT03955887.
Obesity is commonly reported in COVID-19 patients and is associated with poorer outcomes. It is suggested that leptin could be the missing link between obesity and severe COVID-19. Our study aimed to ...unravel the link between adipokines, COVID-19 status, immune response, and outcomes in severe pneumonia.
In this prospective observational single-center study, 63 immunocompetent patients with severe pneumonia (36 non-COVID-19 and 27 COVID-19) were enrolled, most required intensive care. Clinical and biological characteristics (glucose metabolism, plasma adipokines, and cytokine concentrations) and outcomes were compared.
At similar baseline severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (p = 0.0049). Plasma concentrations of leptin and adiponectin were respectively positively and negatively correlated with BMI and glucose metabolism (glycemia and insulinemia), but not significantly different between the two groups. Leptin levels were negatively correlated with IL-1β and IL-6, but the adipokines were not correlated with most other inflammatory mediators, baseline severity (SOFA score), or the duration of mechanical ventilation.
Adipokine levels were correlated with BMI but not with most inflammatory mediators, severity, or outcomes in severe pneumonia, regardless of the origin. The link between obesity, dysregulated immune response, and life-threatening COVID-19 requires further investigation.
ClinicalTrials.gov: NCT03505281.
Background
Nowadays, most patients who undergo colorectal surgery are discharged early. An early predictor of septic complications could avoid readmissions and decrease morbidity. CRP could be a good ...predictor allowing a safe discharge.
Methods
A prospective, observational study was conducted from November 2007 to October 2008. All patients who underwent elective colorectal surgery were included. Clinical (temperature, pulse, abdominal tenderness, bowel movements) and laboratory data (C-reactive protein, leukocyte count) were recorded and evaluated as early predictors of septic complications (namely, anastomotic leaks). All detected leaks were considered fistulas, independently of their clinical significance. Clinical and inflammatory parameters were analyzed with univariate and multivariate techniques; logistic regression was performed and areas under the receiver operating characteristic curve were compared.
Results
A total of 133 patients were included. The overall incidence of anastomotic leaks was 15.5% and mortality was 4.5%. C-reactive protein at postoperative days 2 and 4 was a good predictor of anastomotic leak (areas under the curve were 0.715 and 0.845, respectively) and other postoperative septic complications (areas under the curve were 0.804 and 0.787), showing the highest accuracy among clinical and laboratory data. A cutoff of 125 mg/l in the level of C-reactive protein at postoperative day 4 yielded a sensitivity of 81.8% and a negative predictive value of 95.8% for the detection of anastomotic leakage.
Conclusions
C-reactive protein is a simple way to ensure a safe discharge from hospital after elective colorectal surgery. Patients with CRP values >125 mg/l on the fourth postoperative day should not be discharged.
Low-grade inflammation is constitutive of atherosclerosis, and anti-inflammatory therapy inhibiting interleukin-1β (IL-1β) reduces the rate of cardiovascular events. While cholesterol accumulation in ...atheroma plaque and macrophages is a major driver of the inflammatory process, the role of the LXR cholesterol sensors remains to be clarified. Murine and human macrophages were treated with LXR agonists for 48 h before Toll-like receptor (TLR) stimulation. Unexpectedly, we observe that, among other cytokines, LXR agonists selectively increase IL1B mRNA levels independently of TLR activation. This effect, restricted to human macrophages, is mediated by activation of HIF-1α through LXR. Accordingly, LXR agonists also potentiate other HIF-1α-dependent pathways, such as glycolysis. Treatment of human macrophages with carotid plaque homogenates also leads to induction of IL1B in an LXR-dependent manner. Thus, our work discloses a mechanism by which cholesterol and oxysterols trigger inflammation in atherosclerosis. This suggests perspectives to target IL-1β production in atherosclerotic patients.
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•LXR agonists selectively increase IL1B mRNA levels in human macrophages in vitro•The impact of LXR on IL-1β is dependent on HIF-1α•LXR agonists activate other HIF-1α-dependent pathways, including glycolysis•IL1B induction by atheroma plaque homogenates is blunted by LXR antagonists
Ménégaut et al. show that liver X receptor (LXR) agonists selectively increase IL1β mRNA levels independently of TLR activation. This effect, restricted to human macrophages, is mediated by an activation of hypoxia inducible factor (HIF) 1α through LXR. Accordingly, LXR agonists also potentiate other HIF-1α-dependent pathways, such as glycolysis.
The plasma lipid transfer proteins promote the exchange of neutral lipids and phospholipids between the plasma lipoproteins. Cholesteryl ester transfer protein (CETP) facilitates the removal of ...cholesteryl esters from HDL and thus reduces HDL levels, while phospholipid transfer protein (PLTP) promotes the transfer of phospholipids from triglyceride-rich lipoproteins into HDL and increases HDL levels. Studies in transgenic mouse models and in humans with rare genetic deficiencies (CETP) or common genetic variants (CETP and PLTP) highlight the central role of these molecules in regulating HDL levels. Human CETP deficiency is associated with dramatic elevations of HDL cholesterol and apolipoprotein A-I levels, while PLTP variants with increased expression are associated with higher HDL levels. A recent meta-analysis suggests that common CETP alleles causing reduced CETP and increased HDL levels are associated with reduced coronary heart disease. The failure of a clinical trial with the CETP inhibitor torcetrapib may have been related in part to off-target toxicity. Ongoing phase 3 clinical trials with other CETP inhibitors may help to clarify if this strategy can ultimately be successful in the treatment of atherosclerosis.
LPCAT3 plays a major role in phospholipid metabolism in the liver and intestine. However, the impact of LPCAT3 on hematopoietic cell and macrophage functions has yet to be described. Our aim was to ...understand the functions of LPCAT3 in macrophages and to investigate whether LPCAT3 deficiency in hematopoietic cells may affect atherosclerosis development.
Mice with constitutive Lpcat3 deficiency (Lpcat3−/−) were generated. We used fetal hematopoietic liver cells to generate WT and Lpcat3−/− macrophages in vitro and to perform hematopoietic cell transplantation in recipient Ldlr−/− mice.
Lpcat3-deficient macrophages displayed major reductions in the arachidonate content of phosphatidylcholines, phosphatidylethanolamines and, unexpectedly, plasmalogens. These changes were associated with altered cholesterol homeostasis, including an increase in the ratio of free to esterified cholesterol and a reduction in cholesterol efflux in Lpcat3−/− macrophages. This correlated with the inhibition of some LXR-regulated pathways, related to altered cellular availability of the arachidonic acid. Indeed, LPCAT3 deficiency was associated with decreased Abca1, Abcg1 and ApoE mRNA levels in fetal liver cells derived macrophages. In vivo, these changes translated into a significant increase in atherosclerotic lesions in Ldlr−/− mice with hematopoietic LPCAT3 deficiency.
This study identifies LPCAT3 as a key factor in the control of phospholipid homeostasis and arachidonate availability in myeloid cells and underlines a new role for LPCAT3 in plasmalogen metabolism. Moreover, our work strengthens the link between phospholipid and sterol metabolism in hematopoietic cells, with significant consequences on nuclear receptor-regulated pathways and atherosclerosis development.
•LPCAT3 controls arachidonic acid incorporation into glycerophospholipids in macrophages.•Alteration of arachidonic acid availability inhibits LXR pathways such as cholesterol efflux in Lpcat3−/− macrophages.•LPCAT3 deficiency in hematopoieic cells promotes atherosclerosis development in recipient Ldlr−/− mice.
To validate a triple-echo gradient-echo sequence for measuring the fat content of the liver, by using hydrogen 1((1)H) magnetic resonance (MR) spectroscopy as the reference standard.
This prospective ...study was approved by the appropriate ethics committee, and written informed consent was obtained from all patients. In 37 patients with type 2 diabetes (31 men, six women; mean age, 56 years), 3.0-T single-voxel point-resolved (1)H MR spectroscopy of the liver (Couinaud segment VII) was performed to calculate the liver fat fraction from the water (4.7 ppm) and methylene (1.3 ppm) peaks, corrected for T1 and T2 decay. Liver fat fraction was also computed from triple-echo (consecutive in-phase, opposed-phase, and in-phase echo times) breath-hold spoiled gradient-echo sequence (flip angle, 20 degrees), by estimating T2* and relative signal intensity loss between in- and opposed-phase values, corrected for T2* decay. Pearson correlation coefficient, Bland-Altman 95% limit of agreement, and Lin concordance coefficient were calculated.
Mean fat fractions calculated from the triple-echo sequence and (1)H MR spectroscopy were 10% (range, 0.7%-35.6%) and 9.7% (range, 0.2%-34.1%), respectively. Mean T2* time was 14.7 msec (range, 5.4-25.4 msec). Pearson correlation coefficient was 0.989 (P < .0001) and Lin concordance coefficient was 0.988 (P < .0001). With the Bland-Altman method, all data points were within the limits of agreement.
A breath-hold triple-echo gradient-echo sequence with a low flip angle and correction for T2* decay is accurate for quantifying fat in segment VII of the liver. Given its excellent correlation and concordance with (1)H MR spectroscopy, this triple-echo sequence could replace (1)H MR spectroscopy in longitudinal studies.
Recent studies have highlighted an important role for lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine. In these ...organs, LPCAT3 critically supports cell-membrane-associated processes such as lipid absorption or lipoprotein secretion. However, the role of LPCAT3 in macrophages remains controversial. Here, we investigated LPCAT3's role in macrophages both in vitro and in vivo in mice with atherosclerosis and obesity. To accomplish this, we used the LysMCre strategy to develop a mouse model with conditional Lpcat3 deficiency in myeloid cells (Lpcat3KOMac). We observed that partial Lpcat3 deficiency (approximately 75% reduction) in macrophages alters the PUFA composition of all phospholipid (PL) subclasses, including phosphatidylinositols and phosphatidylserines. A reduced incorporation of C20 PUFAs (mainly arachidonic acid AA) into PLs was associated with a redistribution of these FAs toward other cellular lipids such as cholesteryl esters. Lpcat3 deficiency had no obvious impact on macrophage inflammatory response or endoplasmic reticulum (ER) stress; however, Lpcat3KOMac macrophages exhibited a reduction in cholesterol efflux in vitro. In vivo, myeloid Lpcat3 deficiency did not affect atherosclerosis development in LDL receptor deficient mouse (Ldlr−/−) mice. Lpcat3KOMac mice on a high-fat diet displayed a mild increase in hepatic steatosis associated with alterations in several liver metabolic pathways and in liver eicosanoid composition. We conclude that alterations in AA metabolism along with myeloid Lpcat3 deficiency may secondarily affect AA homeostasis in the whole liver, leading to metabolic disorders and triglyceride accumulation.
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